Version July 2025
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Anyone considering the use of doxepin or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults >24 years of age; there was a reduction in risk with antidepressants compared to placebo in adults 65 years of age and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin is not approved for use in pediatric patients.
Anxiety:
Note: Although anxiety is an FDA-approved use, guidelines no longer mention a place in therapy for doxepin, and alternative agents are available without the risks associated with doxepin use (Ref).
Oral: Capsule and oral concentrate: Initial: 25 to 75 mg as a single dose at bedtime; increase dose based on response and tolerability in 25 to 50 mg increments at intervals ≥3 days up to a usual dose of 100 to 300 mg once daily at bedtime or in 2 to 3 divided doses; maximum single dose: 150 mg (Ref). In patients who are more sensitive to adverse effects (eg, anxious depression, medically ill), some experts recommend starting with 10 to 25 mg/day at bedtime and increasing in 10 to 25 mg increments every 1 to 2 days (Ref).
Bipolar disorder, depressive episode :
Note: Overdose may be fatal; avoid use in patients at risk of intentional overdose (Ref).
Oral: Capsule and oral concentrate: Initial: 25 to 50 mg as a single dose at bedtime in combination with an antimanic agent; increase dose based on response and tolerability in 25 to 50 mg increments at intervals ≥3 days up to a usual dose of 100 to 300 mg once daily at bedtime or in 2 to 3 divided doses; maximum single dose: 150 mg (Ref). In patients who are more sensitive to adverse effects (eg, anxious depression or medically ill), some experts recommend starting with 10 to 25 mg/day at bedtime (Ref).
Insomnia, sleep maintenance:
Oral:
Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (Ref).
Tablet: 3 to 6 mg once daily within 30 minutes of bedtime; maximum dose: 6 mg/day.
Capsule (off-label formulation): 10 mg once daily within 30 minutes of bedtime. Note: Manufacturer's labeling for tablets recommends maximum dose of 6 mg/day; however, some experts may initiate with 10 mg capsule based on product availability (Ref).
Major depressive disorder (unipolar), treatment resistant:
Note: Overdose may be fatal; avoid use in patients at risk of intentional overdose (Ref).
Oral: Capsule and oral concentrate: Initial: 25 to 50 mg as a single dose at bedtime; increase dose based on response and tolerability in 25 to 50 mg increments at intervals ≥3 days up to a usual dose of 100 to 300 mg once daily at bedtime or in 2 to 3 divided doses; maximum single dose: 150 mg (Ref). In patients who are more sensitive to adverse effects (eg, anxious depression or medically ill), some experts recommend starting with 10 to 25 mg/day at bedtime (Ref).
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks) may taper over 1 to 2 weeks; <2 weeks treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over 4 weeks) include history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches but is contraindicated when switching to or from a monoamine oxidase inhibitor (MAOI). A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between 2 selective serotonin reuptake inhibitors), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from an MAOI:
Allow 14 days to elapse between discontinuing an MAOI and initiation of doxepin.
Allow 14 days to elapse between discontinuing doxepin and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (<3% excreted in the urine) (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
No dosage adjustment necessary (Ref)
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed (large volume of distribution): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzed (large volume of distribution): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref)
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
Capsule, oral concentrate: There are no dosage adjustments provided in manufacturer's labeling; however, use caution because hepatically metabolized. Some experts recommended reducing initial and maintenance doses by 50% in patients with hepatic impairment, with cautious dose adjustments based on response and tolerability (Ref).
Tablet: Oral: Initial: 3 mg once daily within 30 minutes of bedtime is recommended for unspecified liver impairment (Ref).
Insomnia, sleep maintenance: Tablet: Oral: 3 mg once daily within 30 minutes of bedtime; increase to 6 mg once daily if clinically needed; maximum dose: 6 mg/day (Ref).
Major depressive disorder (unipolar), treatment resistant: Avoid use (Ref).
Discontinuation of therapy: Refer to adult dosing.
Switching antidepressants: Refer to adult dosing.
(For additional information see "Doxepin (systemic): Pediatric drug information")
Depression, unipolar: Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents. Although FDA approved in children ≥12 years and adolescents, a selective serotonin reuptake inhibitor (SSRI) is recommended first line for treatment of depression in children and adolescents with/without psychotherapeutic interventions; doxepin may be beneficial for patients with comorbid conditions or for those in whom first- and second-line treatment options have failed (Ref).
Children ≥12 years and Adolescents: Capsules, oral concentrate: Oral: Initial: 25 to 75 mg/day at bedtime or in 2 to 3 divided doses; begin at the low end of range and gradually titrate; select patients may respond to 25 to 50 mg/day; maximum single dose: 150 mg/dose; maximum daily dose: 300 mg/day.
Insomnia: Limited data available: Children ≥2 years and Adolescents: Oral concentrate, tablets: Oral: Initial: 2 mg at bedtime; may titrate in 2 mg/day increments at 3-day intervals; reported mean effective dose: 8.5 ± 1.9 mg/dose (0.26 ± 0.147 mg/kg/dose). Dosing based on a retrospective trial evaluating 29 patients (age: 9.3 ± 5.2 years; range: 2 to 17 years), of which 58.6% had comorbid diagnosis of autism spectrum disorder and 7% attention-deficit/hyperactivity disorder; results showed improvement in both sleep initiation and sleep maintenance (Ref).
Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of reemerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥12 years and Adolescents: Oral: There are no pediatric dosage adjustments provided in the manufacturer's labeling. Based on adult pharmacokinetic data (<3% excreted in the urine) and experience, no dosage adjustment necessary for any degree of kidney impairment (Ref).
