ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Doxepin (systemic): Drug information

Doxepin (systemic): Drug information
(For additional information see "Doxepin (systemic): Patient drug information" and see "Doxepin (systemic): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidality and antidepressant drugs:

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.

Brand Names: US
  • Silenor
Brand Names: Canada
  • NOVO-Doxepin;
  • Silenor;
  • SINEquan
Pharmacologic Category
  • Antidepressant, Tricyclic (Tertiary Amine)
Dosing: Adult
Anxiety

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).

Insomnia, sleep maintenance

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, treatment resistant

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: Due to its prolonged half-life (parent and active metabolite), withdrawal symptoms are typically not observed after abrupt discontinuation; however, tapering should still be considered to assess for symptom reoccurrence. When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (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.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

Capsule, concentrate solution: 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: Initial: 3 mg once daily.

Dosing: Older Adult

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.

Dosing: Pediatric

(For additional information see "Doxepin (systemic): Pediatric drug information")

Depression and/or anxiety

Depression and/or anxiety: Oral: Note: Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents; not recommended as first line medication; may be beneficial for patients with comorbid conditions (Ref).

Children 7 to 11 years: Limited data available; efficacy results variable: 1 to 3 mg/kg/day in single or divided doses (Ref).

Children ≥12 years and Adolescents: 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; maximum daily dose: 300 mg/day.

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.

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of doxepin.

Allow 14 days to elapse between discontinuing doxepin and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Use with other MAO inhibitors (such as linezolid or IV methylene blue):

Do not initiate doxepin in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving doxepin and potential benefits outweigh potential risks, discontinue doxepin promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume doxepin 24 hours after the last dose of linezolid or IV methylene blue.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no pediatric-specific recommendations; however, use caution because hepatically metabolized; based on experience in adult patients, dosage adjustment suggested.

Adverse Reactions (Significant): Considerations
Anticholinergic effects

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)

Bleeding risk

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)

Cardiac conduction abnormalities

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)

CNS depression

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)

Fragility fractures

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)

Hyponatremia

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)

Ocular effects

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)

Orthostatic hypotension

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)

Suicidal thinking/behavior

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

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 gradual dose reduction) of an antidepressant treatment that has lasted for >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)

• Prior history of antidepressant withdrawal symptoms (Ref)

• High dose (Ref)

Adverse Reactions

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)

Doxepin (Systemic): Adverse Reaction: Drowsiness

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

Doxepin (Systemic): Adverse Reaction: 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])

Contraindications

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

Warnings/Precautions

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 may be effective for acute treatment of bipolar major depressive episodes, but should 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, definitive drug interactions have not been widely reported in the literature and continuation of TCAs is generally recommended as long as precautions are taken to reduce the significance of any adverse events that may occur. Norepinephrine should be considered the vasopressor of choice for TCA-related hypotension (Pass 2004). Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

Dosage Forms: US

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

Generic Equivalent Available: US

Yes

Pricing: US

Capsules (Doxepin HCl Oral)

10 mg (per each): $0.38 - $0.73

25 mg (per each): $0.47 - $0.96

50 mg (per each): $0.72 - $1.33

75 mg (per each): $1.10 - $1.81

100 mg (per each): $1.20 - $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): $16.30 - $17.25

6 mg (per each): $16.30 - $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.

Dosage Forms: Canada

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, 6 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carm) aluminum lake, fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]

Administration: Adult

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).

Administration: Pediatric

Oral: Depression/anxiety: Administer with food to decrease GI upset.

Medication Guide and/or Vaccine Information Statement (VIS)

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

Use: Labeled Indications

Anxiety (capsule and oral concentrate): Treatment of anxiety.

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 and bipolar depression.

Medication Safety Issues
Sound-alike/look-alike issues:

Doxepin may be confused with digoxin, doxapram, doxazosin, Doxidan, doxycycline.

SINEquan may be confused with saquinavir, Seroquel, Singulair, Zeniquin (veterinary drug), Zonegran.

Older Adult: High-Risk Medication:

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]).

International issues:

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].

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Adagrasib: May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Adagrasib may increase the 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

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Almotriptan: May enhance the serotonergic effect 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 therapy

Alosetron: May enhance the serotonergic effect 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 therapy

Alpha-/Beta-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect 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 enhance the therapeutic effect of Alpha1-Agonists. Tricyclic Antidepressants may diminish the therapeutic effect of Alpha1-Agonists. Risk C: Monitor therapy

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect 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

Alpha2-Agonists (Ophthalmic): Tricyclic Antidepressants may diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic). Risk C: Monitor therapy

Altretamine: May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapy

Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the adverse/toxic effect of Amphetamines. Tricyclic Antidepressants may potentiate the cardiovascular effects of Amphetamines. Amphetamines may enhance the serotonergic effect 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 therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect 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 therapy

ARIPiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Barbiturates: May increase the 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 Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect 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

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brexpiprazole: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Tricyclic Antidepressants. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect 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 enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

BusPIRone: May enhance the serotonergic effect 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 therapy

Cannabinoid-Containing Products: Tricyclic Antidepressants may enhance the tachycardic effect of Cannabinoid-Containing Products. Blood pressure raising effects and drowsiness may also be enhanced. Risk C: Monitor therapy

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination

Citalopram: May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Citalopram may enhance the serotonergic effect of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Citalopram may increase the 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 therapy

Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

CloZAPine: Anticholinergic Agents may enhance the constipating effect 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 enhance the constipating effect of CloZAPine. CloZAPine may enhance the QTc-prolonging effect 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 enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cocaine (Topical): May enhance the adverse/toxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect 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 therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Doxepin (Systemic). Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Doxepin (Systemic). Risk C: Monitor therapy

Dabrafenib: May enhance the QTc-prolonging effect 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 therapy

Dapoxetine: May enhance the serotonergic effect 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 combination

Daridorexant: May enhance the CNS depressant effect 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

Desmopressin: Tricyclic Antidepressants may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect 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 enhance the serotonergic effect 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 therapy

Dextromethorphan: May enhance the serotonergic effect 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 therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. 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

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronedarone: QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DroPERidol: May enhance the CNS depressant effect 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 enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may increase the 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 therapy

Eletriptan: May enhance the serotonergic effect 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 therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Ergot Derivatives: May enhance the serotonergic effect 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 therapy

Escitalopram: May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Escitalopram may enhance the serotonergic effect of QT-prolonging Antidepressants (Moderate Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Fexinidazole: QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect 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 therapy

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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 enhance the QTc-prolonging effect 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 therapy

FLUoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. FLUoxetine may increase the 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 enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

FluvoxaMINE: May enhance the serotonergic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the 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 therapy

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Gilteritinib: QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect 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 therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Guanethidine: Tricyclic Antidepressants may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

Haloperidol: QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Haloperidol may enhance the serotonergic effect 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 therapy

Haloperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of Iloperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: Tricyclic Antidepressants may diminish the therapeutic effect 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 combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 enhance the adverse/toxic effect 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 enhance the adverse/toxic effect 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 (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy

Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lasmiditan: May enhance the serotonergic effect 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 therapy

Lemborexant: May enhance the CNS depressant effect 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

Levoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination

Linezolid: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect of Lofexidine. QT-prolonging Antidepressants (Moderate Risk) may diminish the therapeutic effect 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

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Lorcaserin (Withdrawn From US Market) may increase the 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 therapy

Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metaxalone: May enhance the serotonergic effect 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 therapy

Methadone: Doxepin-Containing Products may enhance the QTc-prolonging effect 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 enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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

Methylene Blue: Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metoclopramide: May enhance the serotonergic effect 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 therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy

Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination

Nefazodone: Tricyclic Antidepressants may enhance the serotonergic effect 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 therapy

Nicorandil: Tricyclic Antidepressants may enhance the hypotensive effect of Nicorandil. Risk C: Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Tricyclic Antidepressants may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Tricyclic Antidepressants may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Ondansetron may enhance the serotonergic effect 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 therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect 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 therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect 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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect 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

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

PARoxetine: May enhance the serotonergic effect of Tricyclic Antidepressants. PARoxetine may increase the 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 enhance the QTc-prolonging effect 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 therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pitolisant: Tricyclic Antidepressants may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect 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 combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect 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 combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect 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 enhance the anticholinergic effect of other QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may enhance the CNS depressant effect of other QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect of other QT-prolonging Antidepressants (Moderate Risk). QT-prolonging Antidepressants (Moderate Risk) may enhance the serotonergic effect of other 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 may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect 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 therapy

QT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect 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 therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect 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 therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect 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 therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Antidepressants (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). Risk C: Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect 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 therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Risk C: Monitor therapy

QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ramosetron: May enhance the serotonergic effect 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 therapy

Rasagiline: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination

RisperiDONE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of RisperiDONE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Safinamide: May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination

Secretin: Anticholinergic Agents may diminish the therapeutic effect 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 enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Risk X: Avoid combination

Serotonergic Agents (High Risk, Miscellaneous): Tricyclic Antidepressants may enhance the serotonergic effect 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 therapy

Serotonergic Non-Opioid CNS Depressants: Tricyclic Antidepressants may enhance the CNS depressant effect of Serotonergic Non-Opioid CNS Depressants. Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. 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 CNS depression when these agents are combined. Risk C: Monitor therapy

