Surmontil

Tricyclic Antidepressants

Oral Administration

May take without regard to food.
Administration of the entire daily dose at bedtime may increase compliance and reduce daytime sedation.

Severe

seizures / Delayed / 0-1.0
agranulocytosis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
serotonin syndrome / Delayed / 0-1.0
ileus / Delayed / Incidence not known
neuroleptic malignant syndrome / Delayed / Incidence not known
suicidal ideation / Delayed / Incidence not known
stroke / Early / Incidence not known
heart failure / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
ventricular tachycardia / Early / Incidence not known
ocular hypertension / Delayed / Incidence not known
SIADH / Delayed / Incidence not known

Moderate

dysarthria / Delayed / 1.0-10.0
blurred vision / Early / 1.0-10.0
dystonic reaction / Delayed / 0-1.0
pseudoparkinsonism / Delayed / 0-1.0
dyskinesia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
hepatitis / Delayed / 0-1.0
hyperthyroidism / Delayed / 0-1.0
hypothyroidism / Delayed / 0-1.0
goiter / Delayed / 0-1.0
constipation / Delayed / 10.0
ejaculation dysfunction / Delayed / 10.0
impotence (erectile dysfunction) / Delayed / 10.0
withdrawal / Early / 10.0
glossitis / Early / Incidence not known
stomatitis / Delayed / Incidence not known
parotitis / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
EEG changes / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
depression / Delayed / Incidence not known
mania / Early / Incidence not known
confusion / Early / Incidence not known
psychosis / Early / Incidence not known
delirium / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
PR prolongation / Rapid / Incidence not known
palpitations / Early / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
hypertension / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
eosinophilia / Delayed / Incidence not known
cycloplegia / Early / Incidence not known
testicular swelling / Early / Incidence not known
galactorrhea / Delayed / Incidence not known
edema / Delayed / Incidence not known
erythema / Early / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
urinary retention / Early / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known

Mild

anorexia / Delayed / 1.0-10.0
vomiting / Early / 1.0-10.0
abdominal pain / Early / 1.0-10.0
insomnia / Early / 1.0-10.0
yawning / Early / 1.0-10.0
xerophthalmia / Early / 1.0-10.0
diarrhea / Early / 0-1.0
fever / Early / 0-1.0
purpura / Delayed / 0-1.0
nausea / Early / 10.0
xerostomia / Early / 10.0
dyspepsia / Early / 10.0
weight gain / Delayed / 10.0
appetite stimulation / Delayed / 10.0
drowsiness / Early / 10.0
fatigue / Early / 10.0
headache / Early / 10.0
dizziness / Early / 10.0
tremor / Early / 10.0
libido decrease / Delayed / 10.0
tongue discoloration / Delayed / Incidence not known
pyrosis (heartburn) / Early / Incidence not known
dysgeusia / Early / Incidence not known
nightmares / Early / Incidence not known
tinnitus / Delayed / Incidence not known
weakness / Early / Incidence not known
paresthesias / Delayed / Incidence not known
restlessness / Early / Incidence not known
agitation / Early / Incidence not known
anxiety / Delayed / Incidence not known
ocular pain / Early / Incidence not known
mydriasis / Early / Incidence not known
gynecomastia / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
alopecia / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
flushing / Rapid / Incidence not known
increased urinary frequency / Early / Incidence not known

Children, suicidal ideation

Safety and efficacy of trimipramine for the treatment of depression have not been established in pediatric patients less than 18 years of age. There are limited data in pediatric patients; 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. 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 children, adolescent, and young adult 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 trimipramine may be necessary in patients with emerging suicidality or worsening depression. Trimipramine 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.

Surmontil

Rx

Tertiary amine tricyclic antidepressant (TCA), considerable sedative and anxiolytic effects
FDA-approved to treat major depression in adult patients; especially useful for those with co-existing sleep disturbances or anxiety
Boxed warning for use in pediatric patients and young adults due to risk for suicidality

For the treatment of major depression. Oral dosage Adults

For OUTPATIENTS: Initiate with 75 mg/day PO in divided doses; may increase to 150 mg/day PO in divided doses, then up to a maximum of 200 mg/day PO. INPATIENTS under close supervision: May initiate with 100 mg/day PO in divided doses; may increase gradually up to a maximum of 250 to 300 mg/day PO. Doses greater than 200 mg/day PO should typically be given in divided doses. Following remission, maintenance medication may be required. Use the lowest dose that will maintain remission, preferably as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about 3 months.

Geriatric Adults

50 mg/day PO initially, with gradual increments up to 100 mg/day PO, depending upon patient response and tolerance. Following remission, use the lowest dose that will maintain remission, preferably as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about 3 months.

Adolescents

Initially, 50 mg/day PO, with gradual increments up to 100 mg/day, depending upon patient response and tolerance. Following remission, use the lowest dose that will maintain remission, preferably as a single dose at bedtime. To minimize relapse, maintenance therapy should be continued for about 3 months. 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.

Hepatic Impairment

Trimipramine should be used with caution in those with hepatic impairment; if the drug must be used, a lower initial dosage and cautious titration are recommended.