Children ≥12 years and Adolescents: Oral: There are no pediatric-specific recommendations; however, use caution because hepatically metabolized; based on experience in adult patients, dosage adjustment suggested.
Doxepin may cause anticholinergic effects, such as constipation, xerostomia, blurred vision, and urinary retention.
Mechanism: Dose-dependent; binding affinity to the muscarinic receptor(s), permeability of the blood-brain barrier, and serum and tissue concentrations all influence the risk of anticholinergic effects (Ref). Doxepin is considered to have high anticholinergic activity at doses typically used for the treatment of depression (Ref).
Risk factors:
• Older age (Ref)
• Higher doses (Ref)
• Concomitant use of drugs with anticholinergic properties (Ref)
• Specific tricyclic antidepressants: Doxepin has a higher degree of anticholinergic effects relative to other tricyclic antidepressants, while desipramine and nortriptyline have modest effects (Ref)
In general, use of antidepressants may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/or anticoagulants. Multiple observational studies with other drugs that interfere with serotonin reuptake (eg, selective serotonin reuptake inhibitors [SSRIs]) have found an association with use and a variety of bleeding complications. However, the risk of bleeding may be lower in patients who are exposed to an agent with low serotonin transporter binding affinity (eg, doxepin) as compared to agents with high serotonin transporter binding affinity (eg, SSRIs) (Ref).
Mechanism: Possibly via inhibition of serotonin-mediated platelet activation and subsequent platelet dysfunction. Doxepin is considered to display low affinity for the serotonin reuptake receptor (Ref).
Onset: Varied; per SSRI-derived literature (ie, doxepin not included), bleeding risk is likely delayed for several weeks until SSRI-induced platelet serotonin depletion becomes clinically significant (Ref).
Risk factors:
• Concomitant use of antiplatelet agents and/or anticoagulants (based on SSRI-derived literature) (Ref).
• Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)
Tricyclic antidepressants (TCAs), including doxepin, are associated with cardiotoxicity, particularly at supratherapeutic doses. At therapeutic doses, TCAs can cause slowing of intraventricular conduction, manifested by prolonged PR, QRS, and QT intervals on ECG in children, adolescents, and adults (Ref). Sinus tachycardia and potentially life-threatening ventricular arrhythmias, or heart block leading to sudden cardiac death are associated with supratherapeutic doses or therapeutic doses of TCAs in select patients with severe heart disease or preexisting conduction disorders (eg, Brugada syndrome or bundle branch block, long QT syndrome) (Ref). Typical doxepin doses used for the treatment of insomnia were not associated with QTc prolongation in one trial (Ref).
The risk of conduction abnormalities with doxepin is moderate relative to other antidepressants (Ref). In a scientific statement from the American Heart Association, doxepin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: Moderate) (Ref).
Mechanism: Dose-related (some mechanisms); at therapeutic doses, TCAs inhibit sodium channel conduction, potentially delaying cardiac depolarization and causing prolongation of the QRS complex on ECG. Multiple other mechanisms contribute to the cardiac effects associated with TCAs, including inhibition of central cholinergic neurotransmission (potentially causing tachycardia), norepinephrine reuptake inhibition (potentially exacerbating tachycardia), and blockade of alpha-adrenergic receptors (potentially lowering systemic vascular resistance and causing hypotension or orthostatic hypotension). In addition, high doses increase sympathetic and decrease parasympathetic effects on heart rate (Ref). Sinus tachycardia is attributed to the inhibition of norepinephrine and anticholinergic action (Ref).
Risk factors:
• Increased age (Ref)
• Females (Ref)
• Presence of metabolic disease (Ref)
• Coronary artery disease (Ref)
• Hypokalemia (Ref)
• Coadministration of drugs independently associated with QT interval prolongation or further increase risk of arrhythmia (doxepin shares electrophysiologic properties of type Ia antiarrhythmics such as quinidine, procainamide, and disopyramide) (Ref)
• Preexisting conduction disease, particularly bundle branch block or Brugada syndrome, or family history of congenital long QT syndrome (Ref). Note: Use is relatively contraindicated in patients with conduction abnormalities
• Higher doses, particularly in children (Ref)
Tricyclic antidepressants (TCAs), including doxepin, may cause dose-dependent CNS depression, including dizziness, drowsiness, a sedated state, ataxia, cognitive dysfunction (particularly in older adults), confusion, disorientation, fatigue, and psychomotor impairment (Ref).
Mechanism: Dose-related; drowsiness and psychomotor effects are due to anticholinergic and antihistaminergic properties of TCAs, with varying degrees of effects depending on the specific agent. TCAs also produce alpha1-adrenergic blockade which can contribute to sedation and dizziness (from orthostatic hypotension) (Ref).
Onset: Varied; difficult to define; some symptoms may occur with first dose. A meta-analysis in inpatients treated with other TCAs suggested that CNS toxicity (defined primarily as delirium or its prodromal symptoms) may have an insidious onset over 1 to 3 weeks following initiation or dose increase (Ref).
Risk factors:
• Concomitant alcohol (Ref)
• Concomitant CNS depressants (eg, anticholinergics, antihistamines) (Ref)
• Females (Ref)
• Older adults (eg, age >55 years (Ref)) (Ref)
• Increased TCA plasma levels (Ref)
• Specific TCA: Doxepin is associated with a high propensity for causing sedation relative to other TCAs (Ref). Doxepin is associated with a high propensity for producing anticholinergic effects compared to other TCAs (Ref)
Antidepressants (primarily selective serotonin reuptake inhibitors [SSRIs]) have been associated with an increased risk of bone fractures in observational studies (Ref). Tricyclic antidepressants (TCAs), including doxepin, have also been associated with increased fracture risk (Ref).