Serotonergic Opioids (High Risk): Tricyclic Antidepressants may enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. 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 enhance the serotonergic effect 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 therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the serotonergic effect 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 therapy

Sertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Sertraline: May enhance the serotonergic effect of Tricyclic Antidepressants. Sertraline may increase the 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 therapy

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect 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 therapy

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the 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 therapy

Sulpiride: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect 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 enhance the serotonergic effect 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 therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Thioridazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thioridazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Thyroid Products: May enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the anticholinergic effect of other Tricyclic Antidepressants. Tricyclic Antidepressants may enhance the CNS depressant effect of other Tricyclic Antidepressants. Tricyclic Antidepressants may enhance the serotonergic effect of other 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 therapy

Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valproate Products: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy

Vilazodone: Tricyclic Antidepressants may enhance the serotonergic effect 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 therapy

Vortioxetine: Tricyclic Antidepressants may enhance the serotonergic effect 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 therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect 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 Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Zuclopenthixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Zuranolone: May enhance the CNS depressant effect 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

Food Interactions

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.

Reproductive Considerations

If treatment for major depressive disorder (MDD) is initiated for the first time in a patient who may become pregnant, agents other than doxepin are recommended. Doxepin is not preferred for the treatment of MDD in patients planning to become pregnant due to limited outcome information following maternal use during pregnancy (Larsen 2015).

Data are lacking on possible fertility effects in humans.

Pregnancy Considerations

According to the manufacturer, an increased risk of major birth defects or miscarriage has not been observed following maternal use of doxepin during pregnancy. However, data are limited (Larsen 2015).

Adverse effects in the newborn following doxepin exposure late in the third trimester include apnea, constant crying, cyanosis, feeding difficulty, hyperreflexia, hypotonia, hypoglycemia, irritability, jitteriness, respiratory distress, seizures, temperature instability, tremor, and vomiting. Prolonged hospitalization, respiratory support, or tube feedings may be required. Paralytic ileus has also been reported in one neonate following in utero exposure to doxepin. The long-term effects of in utero tricyclic antidepressant (TCA) exposure on infant neurodevelopment and behavior are not known (Larsen 2015).

Untreated or inadequately treated psychiatric illness may lead to poor compliance with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]).

If treatment for major depressive disorder is initiated for the first time during pregnancy, agents other than doxepin are recommended (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]). If pregnancy occurs during treatment with a TCA, maternal plasma monitoring is recommended (Larsen 2015).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants. Pregnant patients 18 to 45 years of age or their health care providers may contact the registry by calling 1-844-405-6185. Enrollment should be done as early in pregnancy as possible.

Breastfeeding Considerations

Doxepin and N-desmethyldoxepin are present in breast milk (Frey 1999; Kemp 1985).

Drowsiness, vomiting, poor feeding, and muscle hypotonia were noted in a breastfeeding infant following maternal use of doxepin. Symptoms began to resolve 24 hours after feedings with breast milk were discontinued (Frey 1999). In addition, product labeling notes that drowsiness and apnea have been reported in a breastfeeding infant following maternal use of doxepin for depression.

Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; however, antidepressant medication is recommended when psychotherapy is not an option or when symptoms are moderate to severe. If a specific tricyclic antidepressant was used effectively during pregnancy, it can be continued while breastfeeding if no contraindications exist (ABM [Sriraman 2015]). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends that breastfeeding be discontinued during therapy.

Due to significant adverse events associated with exposure via breast milk, agents other than doxepin are recommended when first initiating an antidepressant in a patient who is breastfeeding (CANMAT [MacQueen 2016]); Larsen 2015). Infants exposed to psychotropic medication via breast milk should be monitored for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]).

Monitoring Parameters

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).

Reference Range

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)

Mechanism of Action

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).

Pharmacokinetics (Adult Data Unless Noted)