Renal Impairment

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

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 trimipramine-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of trimipramine may be necessary. Trimipramine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of trimipramine may become abruptly toxic when given abiraterone is concomitant therapy.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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; 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; 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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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; 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) 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. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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; 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; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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.
Adagrasib: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
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.
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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Amantadine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
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.
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for trimipramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of trimipramine. Celecoxib is a CYP2D6 inhibitor, and trimipramine 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.
Amphetamine: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Amphetamine; Dextroamphetamine: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Amphetamines: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
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.
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 trimipramine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in trimipramine-related adverse effects, including QT prolongation and torsade de pointes (TdP), for several days after administration of a multi-day aprepitant regimen. Trimipramine 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 trimipramine. 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.
Aripiprazole: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of aripiprazole and tricyclic antidepressants due to the risk for additive CNS depression.
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) Avoid use of epinephrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the vasopressor effects of 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; 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 trimipramine 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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Azelastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Azelastine; Fluticasone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Baclofen: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of baclofen and tricyclic antidepressants due to the risk for additive CNS depression.
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.
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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and belladonna use. Concomitant use may result in additive anticholinergic adverse effects.
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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer, treatment initiation with trimipramine 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 trimipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trimipramine and requiring urgent treatment with IV methylene blue, trimipramine 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. Trimipramine 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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Benzphetamine: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Benztropine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and benztropine use. Concomitant use may result in additive anticholinergic adverse effects.
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.
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; 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; 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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
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; Epinephrine: (Major) Avoid use of epinephrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the vasopressor effects of epinephrine. (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) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. 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) Concomitant use of tricyclic antidepressants (TCAs) and buprenorphine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), serotonin syndrome, hypotension, profound sedation, coma, respiratory depression, or death. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. 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: (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as tricyclic antidepressants. Use low initial doses of bupropion and increase the dose gradually. Monitor patients for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Tricyclic antidepressants are CYP2D6 substrates and bupropion is a CYP2D6 inhibitor.
Bupropion; Naltrexone: (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as tricyclic antidepressants. Use low initial doses of bupropion and increase the dose gradually. Monitor patients for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Tricyclic antidepressants are CYP2D6 substrates and bupropion is a CYP2D6 inhibitor.
Buspirone: (Moderate) Coadministration of buspirone with tricyclic antidepressants (TCAs) may increase the risk of serotonin syndrome. Both types of medications have serotonergic properties. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
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.
Butalbital; Aspirin; 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.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and trimipramine. Concurrent use may result in additive CNS depression.
Capsaicin; Metaxalone: (Moderate) Coadministration of tricyclic antidepressants (TCAs) with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
Carbamazepine: (Moderate) Monitor for loss of tricyclic antidepressant efficacy during concomitant carbamazepine use. Concomitant use may result in decreased tricyclic antidepressant exposure.
Carbidopa; Levodopa: (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
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) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Carbinoxamine: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants are used concomitantly with sedating H1-blockers. Antimuscarin