Mechanism: Not fully elucidated; per SSRI-derived literature, may be related to a direct effect on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity (Ref). Fall risk with TCAs may also be attributed to sedation, syncope, orthostatic hypotension, and/or confusion (Ref).
Onset: Intermediate; observational studies suggest the increased fracture risk observed with TCAs occurs early and reaches a peak within 1 month of initiation of therapy (Ref).
Risk factors:
• Concomitant use with other agents that may further affect physical balance and contribute to falls (eg, anxiolytics) (Ref)
Tricyclic antidepressants (TCAs) have been rarely associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia, predominately in older adults (Ref).
Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).
Onset: Varied; overall, hyponatremia risk is much higher within 2 to 4 weeks of initiating therapy and the risk seems to diminish over time. By 3 to 6 months, the hyponatremia risk is the same as for patients who do not take antidepressants (Ref).
Risk factors:
• Older age (Ref)
• Females (Ref)
• Concomitant use of diuretics (Ref)
• Low body weight (Ref)
• Lower baseline serum sodium concentration (Ref)
• Volume depletion (potential risk factor) (Ref)
• History of hyponatremia (potential risk factor) (Ref)
• Symptoms of psychosis (potential risk factor) (Ref)
• Specific antidepressant: TCAs have a lower risk for hyponatremia in comparison to selective serotonin reuptake inhibitors (Ref)
Tricyclic antidepressants (TCAs) may cause mydriasis and cycloplegia resulting in transient accommodation disturbances and blurred vision (Ref). Mydriasis and cycloplegia usually improve over time as patients develop a tolerance to these effects (Ref). In susceptible individuals, TCA-induced mydriasis may result in the exacerbation of chronic angle-closure glaucoma and/or induction of acute angle-closure glaucoma (AACG). AACG may cause symptoms including eye pain, changes in vision, swelling, and eye redness, which can rapidly lead to permanent blindness if not treated (Ref).
Mechanism: Mydriasis and cycloplegia are likely due to the anticholinergic effect of TCAs (Ref). TCA-induced effects on norepinephrine and serotonin receptors in the iris and ciliary body of the eye, as well as alpha-adrenergic receptors may also play a role (Ref). In susceptible individuals, mydriasis can lead to AACG, which is caused by the physical obstruction of the outflow of intraocular fluid.
Onset: Blurred vision occurs in the initial stages of treatment with a TCA (Ref).
Risk factors:
For AACG:
• Females (Ref)
• Age ≥50 years (slight increase) (Ref)
• Hyperopia (slight increase) (Ref)
• Personal or family history of AACG (Ref)
• Inuit or Asian descent (Ref)
• Narrow-angle glaucoma (avoid or use with extreme caution in these patients) (Ref)
• Specific tricyclic antidepressants: Doxepin is considered to display high anticholinergic activity at typical doses (Ref)
Tricyclic antidepressants (TCAs), including doxepin, may cause orthostatic hypotension, which may lead to syncope and subsequent falls, particularly in older adults (Ref)
Mechanism: Alpha-adrenergic receptor blockade may lower systemic vascular resistance and result in hypotension, including orthostatic hypotension (Ref).
Onset: Varied. In trials of other TCAs, orthostatic hypotension appeared within the first week of initiation and persisted for the duration of treatment (Ref).
Risk factors:
• Cerebrovascular disease
• Cardiovascular disease
• Hypovolemia/dehydration (Ref)
• Concurrent medication use that may predispose to hypotension/bradycardia (Ref)
• Older adults, especially in those with preexisting heart conditions (Ref)
Antidepressants have been associated with an increased risk of suicidal thinking and suicidal behavior in pediatric and young adult patients (18 to 24 years) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, some evidence shows a trend of an elevated risk of suicidality in younger age groups with certain antidepressants (Ref). Additionally, an observational study suggested an association with decreased rate of antidepressant prescribing and an increase in suicide rates in children and adolescents after the labeling was updated with the warnings (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.
Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).
Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).
Risk factors:
• Children and adolescents (Ref)
• Depression (risk of suicide is associated with major depression and may persist until remission occurs)
Withdrawal syndrome has been reported in children and adults following abrupt discontinuation of tricyclic antidepressants (TCAs). Common symptoms include somatic symptoms (eg, lethargy, headache, tremor, sweating, anorexia); affective symptoms (eg, irritability, anxiety, agitation, low mood); sleep disorders (insomnia, excessive dreaming); and gastrointestinal disturbances (eg, nausea/vomiting, abdominal pain, anorexia). Rarely, movement disorders, such as akathisia or parkinsonism, hypomania/mania, psychosis, and/or cardiac arrhythmias may also occur. Of note, sensory abnormalities (eg, shock-like sensations, numbness), which are commonly reported with selective serotonin reuptake inhibitor withdrawal, are rarely seen with TCA withdrawal. Withdrawal symptoms may also occur following gradual tapering (Ref).
Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the serotonergic agent. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected, as well as the hypothalamic-pituitary-adrenal axis (Ref). TCA-associated withdrawal symptoms may also be related in part to an adaptive hypersensitivity of muscarinic cholinergic receptors called cholinergic rebound or cholinergic overdrive and to involve noradrenergic mechanisms (Ref)
Onset: Intermediate; based on data of withdrawal syndrome following selective serotonin reuptake inhibitor (SSRI) discontinuation, expected onset is 1 to 10 days (following either abrupt or tapered discontinuation) (Ref). Onset >1 week later is unusual (Ref).
Risk factors:
• Abrupt discontinuation (rather than dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Cardiovascular: Hypertension (≤3%)
Gastrointestinal: Gastroenteritis (2%; viral gastroenteritis: <1%), nausea (2%)
Nervous system: Dizziness (≥1%), drowsiness (≤9%) (table 1), sedated state (≤9%) (table 2)
|
Drug (Doxepin) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Doxepin) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|
|
9% |
4% |
6 mg once daily |
Oral tablets |
Insomnia |
203 |
278 |
Shared term with sedated state |
|
6% |
4% |
3 mg once daily |
Oral tablets |
Insomnia |
157 |
278 |
Shared term with sedated state |
|
Drug (Doxepin) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Doxepin) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|---|---|
|
9% |
4% |
6 mg once daily |
Oral tablets |
Insomnia |
203 |
278 |
Shared term with drowsiness |
|
6% |
4% |
3 mg once daily |
Oral tablets |
Insomnia |
157 |
278 |
Shared term with drowsiness |
Respiratory: Nasopharyngitis (≤4%), upper respiratory tract infection (≤4%)
<1%:
Cardiovascular: Atrioventricular block, chest pain, decreased heart rate, ECG abnormality (ST-T segment, QRS complex, QRS axis), palpitations, peripheral edema, syncope, tachycardia, vasodepressor syncope, ventricular premature contractions
Dermatologic: Dermatitis, diaphoresis, erythema of skin, folliculitis, hyperhidrosis, lip blister, malignant melanoma, onychomycosis, pallor, pruritus, rosacea, skin irritation, skin rash
Endocrine & metabolic: Decreased libido, hot flash, hyperkalemia, hypermagnesemia, hypokalemia
Gastrointestinal: Abdominal pain, ageusia, anorexia, constipation, decreased appetite, dysgeusia, dyspepsia, gastroesophageal reflux disease, gingival recession, hematochezia, increased appetite, motion sickness, tooth infection, vomiting, xerostomia
Genitourinary: Breast cyst, dysmenorrhea, dysuria, hemoglobinuria, nocturia, urinary incontinence, urinary tract infection
Hematologic & oncologic: Adenocarcinoma (lung), anemia, decreased neutrophils, hematoma, thrombocytopenia
Hepatic: Hyperbilirubinemia, increased serum alanine aminotransferase, increased serum transaminases
Hypersensitivity: Hypersensitivity reaction
Infection: Fungal infection, herpes zoster infection, influenza, staphylococcal skin infection, viral infection
Nervous system: Abnormal dreams, abnormal gait, adjustment disorder, anxiety, asthenia, ataxia, cerebrovascular accident, chills, confusion, depression, disturbance in attention, falling, fatigue, feeling of heaviness, insomnia, lethargy, migraine, mood elevation, nightmares, paresthesia, sleep paralysis, tremor
Neuromuscular & skeletal: Arthralgia, back injury, back pain, bone fracture, decreased range of motion (joints), joint sprain, limb pain, muscle cramps, myalgia, neck pain, tenosynovitis
Ophthalmic: Blepharospasm, blurred vision, decreased lacrimation, diplopia, eye infection, eye pain, eye redness
Otic: Hypoacusis, otalgia, perforated tympanic membrane, tinnitus
Respiratory: Bronchitis, cough, dyspnea, laryngitis, lower respiratory tract infection, nasal congestion, nasopharyngeal disorder, paranasal sinus congestion, pharyngitis, pharyngolaryngeal pain, pneumonia, rales, rhinorrhea, sinusitis, wheezing
Miscellaneous: Laceration
Frequency not defined:
Cardiovascular: Edema, flushing
Dermatologic: Alopecia, skin photosensitivity
Endocrine & metabolic: Increased serum glucose, weight gain
Hematologic & oncologic: Agranulocytosis, eosinophilia, leukopenia, purpuric disease
Hepatic: Jaundice
Nervous system: Disorientation, extrapyramidal reaction, hallucination, headache, numbness, seizure, suicidal ideation, suicidal tendencies, tardive dyskinesia
Ophthalmic: Angle-closure glaucoma, mydriasis
Respiratory: Exacerbation of asthma
Postmarketing:
Cardiovascular: Hypotension
Gastrointestinal: Aphthous stomatitis, diarrhea, stomatitis (Salem 1981)
Genitourinary: Urinary retention
Nervous system: Somnambulism (complex sleep-related behavior [sleep-driving, cooking or eating food, making phone calls])
Hypersensitivity to doxepin, dibenzoxepins, or any component of the formulation; glaucoma; urinary retention; use of MAO inhibitors within 14 days
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in the US labeling): During acute recovery phase following myocardial infarction; acute congestive heart failure; history of blood dyscrasias; severe hepatic disease; use in children
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities).
• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus) as anticholinergic effects may exacerbate underlying condition.
• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased. Due to the narrow therapeutic index, use lower initial and maintenance doses of tricyclic antidepressants. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mullish 2014).
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder.
• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, visual problems) as anticholinergic effects may exacerbate underlying condition.
• Respiratory disease: Use with caution in patients with respiratory compromise or sleep apnea; use of doxepin is generally not recommended in patients with severe sleep apnea.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold (APA 2010).
• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.
Special populations:
• Older adult: May cause confusion and oversedation in older adult patients.
Other warnings/precautions:
• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric and/or medical illness.
• Surgery: Recommended by some manufacturers to discontinue tricyclic antidepressants (TCAs) prior to elective surgery; risks exist for drug interactions with anesthesia and for cardiac arrhythmias. However, some experts recommend continuing TCAs prior to surgery (Pass 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
Concentrate, Oral:
Generic: 10 mg/mL (118 mL, 120 mL)
Tablet, Oral:
Silenor: 3 mg [contains fd&c blue #1 (brilliant blue)]
Silenor: 6 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Generic: 3 mg, 6 mg
Yes
Capsules (Doxepin HCl Oral)
10 mg (per each): $0.31 - $0.73
25 mg (per each): $0.38 - $0.96
50 mg (per each): $0.58 - $1.33
75 mg (per each): $0.88 - $1.81
100 mg (per each): $0.96 - $2.28
150 mg (per each): $0.92 - $3.33
Concentrate (Doxepin HCl Oral)
10 mg/mL (per mL): $0.38
Tablets (Doxepin HCl Oral)
3 mg (per each): $4.17 - $17.25
6 mg (per each): $4.17 - $17.25
Tablets (Silenor Oral)
3 mg (per each): $21.55
6 mg (per each): $21.55
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
SINEquan: 10 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
SINEquan: 25 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
SINEquan: 50 mg
SINEquan: 75 mg, 100 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Generic: 10 mg, 25 mg [DSC], 50 mg [DSC], 75 mg [DSC], 100 mg [DSC], 150 mg [DSC]
Tablet, Oral:
Silenor: 3 mg [contains fd&c blue #1 (brill blue) aluminum lake]
Silenor: 6 mg [contains fd&c blue #1 (brill blue) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Depression: Oral: Administer the total daily dosage in divided or once a day dosage schedule. If the once a day schedule is employed the maximum recommended dose is 150 mg once daily at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not for initiation of treatment.
Insomnia: Oral: Administer within 30 minutes prior to bedtime. Do not take within 3 hours of food (high-fat meals delay peak levels of the tablet formulation).
Oral: Time of administration dependent on indication:
Depression: Administer with food to decrease GI upset.
Insomnia: Administer 1 hour before bedtime (Ref).
Oral concentrate: Dilute dose volume with water, whole or skim milk, or any of the following juices: orange, grapefruit, tomato, prune, or pineapple; in adults, suggested volume to dilute dose is ~120 mL. Do not mix with carbonated beverages (physically incompatible).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Silenor: https://www.silenor.com/Content/pdf/medication-guide.pdf
Antidepressant medications: http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdf
Anxiety (capsule and oral concentrate): Treatment of anxiety.
Bipolar disorder, depressive episode: As an adjunct to antimanic agents in the treatment of depressive episodes associated with bipolar disorder (Ref).
Insomnia, sleep maintenance (tablet only): Treatment of insomnia characterized by difficulty with sleep maintenance.
Major depressive disorder (unipolar), treatment resistant (capsule and oral concentrate): Treatment of depression, including psychotic depression.
Doxepin may be confused with digoxin, doxapram, doxazosin, Doxidan, doxycycline.
SINEquan may be confused with saquinavir, Seroquel, Singulair, Zeniquin (veterinary drug), Zonegran.
Beers Criteria: Doxepin, at a dose >6 mg/day, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its strong anticholinergic properties and potential for sedation and orthostatic hypotension. Of note, the safety profile of low-dose (≤6 mg/day) is comparable to that of placebo. In addition, use TCAs with caution due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2023]).
Deptran [Australia] may be confused with Deralin brand name for propranolol [Australia, Israel].
Doxal [Finland] may be confused with Doxil brand name for doxorubicin (liposomal) [US, Israel].
Doxal brand name for doxepin [Finland] but also brand name for pyridoxine/thiamine [Brazil].