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).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Hepatic function impairment: Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Sinequan;
  • (AR) Argentina: Insolid;
  • (AT) Austria: Sinequan;
  • (AU) Australia: Deptran | Sinequan;
  • (BD) Bangladesh: Adnor;
  • (BE) Belgium: Quitaxon | Sinequan;
  • (CH) Switzerland: Sinquan;
  • (CN) China: Doxepin;
  • (CO) Colombia: Expan;
  • (DE) Germany: Aponal | Doneurin | Doxe | Doxepia | Doxepin | Doxepin 1 a pharma | Doxepin azu | Doxepin ratiopharm | Espadox | Mareen | Sinequan | Sinquan;
  • (EE) Estonia: Sinequan;
  • (ES) Spain: Sinequan;
  • (FI) Finland: Doxal | Doxedyn | Sinequan;
  • (FR) France: Quitaxon | Sinequan;
  • (GB) United Kingdom: Doxepin | Doxepin HCL | Sinepin | Sinequan;
  • (GR) Greece: Sinequan;
  • (HK) Hong Kong: Qualiquan | Sinequan;
  • (IE) Ireland: Doxepin | Sinequan;
  • (IL) Israel: Gilex;
  • (IN) India: Dox | Doxedep | Doxin | Doxyril | Somaron | Spectra | Xeprich;
  • (KR) Korea, Republic of: Doxe | Doxecan | Myungcephin | Richnight | Silenor | Sileone | Sinequan | Sleepin | Slipin;
  • (LB) Lebanon: Doxepin;
  • (LT) Lithuania: Doxepin | Doxepin dura | Doxepin Neuraxpharm | Sinequan;
  • (LU) Luxembourg: Aponal | Sinequan;
  • (LV) Latvia: Doxepin | Sinequan;
  • (MX) Mexico: Sinequan;
  • (NL) Netherlands: Sinequan;
  • (NO) Norway: Doxepin teva | Sinequan | Sinquan;
  • (NZ) New Zealand: Anten | Deptran | Sinequan;
  • (PL) Poland: Doxepin | Poldoxin | Sinequan;
  • (PR) Puerto Rico: Doxepin | Doxepin HCL | Silenor | Sinequan;
  • (PT) Portugal: Quitaxon;
  • (RO) Romania: Doxepin;
  • (RU) Russian Federation: Sinequan;
  • (SA) Saudi Arabia: Apo-doxepin;
  • (SI) Slovenia: Sinequan;
  • (TH) Thailand: Sinequan;
  • (TN) Tunisia: Sinequan;
  • (TR) Turkey: Sinequan;
  • (TW) Taiwan: Colian | Doxepin | Hywen | Peaso | Quitaxon | Sinequan;
  • (UA) Ukraine: Doxepin | Doxepinum
  1. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372 [PubMed 37139824]
  2. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001-1020. [PubMed 18378767]
  3. American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Published October 2010. Accessed October 12, 2022. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
  4. Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry. 2010;71(12):1565-1575. doi:10.4088/JCP.09r05786blu [PubMed 21190637]
  5. Asberg M, Germanis M. Ophthalmological effects of nortriptyline--relationship to plasma level. Pharmacology. 1972;7(5):349-356. doi:10.1159/000136309 [PubMed 4566251]
  6. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. doi:10.1177/0269881114525674 [PubMed 24713617]
  7. Bandelow B, Sher L, Bunevicius R, et al; WFSBP Task Force on Mental Disorders in Primary Care; WFSBP Task Force on Anxiety Disorders, OCD and PTSD. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care [published corrections appear in Int J Psychiatry Clin Pract. 2012;16(3):242. Int J Psychiatry Clin Pract. 2013;17(1):76]. Int J Psychiatry Clin Pract. 2012;16(2):77-84. doi:10.3109/13651501.2012.667114 [PubMed 22540422]
  8. Bauer M, Pfennig A, Severus E, et al; World Federation of Societies of Biological Psychiatry Task Force on Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World J Biol Psychiatry. 2013;14(5):334-385. [PubMed 23879318]
  9. Bauer M, Severus E, Köhler S, Whybrow PC, Angst J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Unipolar Depressive Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders. Part 2: maintenance treatment of major depressive disorder – update 2015. World J Biol Psychiatry. 2015;16(2):76-95. doi:10.3109/15622975.2014.1001786 [PubMed 25677972]
  10. Bauer M, Whybrow PC, Anst J, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World J Biol Psychiatry. 2002;3(2):69-86. [PubMed 12479080]
  11. Biringer E, Rongve A, Lund A. A review of modern antidepressants' effects on neurocognitive function. Current Psychiatry Reviews. 2009;5(3):164-174. doi:10.2174/157340009788971137
  12. Birmaher B, Brent D, AACAP Work Group on Quality Issues, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-1526. [PubMed 18049300]
  13. Bixby AL, VandenBerg A, Bostwick JR. Clinical management of bleeding risk with antidepressants. Ann Pharmacother. 2019;53(2):186-194. doi:10.1177/1060028018794005 [PubMed 30081645]