ic 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 trimipramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of trimipramine. Celecoxib is a CYP2D6 inhibitor, and trimipramine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Major) Concomitant use of tramadol with tricyclic antidepressants may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) A dosage adjustment may be warranted for trimipramine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of trimipramine. Celecoxib is a CYP2D6 inhibitor, and trimipramine 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 trimipramine; an interruption of ceritinib 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) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Cetirizine; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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.
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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Chlordiazepoxide; Amitriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Chlordiazepoxide; Clidinium: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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; 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; Ibuprofen; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Monitor blood pressure and for unusual drowsiness or excess sedation during coadministration of clonidine and tricyclic antidepressants. Concomitant use may result in reduced hypotensive effect of clonidine and additive CNS depression.
Chlorzoxazone: (Moderate) Concomitant use of chlorzoxazone with tricyclic antidepressants can result in additive CNS depression.
Cholinergic agonists: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Cimetidine: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as trimipramine, resulting in increased plasma levels of the antidepressant. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
Cinacalcet: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
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.
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.
Clonazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Clonidine: (Moderate) Monitor blood pressure and for unusual drowsiness or excess sedation during coadministration of clonidine and tricyclic antidepressants. Concomitant use may result in reduced hypotensive effect of clonidine and additive CNS depression.
Clorazepate: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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; 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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant promethazine and tricyclic antidepressant use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant promethazine and tricyclic antidepressant use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
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.
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: (Moderate) Monitor for unusual drowsiness, sedation, signs of anticholinergic toxicity, and serotonin syndrome during coadministration of cyclobenzaprine and tricyclic antidepressants. Concomitant use may increase the risk for additive CNS depression, anticholinergic adverse events, and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
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 an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with dacomitinib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; dacomitinib is a CYP2D6 inhibitor.
Dantrolene: (Moderate) Concomitant use of dantrolene with tricyclic antidepressants can result in additive CNS depression.
Daridorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of daridorexant and tricyclic antidepressants. Dosage adjustments of daridorexant 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 daridorexant is taken with other CNS depressants.
Darifenacin: (Moderate) The exposure to tricyclic antidepressants (TCAs) may be increased when coadministered with darifenacin. Appropriate monitoring and dose adjustment may be necessary. Darifenacin is a moderate CYP2D6 inhibitor; TCAs are CYP2D6 substrates.
Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Degarelix: (Minor) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents like trimipramine. 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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
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 co-administered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Moderate) 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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
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; Bupropion: (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. (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as tricyclic antidepressants. Use low initial doses of bupropion and increase the dose gradually. Monitor patients for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Tricyclic antidepressants are CYP2D6 substrates and bupropion is a CYP2D6 inhibitor.
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) 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. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Dicyclomine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and dicyclomine use. Concomitant use may result in additive anticholinergic adverse effects.
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.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of dimenhydrinate and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Diphenhydramine; Naproxen: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
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.
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: (Moderate) Monitor blood pressure and carefully adjust doses during concomitant use of dopamine and tricyclic antidepressants due to the risk for hypertension. Concomitant use of tricyclic antidepressants may potentiate the cardiovascular effects of dopamine.
Doxylamine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Doxylamine; Pyridoxine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
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.
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: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
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.
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.
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.
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:< /strong> (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) Avoid use of epinephrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the vasopressor effects of epinephrine.
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.
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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
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: (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: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants such as tricyclic antidepressants (TCAs). 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 exaggerated clinical effect.
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 trimipramine-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of trimipramine if clinically appropriate. Trimipramine is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of trimipramine.
Fedratinib: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of trimipramine may be necessary. Trimipramine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
Flavoxate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and flavoxate use. Concomitant use may result in additive anticholinergic adverse effects.
Fluconazole: (Minor) Fluconazole has been associated with QT prolongation and rare cases of 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). Fluconazole should be administered together with TCAs with caution. In addition, fluconazole inhibits CYP2C19 and CYP3A4, enzymes that are partially involved in the metabolism of TCAs. Fluconazole has been reported to increase the effects of TCAs such as amitriptyline; in at least one case, the interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case, QT-prolongation and torsades de pointes occurred. Trimipramine may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to trimipramine 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 trimipramine 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: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Fluvoxamine: (Major) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as trimipramine 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, trimipramine is metabolized by CYP2D6, CYP2C9, and CYP2C19. Fluvoxamine is a strong inhibitor of CYP2C19 and a mild inhibitor of CYP2D6. At least one case report exists of a death thought to be due to impaired clearance of the TCA amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluvoxamine is added.
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).
Givosiran: (Major) Avoid concomitant use of givosiran and trimipramine due to the risk of increased trimipramine-related adverse reactions. If use is necessary, consider decreasing the trimipramine dose. Trimipramine is a CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Glycopyrrolate; Formoterol: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Goserelin: (Minor) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving trimipramine. 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; 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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
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.
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).
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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and homatropine use. Concomitant use may result in additive anticholinergic adverse effects.
Hydantoins: (Moderate) 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; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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.
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.
Hydroxyzine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of hydroxyzine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Hyoscyamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer, treatment initiation with trimipramine 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 trimipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trimipramine and requiring urgent treatment with IV methylene blue, trimipramine 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. Trimipramine 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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
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) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects.
Iobenguane I 123: (Major) Discontinue medications that decrease norepinephrine uptake, such as tricyclic antidepressants, for at least 5 biological half-lives prior to iobenguane I 123 administration. Consider medication tapering or additional supportive therapy as appropriate to minimize the risk for precipitating tricyclic antidepressant withdrawal symptoms. Medications that decrease the uptake of norepinephrine can cause false negative imaging results. Increasing the dose of iobenguane I 123 will not overcome any potential uptake limiting effect of this medication.