Substrate of CYP1A2 (Minor), CYP2C19 (Minor), CYP2D6 (Minor), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor
Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Adagrasib: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Adagrasib may increase serum concentration of QT-prolonging Antidepressants (Moderate Risk). Management: Consider alternatives to this combination. If combined, monitor for increased antidepressant toxicities including QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
Agents with Clinically Relevant Anticholinergic Effects: May increase anticholinergic effects of Tricyclic Antidepressants. Risk C: Monitor
Alcohol (Ethyl): CNS Depressants may increase CNS depressant effects of Alcohol (Ethyl). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Almotriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Alosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Alpha-/Beta-Agonists: Tricyclic Antidepressants may increase vasopressor effects of Alpha-/Beta-Agonists. Management: Avoid, if possible, the use of alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Risk D: Consider Therapy Modification
Alpha1-Agonists: Tricyclic Antidepressants may increase therapeutic effects of Alpha1-Agonists. Tricyclic Antidepressants may decrease therapeutic effects of Alpha1-Agonists. Risk C: Monitor
Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may decrease therapeutic effects of Alpha2-Agonists (Ophthalmic). Risk C: Monitor
Alpha2-Agonists: Tricyclic Antidepressants may decrease antihypertensive effects of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider Therapy Modification
Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Amifampridine: Agents With Seizure Threshold Lowering Potential may increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amisulpride (Oral): May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk C: Monitor
Amphetamines: Tricyclic Antidepressants may increase adverse/toxic effects of Amphetamines. Tricyclic Antidepressants may potentiate the cardiovascular effects of Amphetamines. Amphetamines may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased cardiovascular effects when these agents are combined. Risk C: Monitor
Antiemetics (5HT3 Antagonists): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Asenapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Baclofen: Tricyclic Antidepressants may increase adverse neuromuscular effects of Baclofen. Baclofen may increase CNS depressant effects of Tricyclic Antidepressants. Risk C: Monitor
Barbiturates: May increase metabolism of Tricyclic Antidepressants. Management: Monitor for decreased efficacy of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. Tricyclic antidepressant dose adjustments are likely required. Risk D: Consider Therapy Modification
Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor
Beta-Acetyldigoxin: Tricyclic Antidepressants may increase arrhythmogenic effects of Beta-Acetyldigoxin. Risk C: Monitor
Beta2-Agonists: Tricyclic Antidepressants may increase adverse/toxic effects of Beta2-Agonists. Risk C: Monitor
Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider Therapy Modification
Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor
Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Brexanolone: CNS Depressants may increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase adverse/toxic effects of Tricyclic Antidepressants. Risk X: Avoid
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
BuPROPion: Tricyclic Antidepressants may increase neuroexcitatory and/or seizure-potentiating effects of BuPROPion. BuPROPion may increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
BusPIRone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
CarBAMazepine: May decrease serum concentration of Tricyclic Antidepressants. Risk C: Monitor
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider Therapy Modification
Chlorphenesin Carbamate: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Chlorprothixene: May increase QTc-prolonging effects of Tricyclic Antidepressants. Risk X: Avoid
Cimetidine: May increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor
Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid
Citalopram: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Citalopram may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Citalopram may increase serum concentration of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Clothiapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification
CloZAPine: QT-prolonging Antidepressants (Moderate Risk) may increase constipating effects of CloZAPine. CloZAPine may increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Consider alternatives to this combination whenever possible. If combined, consider prophylactic laxatives and monitor closely for signs and symptoms of gastrointestinal hypomotility, QTc prolongation, and serotonin syndrome. Risk D: Consider Therapy Modification
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cocaine (Topical): May increase adverse/toxic effects of Tricyclic Antidepressants. Risk C: Monitor
Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Cyclobenzaprine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
CYP2D6 Inhibitors (Moderate): May increase serum concentration of Doxepin (Systemic). Risk C: Monitor
CYP2D6 Inhibitors (Strong): May increase serum concentration of Doxepin (Systemic). Risk C: Monitor
Dabrafenib: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dapoxetine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid
Daridorexant: May increase CNS depressant effects of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor
Desmopressin: Tricyclic Antidepressants may increase hyponatremic effects of Desmopressin. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Dexmethylphenidate-Methylphenidate: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Dextromethorphan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Domperidone: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Domperidone. Risk X: Avoid
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid
Dronedarone: QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Dronedarone. Risk X: Avoid
DroPERidol: May increase CNS depressant effects of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider Therapy Modification
DULoxetine: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations and effects if these agents are combined. Risk C: Monitor
Eletriptan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Encorafenib: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Epinephrine (Racemic): Tricyclic Antidepressants may increase adverse/toxic effects of Epinephrine (Racemic). Risk X: Avoid
Ergot Derivatives: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Escitalopram: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Escitalopram may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Risk C: Monitor
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor
Fexinidazole: QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Fexinidazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider Therapy Modification
Fluorouracil Products: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
FLUoxetine: May increase serotonergic effects of Tricyclic Antidepressants. FLUoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider Therapy Modification
Flupentixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor
FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
FluvoxaMINE: May increase serotonergic effects of Tricyclic Antidepressants. FluvoxaMINE may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepirone: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Gepirone may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Risk C: Monitor
Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Gilteritinib: QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Gilteritinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor
Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid
Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor
Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Guanethidine: Tricyclic Antidepressants may decrease therapeutic effects of Guanethidine. Risk C: Monitor
Haloperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Haloperidol: QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Haloperidol. Haloperidol may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome/serotonin toxicity (SS/ST) or NMS when these agents are combined. Patients with additional risk factors for QTc prolongation or SS/ST may be at even higher risk. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Iloperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Iobenguane Radiopharmaceutical Products: Tricyclic Antidepressants may decrease therapeutic effects of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid
Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider Therapy Modification
Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lasmiditan: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Lemborexant: May increase CNS depressant effects of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider Therapy Modification
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Levoketoconazole: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Levoketoconazole. Risk X: Avoid
Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid
Linezolid: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Lofexidine. QT-prolonging Antidepressants (Moderate Risk) may decrease therapeutic effects of Lofexidine. Management: Consider avoiding this combination when possible. Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Lumateperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Lurasidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Melperone: Tricyclic Antidepressants may increase adverse/toxic effects of Melperone. Melperone may increase adverse/toxic effects of Tricyclic Antidepressants. Melperone may increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metaxalone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methadone: Doxepin-Containing Products may increase QTc-prolonging effects of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider Therapy Modification