  14. Briggs R, Carey D, McNicholas T, et al. The association between antidepressant use and orthostatic hypotension in older people: a matched cohort study. J Am Soc Hypertens. 2018;12(8):597-604.e1. doi:10.1016/j.jash.2018.06.002 [PubMed 29937420]
  15. Campleman SL, Brent J, Pizon AF, et al. Drug-specific risk of severe QT prolongation following acute drug overdose. Clin Toxicol (Phila). 2020;58(12):1326-1334. doi:10.1080/15563650.2020.1746330 [PubMed 32252558]
  16. Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85(5):270-288. doi:10.1159/000447034 [PubMed 27508501]
  17. Chew ML, Mulsant BH, Pollock BG, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56(7):1333-1341. doi:10.1111/j.1532-5415.2008.01737.x [PubMed 18510583]
  18. Christensen P, Thomsen HY, Pedersen OL, et al. Cardiovascular effects of amitriptyline in the treatment of elderly depressed patients. Psychopharmacology (Berl). 1985;87(2):212-215. doi:10.1007/BF00431810 [PubMed 3931149]
  19. Costagliola C, Parmeggiani F, Semeraro F, Sebastiani A. Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. Curr Neuropharmacol. 2008;6(4):293-310. doi:10.2174/157015908787386104 [PubMed 19587851]
  20. De Picker L, Van Den Eede F, Dumont G, et al. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014;55(6):536-547. doi:10.1016/j.psym.2014.01.010 [PubMed 25262043]
  21. Dhippayom T, Chaiyakunapruk N, Jongchansittho T. Safety of nortriptyline at equivalent therapeutic doses for smoking cessation: a systematic review and meta-analysis. Drug Saf. 2011;34(3):199-210. doi:10.2165/11585950-000000000-00000 [PubMed 21332244]
  22. Dilsaver SC. Withdrawal phenomena associated with antidepressant and antipsychotic agents. Drug Saf. 1994;10(2):103-114. doi:10.2165/00002018-199410020-00002 [PubMed 7912078]
  23. Dopheide JA, "Recognizing and Treating Depression in Children and Adolescents," Am J Health Syst Pharm, 2006, 63(3):233-43. [PubMed 16434782]
  24. Doxepin hydrochloride capsules, USP [prescribing information]. Bedminster, NJ: Alembic Pharmaceuticals Inc; September 2021.
  25. Doxepin hydrochloride solution, concentrate [prescribing information]. Philadelphia, PA: Lannett Company Inc; March 2020.
  26. Fava M. Prospective studies of adverse events related to antidepressant discontinuation. J Clin Psychiatry. 2006;67(Suppl 4):14-21. [PubMed 16683858]
  27. Frey OR, Scheidt P, von Brenndorff AI. Adverse effects in a newborn infant breast-fed by a mother treated with doxepin. Ann Pharmacother. 1999;33(6):690-693. [PubMed 10410181]
  28. Friedman RA, Leon AC. Expanding the black box - depression, antidepressants, and the risk of suicide. N Engl J Med. 2007;356(23):2343-2346. doi:10.1056/NEJMp078015 [PubMed 17485726]
  29. Gal P, Reed M. Medications. In: Kliegman RM, Behrman RE, Jenson HB, et al, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders Elsevier; 2007: 2955-2999.
  30. Geller B, Cooper TB, Carr LG, Warham JE, Rodriguez A. Prospective study of scheduled withdrawal from nortriptyline in children and adolescents. J Clin Psychopharmacol. 1987;7(4):252-254. [PubMed 3624507]
  31. Georgotas A, McCue RE, Friedman E, Cooper TB. A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients. J Clin Psychopharmacol. 1987;7(6):413-416. [PubMed 3323263]
  32. Gibbons RD, Brown CH, Hur K, Davis J, Mann JJ. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):580-587. doi:10.1001/archgenpsychiatry.2011.2048 [PubMed 22309973]
  33. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363. doi:10.1176/appi.ajp.2007.07030454 [PubMed 17728420]
  34. Glassman AH, Preud'homme XA. Review of the cardiovascular effects of heterocyclic antidepressants. J Clin Psychiatry. 1993;54 suppl:16-22. [PubMed 8444830]
  35. Grunze H, Vieta E, Goodwin GM, et al; Members of the WFSBP Task Force on Bipolar Affective Disorders working on this topic. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: Acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2-58. doi:10.1080/15622975.2017.1384850 [PubMed 29098925]
  36. Haddad PM. Antidepressant discontinuation syndromes. Drug Saf. 2001;24(3):183-197. [PubMed 11347722]
  37. Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci. 2007;9(1):47-59. doi:10.31887/DCNS.2007.9.1/dhalperin [PubMed 17506225]
  38. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. doi:10.1001/archpsyc.63.3.332 [PubMed 16520440]
