Sinequan

Sedatives, Other
Topical Antihistamines
Tricyclic Antidepressants

Oral Administration Oral Solid Formulations

Oral capsules: To reduce daytime sedation and improve sleep, administer entire daily dose at bedtime. In the minority of patients that experience stimulation and insomnia with bedtime dosing, the dose should be given in the morning.
 
Oral tablets (e.g., Silenor tablets): Administer within 30 minutes of bedtime. To minimize the potential for next day effects, doxepin tablets should not be taken within 3 hours of a meal.

Oral Liquid Formulations

Oral concentrated solution: prior to administration dilute each dose in approximately 120 mL of water, whole or skimmed milk or pineapple, orange, grapefruit, prune, or tomato juice. The solution and carbonated beverages are incompatible. For patients requiring concurrent doxepin and methadone therapy, doxepin solution and methadone syrup can be mixed together with water, sugar water, Gatorade, orange juice, Tang, or lemonade, but not with grape juice. Do not prepare bulk dilutions for future use.

Topical Administration Cream/Ointment/Lotion Formulations

Cream is for external topical use to the skin only. Do not apply to the eye or administer orally or intravaginally.
Rub cream gently into affected area(s).
Do not use occlusive dressings or bandages or coverings which would be wrapped as to be occlusive.

Severe

seizures / Delayed / 0-1.0
agranulocytosis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
hyperkalemia / Delayed / 0.1-1.0
serotonin syndrome / Delayed / 0-1.0
AV block / Early / 0-0.1
bone fractures / Delayed / 0-0.1
suicidal ideation / Delayed / Incidence not known
ileus / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
torsade de pointes / Rapid / Incidence not known
ventricular tachycardia / Early / Incidence not known
stroke / Early / Incidence not known
vasculitis / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
ocular hypertension / Delayed / Incidence not known

Moderate

dysarthria / Delayed / 1.0-10.0
contact dermatitis / Delayed / 1.0-10.0
hypertension / Early / 0-3.0
dystonic reaction / Delayed / 0-1.0
pseudoparkinsonism / Delayed / 0-1.0
dyskinesia / Delayed / 0-1.0
chest pain (unspecified) / Early / 0.1-1.0
edema / Delayed / 0-1.0
anemia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
eosinophilia / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
hyperthyroidism / Delayed / 0-1.0
goiter / Delayed / 0-1.0
hypothyroidism / Delayed / 0-1.0
diabetes mellitus / Delayed / 0-1.0
wheezing / Rapid / 0.1-1.0
dysuria / Early / 0-1.0
hepatitis / Delayed / 0-1.0
elevated hepatic enzymes / Delayed / 0-1.0
jaundice / Delayed / 0-1.0
hypermagnesemia / Delayed / 0.1-1.0
sinus tachycardia / Rapid / 0-0.1
ST-T wave changes / Rapid / 0-0.1
palpitations / Early / 0-0.1
hematoma / Early / 0-0.1
dyspnea / Early / 0-0.1
hyperbilirubinemia / Delayed / 0-0.1
hypokalemia / Delayed / 0-0.1
blepharospasm / Early / 0-0.1
constipation / Delayed / 10.0
orthostatic hypotension / Delayed / 10.0
impotence (erectile dysfunction) / Delayed / 10.0
ejaculation dysfunction / Delayed / 10.0
urinary retention / Early / 10.0
blurred vision / Early / 10.0
withdrawal / Early / 10.0
memory impairment / Delayed / Incidence not known
migraine / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
EEG changes / Delayed / Incidence not known
mania / Early / Incidence not known
psychosis / Early / Incidence not known
confusion / Early / Incidence not known
delirium / Early / Incidence not known
depression / Delayed / Incidence not known
hallucinations / Early / Incidence not known
complex sleep-related behaviors / Early / Incidence not known
parotitis / Delayed / Incidence not known
glossitis / Early / Incidence not known
stomatitis / Delayed / Incidence not known
PR prolongation / Rapid / Incidence not known
QT prolongation / Rapid / Incidence not known
peripheral edema / Delayed / Incidence not known
galactorrhea / Delayed / Incidence not known
testicular swelling / Early / Incidence not known
erythema / Early / Incidence not known
hyperglycemia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
cycloplegia / Early / Incidence not known
hyperthermia / Delayed / Incidence not known

