What are the medication interactions of doxepin?

Doxepin Medication Interactions

Doxepin, a tricyclic antidepressant (TCA), has critical contraindications with MAO inhibitors and requires careful monitoring when combined with other serotonergic drugs, CYP2D6 inhibitors/substrates, CNS depressants, and specific medications that can cause serious adverse effects including serotonin syndrome, hypertensive crisis, and increased sedation.

Critical Contraindications

MAO Inhibitors (Absolute Contraindication)

• MAO inhibitors must be discontinued at least 2 weeks before initiating doxepin due to risk of serious side effects and death 1
• This includes phenelzine, isocarboxazid, moclobemide, isoniazid, and linezolid 2
• The exact washout period varies depending on the specific MAOI, its duration of use, and dosage 1

High-Risk Drug Interactions

Serotonergic Medications (Risk of Serotonin Syndrome)

Combining doxepin with other serotonergic drugs requires extreme caution as it can trigger serotonin syndrome, characterized by mental status changes (confusion, agitation), neuromuscular hyperactivity (tremors, clonus, hyperreflexia), and autonomic hyperactivity (hypertension, tachycardia, diaphoresis) 2. Advanced symptoms include fever, seizures, arrhythmias, and can be fatal 2.

High-risk combinations include:

• SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, sertraline) 2
• SNRIs (desvenlafaxine, duloxetine, venlafaxine) - notably, doxepin significantly inhibits venlafaxine metabolism, increasing plasma concentrations by 57.7-194.4% 3
• Other TCAs 2
• Opioids (tramadol, meperidine, methadone, fentanyl) 2
• Dextromethorphan (cough medications) 2
• Over-the-counter products (St. John's wort, L-tryptophan) 2

When combining non-MAOI serotonergic drugs with doxepin, start at low doses, increase slowly, and monitor intensively for symptoms in the first 24-48 hours after dosage changes 2.

CYP2D6 Interactions

Doxepin is primarily metabolized by CYP2D6, making it highly susceptible to drug interactions 1:

• CYP2D6 inhibitors increase doxepin plasma concentrations, requiring dose reduction 1:

  • Quinidine
  • SSRIs (especially fluoxetine, paroxetine, sertraline) 2, 1
  • Cimetidine (causes clinically significant fluctuations in TCA levels with serious anticholinergic symptoms including severe dry mouth, urinary retention, blurred vision) 1

• Poor metabolizers (7-10% of Caucasians) have 8-fold higher plasma concentrations at usual doses 1

• Monitor TCA plasma levels when co-administering with CYP2D6 inhibitors 1

• Allow at least 5 weeks washout when switching from fluoxetine to doxepin due to long half-life 1

CNS Depressants (Additive Sedation Risk)

Doxepin potentiates the effects of other CNS depressants, increasing risk of oversedation, respiratory depression, and falls 2:

• Alcohol - significantly increases overdose danger and potentiates sedation 1
• Benzodiazepines (lorazepam, midazolam) - additive sedation, particularly dangerous in elderly 2
• Opioids - risk of severe respiratory depression and hypertensive crisis 2, 4
• Antipsychotics - additive anticholinergic and sedative effects 2
• Other sedating medications - cause confusion and oversedation especially in elderly 1

Cardiovascular Medications

• QT-prolonging drugs - doxepin may interact with drugs that prolong QT interval, increasing arrhythmia risk 2
• Anti-arrhythmic drugs (quinidine, procainamide, disopyramide, amiodarone, sotalol) - additive cardiac effects 2
• Beta blockers and calcium channel blockers - additive effects on heart rate when used together 2

Moderate-Risk Interactions

Sympathomimetic Drugs

Risk of hypertensive crisis due to potential MAO inhibition by doxepin metabolites 2:

• Pseudoephedrine, phenylephrine (decongestants)
• Amphetamines
• Midodrine, clonidine
• Albuterol, salmeterol, terbutaline

Metabolic Interactions

• Tolazamide - severe hypoglycemia reported in diabetic patients (case report of patient on tolazamide 1g/day developing severe hypoglycemia 11 days after adding doxepin 75mg/day) 1
• Warfarin - potential for altered anticoagulation 2
• Theophylline - conflicting evidence about interactions 2
• Digoxin - conflicting evidence about interactions 2

Special Populations

Elderly Patients

• Start at low doses due to increased sensitivity to anticholinergic and sedative effects 1
• Higher risk of confusion, oversedation, and falls with sedating drug combinations 2, 1
• More likely to have decreased renal function affecting drug clearance 1

Patients with Comorbidities

• Seizure disorders - use cautiously as TCAs lower seizure threshold 2
• Cardiac disease - monitor for arrhythmias, hypotension, tachycardia 1
• Hepatic/renal impairment - dose adjustment required 1
• Angle-closure glaucoma - doxepin can cause pupillary dilation triggering acute episodes 1

Monitoring Recommendations

When doxepin is combined with interacting medications:

• Monitor plasma TCA levels when co-administering CYP2D6 inhibitors 1
• Observe for serotonin syndrome symptoms in first 24-48 hours after initiating or changing doses 2
• Monitor for excessive sedation, respiratory depression, and falls 2
• Assess for anticholinergic effects (dry mouth, urinary retention, blurred vision, constipation) 1
• Cardiac monitoring for QT prolongation and arrhythmias in high-risk patients 2

Clinical Pearls

• Doxepin inhibits venlafaxine metabolism more significantly than other antidepressants, requiring dose adjustment when combined 3
• Therapeutic drug monitoring is cost-effective for TCAs to ensure minimum effective doses and avoid toxicity 2
• Lower doses (25-50mg/day) may suffice for mild symptoms or when used for sedation rather than full antidepressant effect 2, 1
• Gradual discontinuation is essential to avoid withdrawal symptoms (not indicative of addiction) 1