  39. Hawton K, Bergen H, Simkin S, et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry. 2010;196(5):354-358. doi:10.1192/bjp.bp.109.070219 [PubMed 20435959]
  40. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11(11):CD004851. doi:10.1002/14651858.CD004851.pub3 [PubMed 23152227]
  41. Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018;51(1-02):9-62. doi:10.1055/s-0043-116492 [PubMed 28910830]
  42. Hirsch M, Birnbaum RJ. Discontinuing antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 12, 2022.
  43. Hirsch M, Birnbaum RJ. Switching antidepressant medications in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 9, 2021.
  44. Hirsch M, Birnbaum RJ. Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 10, 2023.
  45. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622. doi:10.1345/aph.1G293 [PubMed 16896026]
  46. Jha MK, Rush AJ, Trivedi MH. When discontinuing SSRI antidepressants is a challenge: management tips. Am J Psychiatry. 2018;175(12):1176-1184. doi:10.1176/appi.ajp.2018.18060692 [PubMed 30501420]
  47. Katzman MA, Bleau P, Blier P, et al; Canadian Anxiety Guidelines Initiative Group. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(suppl 1):S1. doi:10.1186/1471-244X-14-S1-S1 [PubMed 25081580]
  48. Kemp J, Ilett KF, Booth J, et al. Excretion of doxepin and N-desmethyldoxepin in human milk. Br J Clin Pharmacol. 1985;20(5):497-499. [PubMed 4074620]
  49. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry. 2003;160(4):790-792. doi:10.1176/appi.ajp.160.4.790 [PubMed 12668373]
  50. Kirkham J, Seitz D. Evidence of ocular side effects of SSRIs and new warnings. Evid Based Ment Health. 2017;20(1):27. doi:10.1136/eb-2016-102528 [PubMed 27993931]
  51. Knegtering H, Eijck M, Huijsman A. Effects of antidepressants on cognitive functioning of elderly patients. A review. Drugs Aging. 1994;5(3):192-199. doi:10.2165/00002512-199405030-00005 [PubMed 7803947]
  52. Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current and future treatment options. Drugs. 2004;64(22):2515-2536. [PubMed 15516152]
  53. Krystal AD, Richelson E, Roth T. Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. Sleep Med Rev. 2013;17(4):263-272. doi:10.1016/j.smrv.2012.08.001 [PubMed 23357028]
  54. Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183(16):1835-1843. doi:10.1503/cmaj.100912 [PubMed 21948719]
  55. Larsen ER, Damkier P, Pedersen LH, et al; Danish Psychiatric Society; Danish Society of Obstetrics and Gynecology; Danish Paediatric Society; Danish Society of Clinical Pharmacology. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28. doi:10.1111/acps.12479 [PubMed 26344706]
  56. Leon AC. The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses. Am J Psychiatry. 2007;164(12):1786-1789. doi:10.1176/appi.ajp.2007.07050775 [PubMed 18056231]
  57. Lewis JD, Strom BL, Localio AR, et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf. 2008;17(4):328-335. doi:10.1002/pds.1546 [PubMed 18188866]
  58. Lien YH. Antidepressants and hyponatremia. Am J Med. 2018;131(1):7-8. doi:10.1016/j.amjmed.2017.09.002 [PubMed 28923523]
  59. MacQueen GM, Frey BN, Ismail Z, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 6. Special populations: youth, women, and the elderly. Can J Psychiatry. 2016;61(9):588‐603. doi:10.1177/0706743716659276 [PubMed 27486149]
  60. Mannesse CK, Jansen PA, Van Marum RJ, et al. Characteristics, prevalence, risk factors, and underlying mechanism of hyponatremia in elderly patients treated with antidepressants: a cross-sectional study. Maturitas. 2013;76(4):357-363. doi:10.1016/j.maturitas.2013.08.010 [PubMed 24094459]
  61. Mansbach RS, Ludington E, Rogowski R, Kittrelle JP, Jochelson P. A placebo- and active-controlled assessment of 6- and 50-mg oral doxepin on cardiac repolarization in healthy volunteers: a thorough QT evaluation. Clin Ther. 2011;33(7):851-862. doi:10.1016/j.clinthera.2011.05.092 [PubMed 21722958]
  62. Masaki KH, Schatz IJ, Burchfiel CM, et al. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation. 1998;98(21):2290-2295. doi:10.1161/01.cir.98.21.2290 [PubMed 9826316]
  63. Matheson E, Hainer BL. Insomnia: pharmacologic therapy. Am Fam Physician. 2017;96(1):29-35. [PubMed 28671376]
  64. Mauri MC, Fiorentini A, Paletta S, Altamura AC. Pharmacokinetics of antidepressants in patients with hepatic impairment. Clin Pharmacokinet. 2014;53(12):1069-1081. doi:10.1007/s40262-014-0187-5 [PubMed 25248846]