Mild

skin irritation / Early / 23.0-23.0
fatigue / Early / 1.0-10.0
yawning / Early / 1.0-10.0
nausea / Early / 1.0-10.0
appetite stimulation / Delayed / 1.0-10.0
hyperhidrosis / Delayed / 1.0-10.0
flushing / Rapid / 1.0-10.0
pharyngitis / Delayed / 2.0-4.0
syncope / Early / 0-1.0
asthenia / Delayed / 0-1.0
insomnia / Early / 0-1.0
nightmares / Early / 0-1.0
paresthesias / Delayed / 0-1.0
anorexia / Delayed / 0-1.0
dysgeusia / Early / 0-1.0
abdominal pain / Early / 0-1.0
gastroesophageal reflux / Delayed / 0-1.0
vomiting / Early / 0-1.0
diarrhea / Early / 0-1.0
alopecia / Delayed / 0-1.0
pruritus / Rapid / 0-1.0
pallor / Early / 0.1-1.0
rash / Early / 0-1.0
purpura / Delayed / 0-1.0
laryngitis / Delayed / 0.1-1.0
nasal congestion / Early / 0.1-1.0
sinusitis / Delayed / 0.1-1.0
infection / Delayed / 0-1.0
nocturia / Early / 0-1.0
arthralgia / Delayed / 0.1-1.0
myalgia / Early / 0.1-1.0
back pain / Delayed / 0.1-1.0
folliculitis / Delayed / 0-0.1
chills / Rapid / 0-0.1
cough / Delayed / 0-0.1
influenza / Delayed / 0-0.1
rhinorrhea / Early / 0-0.1
muscle cramps / Delayed / 0-0.1
diplopia / Early / 0-0.1
xerophthalmia / Early / 0-0.1
ocular pain / Early / 0-0.1
tinnitus / Delayed / 0-0.1
otalgia / Early / 0-0.1
lethargy / Early / 10.0
dizziness / Early / 10.0
drowsiness / Early / 10.0
xerostomia / Early / 10.0
dyspepsia / Early / 10.0
weight gain / Delayed / 10.0
abnormal dreams / Early / Incidence not known
headache / Early / Incidence not known
tremor / Early / Incidence not known
anxiety / Delayed / Incidence not known
restlessness / Early / Incidence not known
agitation / Early / Incidence not known
pyrosis (heartburn) / Early / Incidence not known
tongue discoloration / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known
dysmenorrhea / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
fever / Early / Incidence not known
increased urinary frequency / Early / Incidence not known
mydriasis / Early / Incidence not known

Children, suicidal ideation

The safety and efficacy of doxepin for the treatment of depression and/or anxiety have not been established in pediatric patients less than 12 years of age. The safety and efficacy of low-dose doxepin for insomnia have not been established in pediatric patients under the age of 18 years old. Use of doxepin cream in pediatric patients is not recommended, due to the potential for systemic absorption and adverse effects; a case of toxicity has been reported in a young child. In a pooled analysis of placebo-controlled trials of systemic 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 doxepin may be necessary in patients with emerging suicidality or worsening depression. Doxepin 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.

Prudoxin, Silenor, Sinequan, Zonalon

Rx

Dibenzoxepin type tricyclic antidepressant; has substantial anticholinergic and sedative effects.
Used in adults for the treatment of depression/anxiety; low-dose oral product used in adults with insomnia characterized by difficulty with sleep maintenance
Topical cream used only in adults; used short term to relieve pruritus from atopic dermatitis (eczema) or lichen simplex chronicus
Boxed warning for oral use in pediatric patients and young adults due to risk for suicidality

For the treatment of major depression and/or anxiety, including psychotic depressive disorders with associated anxiety. Oral Dosage Adults

Initially, 75 mg/day PO given as a single dose at bedtime or in 2 to 3 divided doses. May increase gradually depending on response and tolerability. It is advisable to initiate at the low end of the dosing range in the geriatric patient; slowly titrate and closely observe for adverse anticholinergic effects or oversedation. Usual effective dose: 75 to 150 mg/day PO. Higher doses of up to 300 mg/day PO may be required in more severely ill patients. If more than 150 mg/day PO is required, give in divided doses. Patients with mild symptoms may respond to doses as low as 25 to 50 mg/day PO.