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.
Isoflurane: (Minor) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with halogenated anesthetics. Halogenated anesthetics can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, general anesthetics may produce additive CNS depression when used in patients taking tricyclic antidepressants.
Isoniazid, INH: (Major) Due to the risk of serotonin syndrome, concurrent use of tricyclic antidepressants and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, trimipramine and concurrent serotonergic agents should be discontinued.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of tricyclic antidepressants and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, trimipramine 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 tricyclic antidepressants and medications with MAO-like activity, such as isoniazid, INH, should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, trimipramine 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.
Isoproterenol: (Moderate) Monitor hemodynamic parameters during concomitant isoproterenol and tricyclic antidepressant use; dosage adjustments may be necessary. Tricyclic antidepressants may potentiate the effects of isoproterenol.
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.
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.
Labetalol: (Moderate) Monitor for an increase in the incidence and severity of tremor and tricyclic antidepressant (TCA)-related adverse effects during concomitant use of labetalol and TCAs. An increase in the incidence of tremor has been observed during concomitant use of labetalol with tricyclic antidepressants; the mechanism of interaction is unknown. Concomitant use may also increase TCA exposure; TCAs are CYP2D6 substrates and labetalol is a weak CYP2D6 inhibitor.
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) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant 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.
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.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and tricyclic antidepressants. Concomitant use may result in additive CNS depression or anticholinergic effects.
Levodopa: (Moderate) Monitor blood pressure and for symptoms of dyskinesia during concomitant levodopa and tricyclic antidepressant use. There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use.
Levomilnacipran: (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. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
Levonorgestrel; 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.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
Levorphanol: (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. Reduce the initial dose of levorphanol by approximately 50% or more. 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.
Levothyroxine: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Levothyroxine; Liothyronine (Porcine): (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Levothyroxine; Liothyronine (Synthetic): (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Lidocaine: (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.
Lidocaine; Epinephrine: (Major) Avoid use of epinephrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the vasopressor effects of epinephrine. (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.
Lidocaine; Prilocaine: (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. (Major) Use prilocaine and tricyclic antidepressants together with caution. If epinephrine is added to prilocaine, 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. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine.
Linezolid: (Contraindicated) Treatment with tricyclic antidepressants (TCAs) is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than tricyclic antidepressant therapy (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving a TCA and requiring urgent treatment with linezolid, the TCA should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid, whichever comes first. The TCA may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with a TCA can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. 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.
Liothyronine: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Lisdexamfetamine: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potentiation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Lithium: (Moderate) Monitor for serotonin syndrome, particularly during lithium initiation, during concomitant tricyclic antidepressant use. If serotonin syndrome occurs, consider discontinuation of lithium and/or the tricyclic antidepressant.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. 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).
Lopinavir; Ritonavir: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor.
Loratadine; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
Lorazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Lorcaserin: (Moderate) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, tricyclic antidepressants. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Loxapine: (Moderate) Use caution when combining tricyclic antidepressants (TCAs) with loxapine, which both exhibit anticholinergic activity and may cause CNS effects. Some TCAs may be more likely to cause side effects than others. Because secondary amines, such as desipramine, are generally less likely than tertiary amines (e.g., amitriptyline) to cause sedation, orthostatic hypotension, and anticholinergic effects, TCAs such as desipramine may be preferred for use with antipsychotics.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Maprotiline: (Contraindicated) The use of maprotiline 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., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Meclizine: (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.
Melatonin: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of melatonin and tricyclic antidepressants due to the risk for additive CNS depression.
Meperidine: (Major) Concomitant use of meperidine with tricyclic antidepressants (TCAs) may cause excessive sedation and somnolence. Limit the use of opioid pain medications with TCAs 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 or signs of urinary retention or reduced gastric motility. 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. The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Mepivacaine: (Major) Use mepivacaine and tricyclic antidepressants together with caution. If epinephrine is added to mepivacaine, 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. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression, including tricyclic antidepressants. If used together, a reduction in the dose of one or both drugs may be needed.
Metaxalone: (Moderate) Coadministration of tricyclic antidepressants (TCAs) with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
Methadone: (Major) Concomitant use of methadone with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of methadone 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. The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks vs. benefits. Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. 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 therapy (elevated serum concentrations). Monitor patients closely for cardiac conduction changes. Also monitor patients for the emergence of serotonin syndrome and for signs of urinary retention or reduced gastric motility. 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. The concomitant use of opioids with anticholinergic drugs may increase risk of urinary retention or severe constipation, which may lead to paralytic ileus.
Methamphetamine: (Moderate) Monitor blood pressure, heart rate, and for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for potenti ation of cardiovascular effects and serotonin syndrome. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer, treatment initiation with trimipramine 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 trimipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trimipramine and requiring urgent treatment with IV methylene blue, trimipramine 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. Trimipramine 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) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects.
Methocarbamol: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of methocarbamol and tricyclic antidepressants due to the risk for additive CNS depression.
Methohexital: (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.
Methscopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and methscopolamine use. Concomitant use may result in additive anticholinergic adverse effects.
Methsuximide: (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.
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.
Methylene Blue: (Contraindicated) According to the manufacturer, treatment initiation with trimipramine 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 trimipramine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trimipramine and requiring urgent treatment with IV methylene blue, trimipramine 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. Trimipramine 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.
Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and tricyclic antidepressants (TCAs). There are postmarketing reports of serotonin syndrome occurring during use of methylphenidate derivatives and other serotonergic medications. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as tricyclic antidepressants, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
Midazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Milnacipran: (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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as antidepressants. Caution should be exercised when using these agents concurrently.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of tricyclic antidepressants (TCAs), which are CYP2D6 substrates, may be increased when co-administered with mirabegron. In drug interaction studies, mirabegron increased the Cmax of desipramine by 79% and desipramine AUC by 241% after multiple dose administration of 100 mg mirabegron once daily for 18 days and a single dose of 50 mg desipramine before and concomitantly with mirabegron. It is difficult to predict the magnitude of the interaction with each TCA due to differences in the role of CYP2D6 in the metabolism of these drugs. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Molindone: (Moderate) Antipsychotics are associated with anticholinergic effects; therefore, additive effects may be seen during concurrent use of molindone and other drugs having anticholinergic activity such as tricyclic antidepressants. 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 CNS effects may also occur.
Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with tricyclic antidepressants (TCAs) or within 14 days of discontinuing treatment with a TCA. Conversely, TCAs should not be initiated within 14 days of stopping an MAOI. Monitor for serotonin-related side effects during therapy transitions.
Morphine: (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. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. 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.
Morphine; Naltrexone: (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. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. 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.
Nabilone: (Moderate) Nabilone should be combined cautiously with tricyclic antidepressants. Tachycardia, hypertension, drowsiness or other CNS effects may occur.
Nalbuphine: (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.
Naproxen; Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
Nefazodone: (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 nefazodone. Both nefazodone and TCAs inhibit the central 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. Cases of serotonin syndrome or serotonin-related adverse events have been observed during concurrent use of serotonergic antidepressants and nefazodone. If serotonin syndrome is suspected, tricyclic antidepressants and concurrent serotonergic agents should be discontinued.
Neostigmine: (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.
Neostigmine; Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and glycopyrrolate use. Concomitant use may result in additive anticholinergic adverse effects. (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.
Niraparib; Abiraterone: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of trimipramine may be necessary. Trimipramine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of trimipramine may become abruptly toxic when given abiraterone is concomitant therapy.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Tricyclic antidepressants should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Norepinephrine: (Major) Avoid coadministration of norepinephrine with tricyclic antidepressants as concurrent use can cause severe, prolonged hypertension. If administration of norepinephrine cannot be avoided in these patients, monitor for hypertension.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
Norethindrone; 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.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 mcg ethinyl estradiol/day) causing a more significant interaction.
Norgestimate; 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.
Olanzapine: (Moderate) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
Olanzapine; Fluoxetine: (Moderate) Coadministration of fluoxetine and trimipramine 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. (Moderate) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
Olanzapine; Samidorphan: (Moderate) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
Oliceridine: (Major) Concomitant use of oliceridine with tricyclic antidepressants may cause excessive sedation and somnolence. Limit the use of oliceridine 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.
Opicapone: (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.
Oritavancin: (Moderate) Trimipramine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of trimipramine may be reduced if these drugs are administered concurrently.
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.
Osilodrostat: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with osilodrostat is necessary; a dose reduction of trimipramine may be necessary. Concurrent use may increase exposure of trimipramine. Additionally, consider more frequent ECG monitoring due to the risk of additive QT prolongation. Trimipramine is a CYP2D6 substrate that may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Osilodrostat is a CYP2D6 inhibitor that is associated with dose-dependent QT prolongation.
Osimertinib: (Major) If possible, avoid coadministration of trimipramine and osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. 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). Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib.
Oxazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Oxcarbazepine: (Moderate) Use trimipramine with caution in patients with a history of seizures; trimipramine may lower the seizure threshold and thus potentially interfere with the ability of antiepileptics to control seizures. In addition, concomitant use of trimipramine and oxcarbazepine may result in additive CNS depression.
Oxybutynin: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and oxybutynin use. Concomitant use may result in additive anticholinergic adverse effects.
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.
Oxymorphone: (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. Reduce the initial oxymorphone dosage by 1/3 to 1/2. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
Ozanimod: (Contraindicated) Do not use tricyclic antidepressants (TCAs) in patients taking MAOIs or within 14 days of stopping them. An active metabolite of ozanimod inhibits MAO-B, and interactions with TCAs may manifest as serotonin syndrome, hypertensive crisis, QT prolongation or other serious side effects. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving TCAs and MAO inhibiting drugs simultaneously. Consider an alternative to the TCA. Ozanimod is a monoamine oxidase inhibitor that may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. TCAs are serotonergic drugs that 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).
Paliperidone: (Moderate) Concurrent use of paliperidone and tricyclic antidepressants should be avoided if possible. Paliperidone has a risk for QT prolongation and torsade de pointes, and tricyclic antidepressants, primarily at elevated serum concentrations, may produce clinically significant prolongation of the QTc interval. In addition, there is a potential for other pharmacodynamic interactions, such as augmentation of CNS impairment.
Panobinostat: (Major) The co-administration of panobinostat with tricyclic antidepressants such as trimipramine is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, closely monitor patients for signs and symptoms of tricyclic antidepressant toxicity, including QT prolongation and cardiac arrhythmias. Panobinostat is a CYP2D6 inhibitor and tricyclic antidepressants are CYP2D6 substrates. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of trimipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and trimipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
Pazopanib: (Minor) Coadministration of pazopanib and other drugs that prolong the QT interval, such as tricyclic antidepressants is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Amitriptyline, clomipramine and imipramine are CYP3A4 substrates. Coadministration of pazopanib may cause an increase in systemic concentrations of the tricyclic antidepressant. Use caution when administering these drugs concomitantly.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to trimipramine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while trimipramine is a CYP2D6 substrate.
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.
Pentazocine; Naloxone: (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.
Pentobarbital: (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.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as trimipramine. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
Perphenazine: (Moderate) During coadministration of tricyclic antidepressants (TCAs) and perphenazine, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Phenothiazines have been reported to prolong the QT interval. Because tricyclic antidepressants are associated with a possible risk for QT prolongation and torsade de pointes when given in excessive doses or overdosage, concurrent use with phenothiazines should be approached with caution. Additive anticholinergic effects or sedation may also occur.
Perphenazine; Amitriptyline: (Moderate) During coadministration of tricyclic antidepressants (TCAs) and perphenazine, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Phenothiazines have been reported to prolong the QT interval. Because tricyclic antidepressants are associated with a possible risk for QT prolongation and torsade de pointes when given in excessive doses or overdosage, concurrent use with phenothiazines should be approached with caution. Additive anticholinergic effects or sedation may also occur.
Phendimetrazine: (Major) Avoid use of tricyclic antidepressants with phendimetrazine whenever possible. Tricyclic antidepressants (TCAs) may potentiate the pressor response to sympathomimetic agents, such as phendimetrazine. 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.
Phenobarbital: (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.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and hyoscyamine use. Concomitant use may result in additive anticholinergic adverse effects. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and atropine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and scopolamine use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects. (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.
Phentermine: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
Phentermine; Topiramate: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant trimipramine and topiramate use due to the risk for additive CNS depression.
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.
Physostigmine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of cholinesterase inhibitors due to their anticholinergic activity. It may be helpful to choose an alternative antidepressant with lower propensity for anticholinergic activity.
Pilocarpine: (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.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of tricyclic antidepressants with pimozide is contraindicated.
Pitolisant: (Major) Avoid coadministration of pitolisant with tricyclic antidepressants (TCAs) as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like TCAs, may reduce pitolisant efficacy. Pitolisant prolongs 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).
Porfimer: (Major) Avoid coadministration of porfimer with tricyclic antidepressants due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like tricyclic antidepressants may increase the risk of a photosensitivity reaction.
Posaconazole: (Minor) Posaconazole is 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, posaconazole inhibits CYP3A4, CYP2C19, and CYP3A4 may be partially involved in the metabolism of TCAs. Fluconazole has been reported to increase the effects of amitriptyline, perhaps through inhibition of the hepatic microsomal CYP2C19 or CYP3A4 isoenzymes. In at least one case, the interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case, QT-prolongation and torsades de pointes occurred. Monitor for an increased response to amitriptyline if fluconazole, posaconazole, or voriconazole are coadministered.
Pralidoxime: (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.
Pramipexole: (Moderate) Pramipexole may cause additive drowsiness when combined with tricyclic antidepressants.
Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as tricyclic antidepressants, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and tricyclic antidepressants. Concomitant use of pregabalin with tricyclic antidepressants may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Prilocaine: (Major) Use prilocaine and tricyclic antidepressants together with caution. If epinephrine is added to prilocaine, 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. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine.
Prilocaine; Epinephrine: (Major) Avoid use of epinephrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the vasopressor effects of epinephrine. (Major) Use prilocaine and tricyclic antidepressants together with caution. If epinephrine is added to prilocaine, 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. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine.
Primidone: (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.
Procarbazine: (Major) In general, drugs with MAOI activity, such as procarbazine, should not be used with tricyclic antidepressants. Severe hypertensive crises, serotonin syndrome, or increased anticholinergic effects can result from concomitant use. Tricyclic antidepressants can, in some cases, be used concomitantly with MAOIs if tricyclic antidepressant therapy is in effect prior to beginning therapy with a MAOI; tricyclic antidepressants should never be added to an existing MAOI regime. Under careful monitoring for signs or symptoms of hypertension, add the MAOI gradually, starting at a low dose. Patients should also be monitored closely for signs or symptoms of serotonin syndrome (characterized by hyperthermia, diaphoresis, shivering, tremor, myoclonus, seizures, ataxia, delirium, restlessness). Strict adherence to diet restrictions should be emphasized and the patient should not be receiving other sympathomimetics. Most references suggest avoiding this drug interaction entirely if clomipramine or imipramine are being administered.
Prochlorperazine: (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. Phenothiazines have been reported to prolong the QT interval. Because tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP when given in excessive doses or overdosage, concurrent use with phenothiazines should be approached with caution. Lower doses than usually prescribed for either the phenothiazine or the TCA may be required. Additive anticholinergic effects and sedation may also occur.
Promethazine: (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant promethazine and tricyclic antidepressant use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Promethazine; 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. (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant promethazine and tricyclic antidepressant use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Promethazine; 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) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant promethazine and tricyclic antidepressant use. Concomitant use may result in additive CNS depression or anticholinergic adverse effects.
Propafenone: (Minor) Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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) 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. Certain cardiac drugs prolong repolarization at therapeutic or elevated plasma concentrations, and the addition of other drugs may increase the risk of QT prolongation and TdP via pharmacokinetic or pharmacodynamic interactions. TCAs should be used cautiously and with close monitoring in combination with cardiac drugs known to prolong the QT interval such as propafenone. The need to coadminister TCAs with propafenone should be done with a careful assessment of risk versus benefit; consider alternative therapy to the TCA.
Propantheline: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and propantheline use. Concomitant use may result in additive anticholinergic adverse effects.
Propofol: (Moderate) General anesthetics like propofol may produce additive CNS depression when used in patients taking tricyclic antidepressants.
Pseudoephedrine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines.
Pseudoephedrine; Triprolidine: (Major) Avoid use of pseudoephedrine and tricyclic antidepressants as tricyclic antidepressants may potentiate the effects of catecholamines. (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.
Pyridostigmine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
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.
Quazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
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.
Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). In addition, quinine is an inhibitor of CYP2D6. Avoid concurrent use of quinine with other drugs that prolong the QT and are CYP2D6 substrates. Coadministration may result in elevated plasma concentrations of the interacting drug, causing increased risk for adverse events, such as QT prolongation. Drugs that prolong the QT and are substrates for CYP2D6 include tricyclic antidepressants.
Racepinephrine: (Major) Tricyclic antidepressants (TCAs) and maprotiline potentiate the effects of sympathomimetics including epinephrine. Enhanced cardiovascular effects including arrhythmias, severe hypertension, and/or hyperpyrexia are possible with combined use. Concomitant use of racepinephrine inhalations with these agents should be avoided when possible; use caution when concomitant use is not avoidable. If a patient is taking these antidepressants, then they should seek health care professional advice prior to the use of racepinephrine.
Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tricyclic antidepressants.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including tricyclic antidepressants or related compounds (e.g., amoxapine, maprotiline). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any tricyclic antidepressants or related compounds. Conversely, when discontinuing a tricyclic or related compound, it is advisable to wait the length of 4-5 half lives of the individual agent being discontinued prior to initiation with rasagiline.
Relugolix; 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.
Remifentanil: (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.
Remimazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Ribociclib: (Major) Avoid coadministration of ribociclib with trimipramine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-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). Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with trimipramine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-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). Concomitant use may increase the risk for QT prolongation.
Rifampin: (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.
Rifapentine: (Major) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Tricyclic antidepressants are metabolized by CYP3A4 and CYP2C8/9 and may require dosage adjustments when administered concurrently with rifapentine.
Risperidone: (Moderate) Use risperidone and tricyclic antidepressants together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Additionally, coadministration may result in additive CNS effects. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. 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).
Ritonavir: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with ritonavir is necessary; a dose reduction of the TCA may be necessary. Concurrent use may increase exposure of the TCA. TCAs are CYP2D6 substrates and ritonavir is a CYP2D6 inhibitor.
Rivastigmine: (Moderate) Concurrent use of tricyclic antidepressants and rivastigmine should be avoided if possible. Rivastigmine 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 rivastigmine than other tricyclics.
Rolapitant: (Major) Monitor for increased serum concentrations of trimipramine and for trimipramine-related adverse effects, such as nausea, dizziness, hypotension, syncope, and QT prolongation, if coadministered with rolapitant. Lower doses of either drug may be required with coadministration. When rolapitant is withdrawn from co-therapy, an increased dose of trimipramine may be required. Trimipramine is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Ropinirole: (Moderate) Ropinirole may cause additive drowsiness when combined with tricyclic antidepressants.
Rufinamide: (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.
Safinamide: (Contraindicated) Safinamide is contraindicated for use with tricyclic antidepressants (TCAs) due to the risk of serotonin syndrome. 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. At least 14 days should elapse between the discontinuation of safinamide and the initiation of a TCA.
Saquinavir: (Minor) The concurrent use of saquinavir boosted with ritonavir and tricyclic antidepressants should be avoided if possible due to the potential for increased tricyclic antidepressant serum concentrations and the potential for QT prolongation. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many tricyclic antidepressants. During coadministration, elevated serum concentrations of the tricyclic antidepressant can occur; thus, monitoring of therapeutic concentrations is recommended by the manufacturer of saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; if possible, avoid use with other drugs that may prolong the QT or PR interval, such as tricyclic antidepressants. If no alternative therapy is acceptable, perform a baseline ECG prior to initiation of concomitant therapy and follow recommended ECG monitoring.
Scopolamine: (Moderate) Monitor for unusual drowsiness or excess sedation and for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and scopolamine use. Concomitant us e may result in additive CNS depression or anticholinergic adverse effects.
Secobarbital: (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.
Segesterone Acetate; 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.
Selegiline: (Contraindicated) Tricyclic antidepressants (TCAs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a TCA. After stopping treatment with a TCA, a time period equal to 4 to 5 half-lives of the TCA or any active metabolite should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and such antidepressants simultaneously.
Serotonin-Receptor Agonists: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant serotonin-receptor agonist and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc 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, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. 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. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
Sevoflurane: (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.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Minor) There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. While seizures have generally been associated with electrolyte abnormalities, such as hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia, and low serum osmolarity, patients receiving medications that lower the seizure threshold may be at an increased risk for experiencing seizures with bowel preparation products.
Solifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with tricyclic antidepressants. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent. In addition, solifenacin is associated with dose-dependent QT prolongation, and torsades de pointes (TdP) has been reported with post-marketing use. Tricyclic antidepressants also are associated with QT prolongation and should be used cautiously and with close monitoring with solifenacin.
St. John's Wort, Hypericum perforatum: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and tricyclic antidepressants. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (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.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for loss of tricyclic antidepressant efficacy during concomitant sulfamethoxazole; trimethoprim use; adjust the tricyclic antidepressant dose if needed. The efficacy of tricyclic antidepressants can decrease during concomitant use. (Moderate) Monitor therapeutic response and adjust the tricyclic antidepressant dose, if needed, when use sulfamethoxazole; trimethoprim concomitantly. The efficacy of tricyclic antidepressants can decrease when administered with sulfamethoxazole; trimethoprim.
Suvorexant: (Moderate) The use of suvorexant with other CNS depressants (e.g., tricyclic antidepressants) increases the risk of CNS depression. Dosage adjustments of suvorexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of suvorexant with other drugs to treat insomnia, such as tricyclic antidepressants used for insomnia, is not recommended.
Tacrolimus: (Minor) Tacrolimus 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). Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and tricyclic antidepressants (TCAs) should be used together cautiously.
Tapentadol: (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.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and tricyclic antidepressants (TCAs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serontoneric effects with tedizolid. However, tedizolid is an antibiotic that is a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. 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.
Temazepam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Terbinafine: (Moderate) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as tricyclic antidepressants.
Tetrabenazine: (Moderate) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as tricyclic antidepressants. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, concurrent use of tricyclics and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, or orthostatic hypotension may be increased.
Tetracaine: (Major) Use tetracaine and tricyclic antidepressants (TCAs) together with caution. If epinephrine is added to tetracaine, 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. Administration of a phenothiazine or a butyrophenone may reduce or reverse the pressor effect of epinephrine.
Thalidomide: (Major) Avoid the concomitant use of thalidomide with other central nervous system depressants such as tricyclic antidepressants (TCAs) due to the potential for additive sedative effects. Additionally, co-administration of thalidomide and other agents that slow cardiac conduction such as TCAs may increase the potential for additive bradycardia.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension, including tricyclic antidepressants (TCAs). In addition to additive effects on the cardiovascular system, additive anticholinergic effects and sedation may be observed.
Thiothixene: (Moderate) Concurrent use of thiothixene and tricyclic antidepressants (TCAs) may result in additive anticholinergic effects, sedation, and orthostatic hypotension. Additive effects may be more pronounced when thiothixene is used with tertiary TCAs including amitriptyline, clomipramine, doxepin, imipramine, and trimipramine versus secondary TCAs such as desipramine, nortriptyline, and protriptyline.
Thyroid hormones: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of tricyclic antidepressants. Although this drug combination appears to be safe, be aware of the possibility of exaggerated cardiovascular side effects such as arrhythmias and CNS stimulation.
Tiagabine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking tricyclic antidepressants (TCAs). Tobacco smoking may increase the clearance of TCAs, which may reduce their efficacy.
Tolcapone: (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.
Tolterodine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously and with close monitoring with tolterodine. 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). Tolterodine is also associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. In addition, additive anticholinergic effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other antimuscarinics. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when tolterodine is combined with tricyclic antidepressants.
Topiramate: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant trimipramine and topiramate use due to the risk for additive CNS depression.
Tramadol: (Major) Concomitant use of tramadol with tricyclic antidepressants may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Tramadol; Acetaminophen: (Major) Concomitant use of tramadol with tricyclic antidepressants may cause respiratory depression, hypotension, profound sedation, and death and increase the risk for serotonin syndrome, seizures, and anticholinergic effects. Limit the use of opioid pain medications 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. Monitor patients for serotonin syndrome if concomitant use is necessary, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Monitor for signs of urinary retention or reduced gastric motility during coadministration. The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Trazodone: (Moderate) Monitor for unusual drowsiness and excess sedation and signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant trazodone and tricyclic antidepressant use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for additive CNS depression and serotonin syndrome.
Triazolam: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Trifluoperazine: (Moderate) Phenothiazines have been reported to prolong the QT interval. Because tricyclic antidepressants are associated with a possible risk for QT prolongation and TdP when given in excessive doses or overdosage, concurrent use with trifluoperazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Additive anticholinergic effects or sedation may be seen when phenothiazines are used with tricyclic antidepressants.
Trihexyphenidyl: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant tricyclic antidepressant and trihexyphenidyl use. Concomitant use may result in additive anticholinergic adverse effects.
Trimethoprim: (Moderate) Monitor therapeutic response and adjust the tricyclic antidepressant dose, if needed, when use sulfamethoxazole; trimethoprim concomitantly. The efficacy of tricyclic antidepressants can decrease when administered with sulfamethoxazole; trimethoprim.
Triprolidine: (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.
Trospium: (Moderate) Additive anticholinergic and CNS effects may be seen when tricyclic antidepressants (TCAs) are used concomitantly with other antimuscarinics, such as trospium. Antimuscarinic effects might be seen on GI smooth muscle, bladder function, the eye, and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients. Monitor for anticholinergic effects such as such as confusion, constipation, dizziness, urinary retention, dry mouth and eyes, blurred vision, or rarely, fast, irregular heartbeat.
Tryptophan, 5-Hydroxytryptophan: (Major) The concomitant use of tryptophan with tricyclic antidepressants should be avoided. Since tryptophan is converted to serotonin (5-hydroxytryptamine), the use of tryptophan in patients receiving drugs with serotonergic activity could lead to serotonin syndrome. 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, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
Valerian, Valeriana officinalis: (Moderate) Any substances that act on the CNS, including tricyclic antidepressants, may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. Valerian is probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
Valproic Acid, Divalproex Sodium: (Moderate) Tricyclic antidepressants, when used concomitantly with valproic acid, can increase CNS depression and may lower the seizure threshold. Monitor patients on tricyclic antidepressants carefully when valproic acid is used concurrently.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as tricyclic antidepressants. Use together may increase the pressor and antidiuretic effects of vasopressin.
Venlafaxine: (Major) The combination of venlafaxine and tricyclic antidepressants may lead to serotonin syndrome and increased plasma concentrations of TCAs. 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Venlafaxine is an inhibitor of CYP2D6, and many TCAs are metabolized by this isozyme. One case report documented a first-time seizure in a patient receiving venlafaxine and trimipramine at therapeutic dosages.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with tricyclic antidepressants is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like antidepressants may increase the risk of a photosensitivity reaction.
Vigabatrin: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions.
Vilazodone: (Major) Vilazodone and Tricyclic antidepressants (TCAs) may cause additive CNS depression, including dizziness or drowsiness. These drugs can represent duplicate therapies and are not commonly prescribed together. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and a TCA should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the TCA should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Viloxazine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with viloxazine is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; viloxazine is a CYP2D6 inhibitor.
Voriconazole: (Minor) Voriconazole is 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, voriconazole inhibits CYP2C19 and CYP3A4. CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs. Trimipramine may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to trimipramine if voriconazole is coadministered.
Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine 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. Patients receiving a tricyclic antidepressant in combination with vortioxetine should be monitored for the emergence of serotonin syndrome or other adverse effects. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
Zaleplon: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Coadministration of single doses of a tricyclic antidepressant and zaleplon produced additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as tricyclic antidepressants. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Zolpidem: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of tricyclic antidepressants and zolpidem due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day. Coadministration of a tricyclic antidepressant and zolpidem resulted in a 20% decrease in the peak concentrations of the tricyclic antidepressant, but there was an additive effect of decreased alertness.
Zonisamide: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.