  65. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther. 2014;40(8):880-892. doi:10.1111/apt.12925 [PubMed 25175904]
  66. National Collaborating Centre for Mental Health (NCCMH). Depression: The treatment and management of depression in adults (updated edition). National Institute for Health & Clinical Excellence (NICE). 2010. [PubMed 22132433]
  67. Neshkes RE, Gerner R, Jarvik LF, et al. Orthostatic effect of imipramine and doxepin in depressed geriatric outpatients. J Clin Psychopharmacol. 1985;5(2):102-106. doi:10.1097/00004714-198504000-00009 [PubMed 3988967]
  68. Ogle NR, Akkerman SR. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract. 2013;26(4):389-396. doi:10.1177/0897190012467210 [PubMed 23459282]
  69. Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home residents. Am J Med. 2000;108(2):106-111. doi:10.1016/s0002-9343(99)00425-8 [PubMed 11126303]
  70. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des. 2004;10(20):2463-2475. doi:10.2174/1381612043383872 [PubMed 15320756]
  71. Page RL 2nd, O'Bryant CL, Cheng D, et al; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(6):e32-e69. [PubMed 27400984]
  72. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol. 2006;26(1):56-60. doi:10.1097/01.jcp.0000195042.62724.76 [PubMed 16415707]
  73. Pass SE, Simpson RW. Discontinuation and Reinstitution of Medications During the Perioperative Period. Am J Health Syst Pharm. 2004, 61(9):899-912. [PubMed 15156966]
  74. Patterson JF. Psychosis after discontinuation of nortriptyline. J Clin Psychopharmacol. 1984;4(2):117-118. [PubMed 6707238]
  75. Pinder RM, Brogden RN, Speight TM, Avery GS. Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Drugs. 1977;13(3):161-218. [PubMed 321205]
  76. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-158. doi:10.4088/jcp.v66n0201 [PubMed 15704999]
  77. Preskorn SH, Jerkovich GS. Central nervous system toxicity of tricyclic antidepressants: phenomenology, course, risk factors, and role of therapeutic drug monitoring. J Clin Psychopharmacol. 1990;10(2):88-95. doi:10.1097/00004714-199004000-00003 [PubMed 2140373]
  78. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133. doi:10.7326/M15-2175 [PubMed 27136449]
  79. Rabenda V, Nicolet D, Beaudart C, et al. Relationship between use of antidepressants and risk of fractures: a meta-analysis. Osteoporos Int. 2013;24(1):121-137. [PubMed 22638709]
  80. Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther. 2004;75(3):234-241. doi:10.1016/j.clpt.2003.09.019 [PubMed 15001975]
  81. Reeves RR, Brister JC. Serious suicide attempt with duloxetine treatment. South Med J. 2008;101(7):769. doi:10.1097/SMJ.0b013e318177872f [PubMed 19209119]
  82. Refer to manufacturer's labeling.
  83. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24(6):501-526. doi:10.2165/11533180-000000000-00000 [PubMed 20443647]
  84. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167(2):188-194. doi:10.1001/archinte.167.2.188 [PubMed 17242321]
  85. Riedel WJ, van Praag HM. Avoiding and managing anticholinergic effects of antidepressants. CNS Drugs. 1995;3(4):245-259. doi:10.2165/00023210-199503040-00002
  86. Rizzoli R, Cooper C, Reginster JY, et al. Antidepressant medications and osteoporosis. Bone. 2012;51(3):606-613. [PubMed 22659406]
  87. Rollman BL, Block MR, Schulberg HC. Symptoms of major depression and tricyclic side effects in primary care patients. J Gen Intern Med. 1997;12(5):284-291. doi:10.1046/j.1525-1497.1997.012005284.x [PubMed 9159697]
  88. Roos JC. Cardiac effects of antidepressant drugs. A comparison of the tricyclic antidepressants and fluvoxamine. Br J Clin Pharmacol. 1983;15(suppl 3):439S-445S. doi:10.1111/j.1365-2125.1983.tb02135.x [PubMed 6407505]
  89. Roy-Byrne PP. Management of psychiatric disorders in patients with cancer. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 10, 2023.
  90. Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension. 1992;19(6 pt 1):508-519. doi:10.1161/01.hyp.19.6.508 [PubMed 1592445]
  91. Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(2):209-220. doi:10.1111/bcp.12617 [PubMed 25735839]
  92. Sabah KMN, Chowdhury AW, Islam MS, Saha BP, Kabir SR, Kawser S. Amitriptyline-induced ventricular tachycardia: a case report. BMC Res Notes. 2017;10(1):286. doi:10.1186/s13104-017-2615-8 [PubMed 28709467]
  93. Salem RB, Fischer RG, Beghé C. Acute stomatitis associated with doxepin therapy. Drug Intell Clin Pharm. 1981;15(12):992-993. doi:10.1177/106002808101501214 [PubMed 7338196]