Adolescents†

Safety and efficacy have not been established. Weight-based dosing has been described: 1 mg/kg/day to 3 mg/kg/day PO in single or divided doses, start at lower dosage and titrate slowly at weekly intervals. A suggested initial dose is 25 mg/day to 50 mg/day PO. Use lowest effective dose. Do not exceed 3 mg/kg/day PO; usually do not exceed 100 mg/day PO. Tricyclic antidepressants (TCAs) are not drugs of choice for adolescents with depression; there is lack of high-quality data to support efficacy and safety.

For the treatment of insomnia characterized by difficulties with sleep maintenance. Oral dosage (doxepin 3 mg or 6 mg tablets; e.g., Silenor tablets) Adults

6 mg PO once daily within 30 minutes of bedtime; a lower dose of 3 mg PO at bedtime may be of benefit in some patients. Do not exceed 6 mg/day PO.

Geriatric Adults

3 mg PO once daily within 30 minutes of bedtime; may increase to 6 mg PO once daily within 30 minutes of bedtime, if clinically indicated. Max: 6 mg/day PO. The Beers expert panel states that the safety profile of low-dose doxepin (6 mg/day or less) for insomnia in geriatric patients is comparable with that of placebo. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of sedative/hypnotics in long-term care facility (LTCF) residents. Use the lowest effective doxepin dose in these residents. All sleep medications should be used in accordance with approved product labeling. If the sleep agent is used routinely and is beyond the manufacturer's recommendations for duration of use, the facility should attempt a quarterly taper unless clinically contraindicated as defined in the OBRA guidelines.

For the topical treatment of eczematous dermatitis (atopic dermatitis, eczema, or lichen simplex chronicus). Topical dosage (5% topical cream) Adults

Apply to the affected area topically 4 times daily, allowing at least 3 to 4 hours between applications, for up to 8 days. There are no data to establish the safety and efficacy of doxepin cream when used for greater than 8 days. If excessive drowsiness occurs, it may be necessary to reduce the frequency of applications, the amount of cream applied, and/or the percentage of body surface treated or to discontinue the drug. However, efficacy with reduced frequency of application has not been established.

Hepatic Impairment

Dosage adjustment needed in hepatic impairment but specific guidelines are not available for most formulations. For capsules and oral solution (Sinequan), use reduced initial dosage and adjust gradually according to clinical response and tolerance. For tablets (Silenor), initiate at 3 mg/day in patients with hepatic impairment and monitor for adverse effects.

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 doxepin-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of doxepin may be necessary. Doxepin is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of doxepin 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) Monitor for an increase in doxepin-related adverse reactions if concomitant use of celecoxib is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and celecoxib is a CYP2D6 inhibitor.
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.
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: (Minor) Use caution if doxepin and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of doxepin. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Doxepin is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
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 doxepin 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 doxepin 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 doxepin (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving doxepin and requiring urgent treatment with IV methylene blue, doxepin 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. Doxepin 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) Consider a dose reduction of doxepin as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased doxepin exposure is possible. Doxepin is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor. Also monitor for excessive sedation and somnolence during coadministration of cannabidiol and doxepin; additive CNS depression may occur.
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. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including tricyclic antidepressants. Sedation is generally more pronounced with tertiary agents such as amitriptyline, imipramine, doxepin, and clomipramine.
Carisoprodol: (Moderate) Concomitant use of carisoprodol with tricyclic antidepressants can result in additive CNS depression (sedation and dizziness), which can impair the ability to undertake tasks requiring mental alertness.
Celecoxib: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of celecoxib is nece