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider Therapy Modification
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor
Methylene Blue: Tricyclic Antidepressants may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor
Molindone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nefazodone: Tricyclic Antidepressants may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Nicorandil: Tricyclic Antidepressants may increase hypotensive effects of Nicorandil. Risk C: Monitor
Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents: Tricyclic Antidepressants may increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents. Tricyclic Antidepressants may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Risk C: Monitor
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor
OLANZapine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ondansetron: May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Ondansetron may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome when these agents are combined. Patients with additional risk factors for QTc prolongation or serotonin syndrome may be at even higher risk. Risk C: Monitor
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opipramol: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider Therapy Modification
OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor
OxyCODONE: CNS Depressants may increase CNS depressant effects of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider Therapy Modification
Paliperidone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
PARoxetine: May increase serotonergic effects of Tricyclic Antidepressants. PARoxetine may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider Therapy Modification
Pentamidine (Systemic): May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Pimozide: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Piperaquine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Piperaquine. Risk X: Avoid
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pitolisant: Tricyclic Antidepressants may decrease therapeutic effects of Pitolisant. Risk X: Avoid
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid
Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor
Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor
Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor
QT-prolonging Agents (Highest Risk): May increase QTc-prolonging effects of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider Therapy Modification
QT-prolonging Antidepressants (Moderate Risk): May increase anticholinergic effects of QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may increase CNS depressant effects of QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation, ventricular arrhythmias, and serotonin syndrome when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-Prolonging Inhalational Anesthetics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias, including torsades de pointes when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Risk C: Monitor
QT-prolonging Quinolone Antibiotics (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May increase QTc-prolonging effects of QT-prolonging Antidepressants (Moderate Risk). Risk C: Monitor
Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor
Ramosetron: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Rasagiline: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid
Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid
RisperiDONE: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor
Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider Therapy Modification
ROPINIRole: CNS Depressants may increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Safinamide: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid
Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor
Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider Therapy Modification
Selegiline: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid
Serotonergic Agents (High Risk, Miscellaneous): Tricyclic Antidepressants may increase serotonergic effects of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonergic Non-Opioid CNS Depressants: Tricyclic Antidepressants may increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Non-Opioid CNS Depressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor
Serotonergic Opioids (High Risk): May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider Therapy Modification
Serotonin 5-HT1D Receptor Agonists (Triptans): May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Serotonin/Norepinephrine Reuptake Inhibitor: May increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes when these agents are combined. Risk C: Monitor
Sertindole: May increase QTc-prolonging effects of QT-prolonging Agents (Moderate Risk). Risk X: Avoid
Sertraline: May increase serotonergic effects of Tricyclic Antidepressants. Sertraline may increase serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk C: Monitor
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor
Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid
St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider Therapy Modification
Syrian Rue: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thioridazine: QT-prolonging Agents (Moderate Risk) may increase QTc-prolonging effects of Thioridazine. Risk X: Avoid
Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor
Thiothixene: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor
Thyroid Products: May increase arrhythmogenic effects of Tricyclic Antidepressants. Thyroid Products may increase stimulatory effects of Tricyclic Antidepressants. Risk C: Monitor
Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor
Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid
Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor
Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor
Tricyclic Antidepressants: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tricyclic Antidepressants. Risk C: Monitor
Tricyclic Antidepressants: May increase anticholinergic effects of Tricyclic Antidepressants. Tricyclic Antidepressants may increase CNS depressant effects of Tricyclic Antidepressants. Tricyclic Antidepressants may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor closely for increased TCA adverse effects, including serotonin syndrome/serotonin toxicity, CNS depression, and anticholinergic effects. Risk C: Monitor
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor
Trospium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trospium. Risk C: Monitor
Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valproic Acid and Derivatives: May increase serum concentration of Tricyclic Antidepressants. Risk C: Monitor
Vasopressin: Drugs Suspected of Causing SIADH may increase therapeutic effects of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor
Vilazodone: Tricyclic Antidepressants may increase serotonergic effects of Vilazodone. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor
Vortioxetine: Tricyclic Antidepressants may increase serotonergic effects of Vortioxetine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor
Ziprasidone: May increase serotonergic effects of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. QT-prolonging Antidepressants (Moderate Risk) may increase QTc-prolonging effects of Ziprasidone. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider Therapy Modification
Zolpidem: CNS Depressants may increase CNS depressant effects of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider Therapy Modification
Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor
Zuclopenthixol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Administration with a high-fat meal increases the bioavailability of doxepin tablets and delays the peak plasma concentration by ~3 hours. Management: Tablets should not be taken during or within 3 hours of a meal.
Evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression, anxiety, or bipolar disorder, tricyclic antidepressants are not first-line medications for use prior to conception in patients who are treatment naive or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
Data are lacking on possible fertility effects in humans.
Outcome data following maternal use of tricyclic antidepressants (TCAs), including doxepin, during pregnancy are available (Bérard 2017; Huybrechts 2015; McDonagh 2014; McElhatton 1996). Study outcomes vary due to limited data, differences in study design, and confounders (Gentile 2014; Yonkers 2014). According to the manufacturer, an increased risk of major birth defects or miscarriage has not been observed following maternal use of doxepin during pregnancy.
The pharmacokinetics of doxepin may be influenced by pregnancy. Data are not available to make a recommendation; however, therapeutic drug monitoring of TCAs can be considered during pregnancy and postpartum to avoid toxicity and monitor efficacy (Deligiannidis 2014).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low-birth-weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Anxiety disorders during pregnancy are associated with low-birth-weight, preterm birth, and adverse behavioral outcomes in the offspring. Untreated bipolar disorder is associated with fetal growth restriction, preterm birth, adverse neurodevelopment, and may increase the risk of postpartum psychosis. Discontinuing effective medications during pregnancy increases the risk of relapse. Management of mental health conditions should be made as part of a shared decision-making process (ACOG 2023).