  94. Santos AB Jr, Mccurdy L. Delirium after abrupt withdrawal from doxepin: case report. Am J Psychiatry. 1980;137(2):239-240. doi:10.1176/ajp.137.2.239 [PubMed 7352585]
  95. Schatzberg AF, Blier P, Delgado PL, et al. Antidepressant discontinuation syndrome: consensus panel recommendations for clinical management and additional research. J Clin Psychiatry. 2006;67(Suppl 4):27-30. [PubMed 16683860]
  96. Shelton RC. Steps following attainment of remission: discontinuation of antidepressant therapy. Prim Care Companion J Clin Psychiatry. 2001;3(4):168-174. doi:10.4088/pcc.v03n0404 [PubMed 15014601]
  97. Silenor (doxepin) [prescribing information]. Brentwood, TN: Currax Pharmaceuticals LLC; December 2022.
  98. Sinequan (doxepin) [prescribing information]. New York, NY: Pfizer; July 2014.
  99. Sinequan (doxepin) [product monograph]. Vaughan, Ontario, Canada: AA Pharma Inc; August 2018.
  100. Sriraman NK, Melvin K, Meltzer-Brody S. ABM clinical protocol #18: use of antidepressants in breastfeeding mothers. Breastfeed Med. 2015;10(6):290-299. doi:10.1089/bfm.2015.29002 [PubMed 26204124]
  101. Strömberg C, Seppälä T, Mattila MJ. Acute effects of maprotiline, doxepin and zimeldine with alcohol in healthy volunteers. Arch Int Pharmacodyn Ther. 1988;291:217-228. [PubMed 2966613]
  102. Szanto K, Mulsant BH, Houck PR, et al. Emergence, persistence, and resolution of suicidal ideation during treatment of depression in old age. J Affect Disord. 2007;98(1-2):153-161. doi:10.1016/j.jad.2006.07.015 [PubMed 16934334]
  103. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353. doi:10.4088/jcp.07m03780 [PubMed 19254516]
  104. Tamblyn R, Bates DW, Buckeridge DL, et al. Multinational investigation of fracture risk with antidepressant use by class, drug, and indication. J Am Geriatr Soc. 2020;68(7):1494-1503. doi:10.1111/jgs.16404 [PubMed 32181493]
  105. Teicher MH, Glod CA, Cole JO. Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf. 1993;8(3):186-212. doi:10.2165/00002018-199308030-00002 [PubMed 8452661]
  106. Tisdale JE, Chung MK, Campbell KB, et al. Drug-induced arrhythmias: a scientific statement from the American Heart Association. Circulation. 2020;142(15):e214-e233. doi:10.1161/CIR.0000000000000905 [PubMed 32929996]
  107. van Eijk ME, Avorn J, Porsius AJ, de Boer A. Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing. BMJ. 2001;322(7287):654-657. doi:10.1136/bmj.322.7287.654 [PubMed 11250852]
  108. van Geffen EC, Hugtenburg JG, Heerdink ER, van Hulten RP, Egberts AC. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. Eur J Clin Pharmacol. 2005;61(4):303-307. doi:10.1007/s00228-005-0921-x [PubMed 15906018]
  109. Vestergaard P, Rejnmark L, Mosekilde L. Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int. 2008;82(2):92-101. doi:10.1007/s00223-007-9099-9 [PubMed 18219438]
  110. Wadhwa R, Kumar M, Talegaonkar S, Vohora D. Serotonin reuptake inhibitors and bone health: a review of clinical studies and plausible mechanisms. Osteoporos Sarcopenia. 2017;3(2):75-81. doi:10.1016/j.afos.2017.05.002 [PubMed 30775508]
  111. Wagner KD. Pharmacotherapy for Major Depression in Children and Adolescents. Prog Neuropsychopharmacol Biol Psychiatry. 2005, 29(5):819-826. [PubMed 15908090]
  112. Waring WS. Clinical use of antidepressant therapy and associated cardiovascular risk. Drug Healthc Patient Saf. 2012;4:93-101. doi:10.2147/DHPS.S28804 [PubMed 22936860]
  113. Warner CH, Bobo W, Warner C, Reid S, Rachal J. Antidepressant discontinuation syndrome. Am Fam Physician. 2006;74(3):449-456. [PubMed 16913164]
  114. Wilens TE, Biederman J, Baldessarini RJ, et al. Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1491-1501. doi:10.1097/00004583-199611000-00018 [PubMed 8936916]
  115. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609 [PubMed 29536616]
  116. Ziegler VE, Biggs JT, Wylie LT, Rosen SH, Hawf DJ, Coryell WH. Doxepin kinetics. Clin Pharmacol Ther. 1978;23(5):573-579. [PubMed 639432]
  117. Zimmermann-Viehoff F, Kuehl LK, Danker-Hopfe H, Whooley MA, Otte C. Antidepressants, autonomic function and mortality in patients with coronary heart disease: data from the Heart and Soul Study. Psychol Med. 2014;44(14):2975-2984. doi:10.1017/S003329171400066X [PubMed 25065442]
Topic 9112 Version 609.0

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