ssary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and celecoxib is a CYP2D6 inhibitor.
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) Monitor for an increase in doxepin-related adverse reactions if concomitant use of celecoxib is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and celecoxib is a CYP2D6 inhibitor.
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 doxepin; 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) Monitor for an increase in doxepin-related adverse reactions if concomitant use of cimetidine is necessary; a doxepin dose reduction may be necessary. Doxepin exposure is doubled with concomitant administration of cimetidine.
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: (Moderate) Coadministration of doxepin with citalopram may increase the risk of serotonin syndrome. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
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 doxepin. 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 coadministered with desvenlafaxine 100 mg or lower, or when desvenlafaxine is discontinued. The dose of these CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and tricyclic antidepressants (TCAs). Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Monitor for excessive sedation and somnolence during coadministration of TCAs and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexbrompheniramine; Pseudoephedrine: (Major) 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.
Elexacaftor; tezacaftor; ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as doxepin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
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: (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) Monitor patients for signs and symptoms of serotonin syndrome during concomitant use of doxepin and escitalopram, 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.
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.
Eslicarbaze pine: (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 doxepin-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of doxepin if clinically appropriate. Doxepin is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of doxepin.
Fedratinib: (Moderate) Monitor for an increase in doxepin-related adverse reactions if coadministration with fedratinib is necessary; a dose reduction of doxepin may be necessary. Doxepin is a CYP2D6 and CYP2C19 substrate and fedratinib is a moderate CYP2D6 and CYP2C19 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) Use fluconazole and tricyclic antidepressants (TCAs) with caution. Fluconazole is associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, fluconazole inhibits CYP2C19, CYP2C9, and CYP3A4; these enzymes are involved in the metabolism of some TCAs. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. In at least one case, a TCA interaction resulted in an increased incidence of TCA-related side effects, such as dizziness and syncope. In another case involving amitriptyline, QT-prolongation and torsade de pointes occurred. Concurrent administration of doxepin and fluconazole may result in increased doxepin plasma concentrations and subsequent adverse reactions.
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) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant doxepin and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
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: (Moderate) Concomitant use of fluvoxamine and tricyclic antidepressants (TCAs) such as doxepin may increase the risk of serotonin syndrome. In addition, doxepin is a primary substrate of CYP2C19 and CYP2D6, and is metabolized to a lesser extent by CYP1A2 and CYP2C9. Fluvoxamine is a strong inhibitor of CYP2C19 and CYP1A2 and a mild inhibitor of CYP2D6. Increased doxepin exposure is possible. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome or doxepin-related side effects, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
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 doxepin due to the risk of increased doxepin-related adverse reactions. If use is necessary, consider decreasing the doxepin dose. Doxepin 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 doxepin. 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 doxepin 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 doxepin (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving doxepin and requiring urgent treatment with IV methylene blue, doxepin 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. Doxepin 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. Pharmacokinetic interactions are also possible. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and use of isoniazid, a potent inhibitor of CYP2C19, may result in increased doxepin plasma concentrations and subsequent adverse reactions.
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. Pharmacokinetic interactions are also possible. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and use of isoniazid, a potent inhibitor of CYP2C19, may result in increased doxepin plasma concentrations and subsequent adverse reactions. (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. Pharmacokinetic interactions are also possible. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and use of isoniazid, a potent inhibitor of CYP2C19, may result in increased doxepin plasma concentrations and subsequent adverse reactions. (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.
Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as doxepin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
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 a TCA (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 2 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 doxepin or other TCAs 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.
Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of doxepin, which is a CYP2C19 substrate. Monitor patients for adverse effects of doxepin, such as CNS effects and cardiovascular events. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of doxepin by decreasing its systemic exposure. If used together, monitor patients for doxepin efficacy; a doxepin dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dosage. CYP2C19 and CYP2C9 both play a role in doxepin's metabolism. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as doxepin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of doxepin by decreasing its systemic exposure. If used together, monitor patients for doxepin efficacy; a doxepin dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dosage. CYP2C19 and CYP2C9 both play a role in doxepin's metabolism. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and tricyclic antidepressants. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
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 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.