Surmontil/Trimipramine/Trimipramine Maleate Oral Cap: 25mg, 50mg, 100mg

Adults

200 mg/day PO in outpatients; 300 mg/day PO in hospitalized patients.

Elderly

100 mg/day PO.

Adolescents

100 mg/day PO.

Children

Safety and efficacy have not been established. 

Mechanism of Action: The precise mechanism of action of tricyclic antidepressants is not fully understood. In general, it is believed that tricyclics interfere with the reuptake of norepinephrine and serotonin at the presynaptic neuronal membrane. Serotonin and norepinephrine are thought to be involved in the regulation of mood, appetite, attentiveness, sleep, and other brain functions. Because mood elevation secondary to antidepressant therapy occurs only in depressed individuals and may require 2—3 weeks of therapy, a more recent theory has emerged to explain the mood-altering properties of antidepressants which involves the eventual down-regulation of ß-adrenoceptors. Interestingly, animal studies indicate that trimipramine does not appear to have a significant effect on the reuptake of serotonin or norepinephrine, nor does it result in the down-regulation of ß-adrenoceptors. Postsynaptic sensitization to serotonin has been postulated as one possible antidepressant mechanism of trimipramine. Trimipramine also has D2-receptor antagonist properties, with an affinity for the D2 receptor which is similar to molindone. The effectiveness of trimipramine in treating psychotic disorders is inconclusive.The mechanisms responsible for the adverse events due to trimipramine are varied. Trimipramine may exhibit significant anticholinergic effects such as xerostomia, urinary retention, constipation, or blurred vision. A high degree of sedation is a common CNS effect caused by H1-blockade, as well as serotonergic and anticholinergic actions. Weight gain is likely associated with appetite stimulation caused by H1-blockade and a decrease in the patient's activity level from the sedative effects of the drug. Cardiovascular side effects occurring with tricyclic antidepressants are due to their direct quinidine-like action, potent anticholinergic and alpha blocking properties, and ability to potentiate norepinephrine. Tremors can result from norepinephrine-reuptake blockade. Additionally, abnormal movements may be a consequence of dopamine receptor blockade with trimipramine. Unlike many psychotropic agents, trimipramine does not suppress REM sleep. Sleep latency is decreased, REM sleep latency is increased, and time spent asleep is increased in depressed individuals receiving trimipramine. Monoamine oxidase is not inhibited by tricyclic antidepressants.

Trimipramine is administered orally. Tricyclic antidepressants are highly protein-bound (predominantly to alpha1-acid glycoprotein) in plasma and tissues. Because trimipramine is long-acting, a single daily dose may be given to improve patient compliance. Half-life values range from 20—26 hours. It is unknown if trimipramine is excreted into breast milk.
 
Trimipramine is prepared as a racemic mixture, and stereoselective metabolism is thought to occur with the drug. (D)-trimipramine primarily undergoes N-demethylation while (L)-trimipramine is preferentially hydroxylated. The drug is metabolized in the liver to desmethyltrimipramine, and 2-hydroxytrimipramine. These byproducts are further metabolized to 2-hydroxy desmethyltrimipramine. Multiple CYP450 isoenzymes appear to be involved in the transformation of the drug and its metabolites including 2D6, 2C19, and 3A4. Although desmethyltrimipramine is an active metabolite, it is found in low concentrations in the blood and is therefore not thought to be a primary factor in the antidepressant effect of the drug. Excretion occurs through the kidneys. Tricyclics are metabolized via CYP2D6; therefore, slow metabolizers of this isozyme are expected to have higher plasma levels of the drugs. In general, trimipramine is not dialyzable. However, in cases of trimipramine toxicity with acute refractory cardiovascular instability, patients may occasionally benefit from hemoperfusion.

Oral Route

The absorption of trimipramine has not been described; however, tricyclic antidepressants are generally well absorbed from the GI tract. The full antidepressant effect can take several weeks to become evident, although adverse effects can occur after the first dose. Peak plasma concentrations are attained within 2—6 hours following oral administration. Trimipramine undergoes extensive first-pass metabolism.

Pregnancy

There are no adequate and well-controlled studies of trimipramine administration in pregnant women; therefore, the drug should only be used in pregnancy if the benefits to the mother outweigh the possible risks to the fetus. Trimipramine has shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. Tricyclic antidepressants (TCAs) cross the placenta. Whether there is an increased risk of major malformations is not known. Neonatal complications including hypoglycemia, respiratory diagnoses, developmental delays, jaundice, and withdrawal have been reported after in utero exposure to TCAs. 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 infants 15 to 71 months of age compared to similar non-exposed controls, exposure to antidepressants did not adversely affect IQ, language, behavior, or temperament. The effects of trimipramine during labor and obstetric delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to trimipramine; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants or by calling 1-866-961-2388.