Patients effectively treated for depression, anxiety, or bipolar disorder pre-pregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status (ACOG 2023). TCAs are not considered first-line medications for pregnant patients who are treatment naive or who do not have a history of effective treatment with another medication (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Close monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Encourage pregnant patients 45 years of age and younger with a history of psychiatric illness to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).
Doxepin and N-desmethyldoxepin are present in breast milk.
• The presence of doxepin and N-desmethyldoxepin in breast milk was evaluated in a mother taking doxepin 75 mg/day during pregnancy. The dose was decreased to 35 mg/day by delivery and continued postpartum. Breast milk concentrations of doxepin plus the metabolite were 60 mcg/L on day 11 and 100 mcg/L on days 12 and 13 after delivery (all 3 samples collected 13 to 15 hours after the dose). Authors of the study calculated the estimated infant dose of doxepin via breast milk to be 10 to 20 mcg/kg/day providing a relative infant dose (RID) of 2.5% compared to the weight adjusted maternal dose. Poor sucking and swallowing, hypotonia, and vomiting were reported in the breastfed infant at 9 days of age. Doxepin and the metabolite were below the limit of quantification in the infant plasma. Feeding with breast milk was discontinued at 14 days of age due to persistent drowsiness and vomiting in the infant. Symptoms began to resolve 24 hours after feedings with breast milk were discontinued (Frey 1999).
• Doxepin and N-desmethyldoxepin were present in breast milk and the metabolite was present in the plasma and urine of an 8-week-old fully breastfed infant. Doxepin 10 mg was initiated in the mother 2 weeks postpartum, then increased to 25 mg three times daily, 4 days prior to the study. Breast milk was sampled at random times over 3 days, between 0 and 6 hours after the dose. Average breast milk concentrations were 18 mcg/L (doxepin) and 9 mcg/L (N-desmethyldoxepin). Doxepin concentrations in the infant's serum were 3 mcg/L; the metabolite was present in the infant's serum (highest concentration 66 mcg/L) and urine (39 mcg/L). Authors of the study calculated the estimated infant dose of doxepin via breast milk to be 14 mcg/day and 7 mcg/day for the metabolite, providing a RID of 0.3% compared to the weight adjusted maternal dose. The baby initially presented very pale, limp, and almost not breathing. Resuscitation improved skin coloration but the child remained limp, drowsy, had shallow respiration, and responded to stimuli with a weak cry. Once breastfeeding was discontinued, the infant returned to normal within 24 hours (Matheson 1985).
• Data are available from a lactating mother who was prescribed doxepin 150 mg nightly 30 days postpartum. Breast milk was sampled 8 times ~18 hours after the dose between 7 and 99 days of treatment. Doxepin and N-desmethyldoxepin were present in breast milk. Using mean breast milk concentrations of 60 mcg/L (doxepin) and 111 mcg/L (N-desmethyldoxepin), authors of the study calculated the average estimated infant dose of doxepin via breast milk to be 71 mcg/day and 131 mcg/day of N-desmethyldoxepin, providing a RID of 2.2% compared to the weight adjusted maternal dose (based on actual maternal and infant weight). The metabolite was present in infant plasma sampled after 43 days of maternal treatment. Adverse events were not observed in the breastfeeding infant (Kemp 1985).
• In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Anderson 2021).
Monitor infants exposed to psychotropic medication via breast milk for adverse effects (eg, over sedation, poor feeding) (BAP [McAllister-Williams 2017]).
Due to the potential for serious adverse reactions in the breastfed infant (including excess sedation and respiratory depression), the manufacturer recommends that breastfeeding be discontinued during doxepin therapy. Patients effectively treated for depression with a tricyclic antidepressant during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first-time postpartum. Doxepin is not preferred when first initiating an antidepressant in a patient who is treatment naive and breastfeeding (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]).
ECG, heart rate, and BP (in patients with preexisting cardiac disease or at increased risk for QT-prolonging effects); electrolytes (potassium, magnesium, and sodium concentrations at baseline and as clinically indicated); LFTs (baseline; as clinically indicated); mental alertness; closely monitor all patients for depression, clinical worsening, suicidality, psychosis, or unusual changes in behavior (such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, and social functioning), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); blood glucose (baseline and as clinically indicated); weight and BMI (at baseline; periodic intervals) (APA 2010).
Depression:
Timing of serum samples: Draw trough just before next dose.
Therapeutic reference range: Doxepin plus N-desmethyldoxepin: 50 to 150 ng/mL
Laboratory alert level: 300 ng/mL (Hiemke 2018)
Increases the synaptic concentration of serotonin and norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane (Pinder 1977); antagonizes the histamine (H1) receptor for sleep maintenance.
Efficacy of doxepin in the off-label use of chronic urticaria is believed to be related to its potent H1 and H2 receptor antagonist activity (Kozel 2004).
Onset of action: Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).
Absorption: Tablet: Administration with a high-fat meal increases the bioavailability and delays the peak plasma concentration by ~3 hours.
Distribution: Vd: 20.2 L/kg (Ziegler 1978); tablet: 11,930 L.
Protein binding: ~80%.
Metabolism: Hepatic via CYP2C19 and 2D6; primary metabolite is N-desmethyldoxepin (active).
Bioavailability: 27% (Hiemke 2018).
Half-life elimination: Adults: Doxepin: ~15 hours; N-desmethyldoxepin: 31 to 51 hours (Hiemke 2018).
Time to peak, serum: Fasting: Tablet: 3.5 hours.
Excretion: Urine (<3% as unchanged drug or N-desmethyldoxepin).
Hepatic function impairment: Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.