Methenam ine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer, treatment initiation with doxepin 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 doxepin (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving doxepin and requiring urgent treatment with IV methylene blue, doxepin 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. Doxepin 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 doxepin 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 doxepin (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving doxepin and requiring urgent treatment with IV methylene blue, doxepin 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. Doxepin 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.
Modafinil: (Moderate) Modafinil inhibits CYP2C19 at pharmacologically relevant concentrations. In patients deficient in the CYP2D6 enzyme (poor metabolizers, 7% to 10% of the Caucasian population), the metabolism of certain tricyclics (i.e., clomipramine, desipramine, doxepin, imipramine) may be largely dependent on CYP2C19. One case of a narcoleptic patient is available in which the patient experienced increased side effects and increased serum levels of clomipramine and its active metabolite, desmethylclomipramine, during modafinil treatment. Because tricyclic antidepressants may be given to the narcoleptic patient for the treatment of cataplexy, the health care professional should be aware of the potential for interactions with modafinil. Patients on tricyclic antidepressants may require antidepressant dose reductions.
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 doxepin-related adverse reactions if coadministration with abiraterone is necessary; a dose reduction of doxepin may be necessary. Doxepin is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor. Patients who are stable on a given dose of doxepin 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) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant doxepin and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome. (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) Monitor for an increase in doxepin-related adverse reactions if concomitant use of oritavancin is necessary. Concomitant use may increase doxepin exposure; doxepin is metabolized by CYP2C19 and oritavancin is a CYP2C19 inhibitor.
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 doxepin-related adverse reactions if coadministration with osilodrostat is necessary; a dose reduction of doxepin may be necessary. Concurrent use may increase exposure of doxepin. Additionally, consider more frequent ECG monitoring due to the risk of additive QT prolongation. Doxepin 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 doxepin 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 doxepin with caution in patients with a history of seizures; doxepin may lower the seizure threshold and thus potentially interfere with the ability of antiepileptics to control seizures. In addition, concomitant use of doxepin and oxcarbazepine may result in additive CNS depression. Oxcarbazepine, a CYP2C19 inhibitor, can increase plasma concentrations of doxepin, a substrate of CYP2C19.
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 doxepin 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: (Moderate) Monitor patients for an increase in doxepin-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of doxepin and paroxetine, particularly during treatment initiation and dosage increases; a dose reduction of doxepin 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 also increase the exposure of doxepin. Doxepin is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor.
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) Caution is warranted with the use of doxepin and peginterferon alfa-2b. Doxepin is a substrate of CYP2D6 and CYP1A2, while peginterferon alfa-2b inhibits these enzymes. The pharmacologic effects of CYP2D6 and CYP1A2 substrates may be increased when administered with peginterferon alfa-2b.
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 doxepin. 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 doxepin 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.
Pirtobrutinib: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of pirtobrutinib is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and pirtobrutinib is a CYP2C19 inhibitor.
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.
Ramelteon: (Moderate) Concurrent use of doxepin and ramelteon results in increased ramelteon exposure. If these agents are used together, monitor the patient closely for adverse effects. Use of doxepin 10 mg/day for 23 days and ramelteon as a single 8 mg dose resulted in increased mean AUC and Cmax of ramelteon of approximately 66% and 69%, respectively. No change was observed with regard to the active metabolite, M-II. Clinically meaningful changes in peak and total exposure of doxepin have not been observed.
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 doxepin 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 doxepin 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 doxepin and for doxepin-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 doxepin may be required. Doxepin 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 an d 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 use 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: (Moderate) Monitor for an increase in doxepin-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use, 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. Concomitant use may increase doxepin exposure. 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. Doxepin is a CYP2D6 substrate and sertraline is a CYP2D6 inhibitor.
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.
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.
Tezacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as doxepin. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
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 doxepin 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. Increased concentrations of doxepin are also possible. Valproic acid inhibits CYP2C9; doxepin is a CYP2C9 substrate. Monitor patients closley when taking doxepin with valproic acid; the dose of doxepin may need to be reduced.
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.
Vonoprazan; Amoxicillin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of vonoprazan is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and vonoprazan is a CYP2C19 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of vonoprazan is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and vonoprazan is a CYP2C19 inhibitor.
Voriconazole: (Major) 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, CYP2C9, and CYP3A4. Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. 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. Doxepin may be affected by this potential interaction, but specific data are lacking. Monitor for an increased response to doxepin if fluconazole, posaconazole, or voriconazole are 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.

Doxepin/Doxepin Hydrochloride/Prudoxin/Zonalon Topical Cream: 5%
Doxepin/Doxepin Hydrochloride/Silenor Oral Tab: 3mg, 6mg
Doxepin/Doxepin Hydrochloride/Sinequan Oral Cap: 10mg, 25mg, 50mg, 75mg, 100mg, 150mg
Doxepin/Doxepin Hydrochloride/Sinequan Oral Sol: 1mL, 10mg

Adults

For the capsules and solution, 300 mg/day PO; for the tablets (Silenor), 6 mg/day PO.

Geriatric

For the capsules and solution, 300 mg/day PO; for the tablets (Silenor), 6 mg/day PO.

Adolescents

Safety and efficacy have not been established; a maximum of 100 mg/day PO or 3 mg/kg/day PO has been suggested for depression; safety and efficacy not established for treatment of insomnia.

Children

7 years and older: Safety and efficacy have not been established; a maximum of 3 mg/kg/day PO has been suggested for depression.
6 years and younger: Safety and efficacy have not been established.

The concise action of tricyclic antidepressants in the treatment of depression or anxiety is not fully understood, but it is believed that their most important effect is to enhance the actions of norepinephrine and serotonin by blocking the reuptake of various neurotransmitters at the neuronal membrane. Doxepin most closely resembles amitriptyline in mechanism of action: both agents exert effects on norepinephrine and serotonin. Recent evidence suggests that the upset of monoamine output seen in depressed patients may be regulated by long-term treatment with antidepressants due to their action on beta-adrenergic receptors. This action on beta-receptors may be a better explanation than the reuptake theory of these agents' antidepressant effects. The exact mechanism by which doxepin exerts its effects in treating insomnia also has not been clearly established; however, it is thought to occur through antagonism of the H-1 receptor.
 
Monoamine oxidase is not inhibited by tricyclic drugs. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, being high with doxepin, due to strong binding affinity for histamine H-1 receptors, and the seizure threshold can be lowered. The antipruritic action of doxepin is thought to be secondary to blockade of H-1 receptors. Anticholinergic activity is moderate and may be responsible for the inhibition of urination in the treatment of enuresis. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose can result from doxepin's effect on the endocrine system.

Doxepin is administered orally and topically. There is wide distribution throughout the body. The active metabolite is known to be distributed into breast milk. The full antidepressant effects can take 2 or more weeks to stabilize, but adverse effects may be seen within a few hours. It is approximately 80% bound to plasma proteins. Because the tricyclic antidepressants are long-acting, a single daily dose may be given to improve patient compliance. Plasma concentrations of both doxepin and its metabolite N-desmethyldoxepin are highly variable and are poorly correlated with dosage.
 
Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Approximately 7—10% of the population have reduced activity of CYP2D6 and are considered poor metabolizers; these persons, as well as poor metabolizers of CYP2C19, are at increased risk for adverse reactions. In addition, the metabolism of doxepin may be affected by drugs that inhibit or induce the isoenzymes responsible for its metabolism, particularly CYP2C19 and CYP2D6. The primary metabolite is N-desmethyldoxepin (nordoxepin). Further glucuronidation results in urinary excretion of both the parent drug and the metabolites. The half-life of doxepin is 6—8 hours; desmethyldoxepin has a half-life ranging from 28—52 hours and is not affected by chronic dosing. Due to extensive hepatic metabolism, less than 3% of a dose is excreted in the urine as doxepin or N-desmethyldoxepin. Doxepin is excreted in the urine mainly in the form of glucuronide conjugates.
 
Affected cytochrome P450 isoenzymes: CYP2C19, CYP2D6, CYP1A2, CYP2C9

Oral Route

Doxepin appears to be well absorbed from the gut after oral administration. The median time to peak concentrations (Tmax) after oral administration of a 6 mg dose of doxepin (Silenor) is 3.5 hours under fasting conditions. Administration of Silenor with a high fat meal increases the AUC by 41% and the Cmax by 15%, and Tmax is delayed by approximately 3 hours. Therefore, it is recommended to avoid administration of Silenor within 3 hours of a meal.

Topical Route

Following topical administration doxepin is absorbed through the skin. Plasma concentrations from percutaneous absorption are highly variable and range from non-detectable to 47 ng/mL. The amount of absorption is increased by use of occlusive dressings. Plasma levels from topical application of doxepin can result in CNS and other systemic side effects.

Pregnancy

Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects, miscarriage, or adverse maternal outcomes in women exposed to tricyclic antidepressants (TCAs), including doxepin, during pregnancy; however, neonates exposed to TCAs late in the third trimester have developed complications requiring prolonged hospitalizations, respiratory support, and tube feeding. Findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. Neonates exhibiting signs or symptoms of drug toxicity or withdrawal should be carefully monitored for poor neonatal adaptation syndrome. The impact of in utero exposure to antidepressants or antipsychotics 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. 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). Results of one prospective trial evaluating infants 15 to 71 months of age with in utero exposure to TCAs showed no adverse effects on IQ, language, behavior, or temperament. The effects of doxepin during labor or obstetric delivery are unknown. Experts state that other treatments are often preferred over topical doxepin for pruritus in the pregnant patient. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to doxepin; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants or by calling 1-866-961-2388.