What are the side effects and safety considerations of doxepin?

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Doxepin Side Effects and Safety Profile

Doxepin causes anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention), sedation/drowsiness, and orthostatic hypotension as its most common side effects, with cardiovascular effects comparable to other tricyclic antidepressants despite historical beliefs otherwise. 1

Most Common Side Effects

Anticholinergic Effects

  • Dry mouth, blurred vision, constipation, and urinary retention are the predominant anticholinergic side effects 1
  • These effects may subside with continued therapy, but if they become severe, dose reduction is necessary 1
  • Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) can occur, particularly when combined with cimetidine 1
  • Elderly patients are particularly vulnerable to anticholinergic effects and confusion from sedating drugs like doxepin 1

Central Nervous System Effects

  • Drowsiness is the most commonly reported side effect and typically diminishes as therapy continues 1, 2
  • Other CNS effects include confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor 1
  • The sedative properties make doxepin useful for patients with sleep disturbances but require caution regarding daytime functioning 2

Cardiovascular Effects

Critical caveat: Despite longstanding clinical belief that doxepin is safer for the heart, rigorous evidence contradicts this assumption.

  • Cardiovascular effects include hypotension, hypertension, and tachycardia 1
  • Orthostatic hypotension is a significant concern, with one study showing 16% dropout rate due to cardiovascular side effects in cardiac patients 3
  • Doxepin slows cardiac conduction comparably to other tricyclics 3, 4
  • The cardiovascular effects are comparable to imipramine and nortriptyline, offering no greater margin of safety in patients with heart disease 3, 4
  • Intrinsic cardiotoxicity on overdosage is similar to other tricyclic antidepressants 2

Less Common but Serious Side Effects

Hematologic Effects

  • Eosinophilia has been reported occasionally 1
  • Bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura have been reported 1

Allergic Reactions

  • Skin rash, edema, photosensitization, and pruritus occur occasionally 1

Gastrointestinal Effects

  • Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis 1

Endocrine Effects

  • Altered libido (raised or lowered), testicular swelling, gynecomastia in males 1
  • Breast enlargement and galactorrhea in females 1
  • Blood sugar level fluctuations and syndrome of inappropriate antidiuretic hormone secretion 1

Other Notable Effects

  • Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing 1
  • Jaundice, alopecia, headache, exacerbation of asthma 1
  • Angle closure glaucoma, mydriasis, and hyperpyrexia (particularly with chlorpromazine) 1

Critical Drug Interactions and Warnings

MAO Inhibitors

  • Absolute contraindication: Do not use doxepin with or within 14 days of MAO inhibitor therapy due to risk of serious reactions including hyperpyrexia, severe convulsions, and death 1

Alcohol

  • Alcohol potentiates doxepin's effects and increases overdose danger, particularly important in patients who may use alcohol excessively 1

Cimetidine

  • Produces clinically significant fluctuations in tricyclic antidepressant serum levels 1
  • Can cause serious anticholinergic symptoms when initiated in patients on doxepin 1

Tolazamide

  • Severe hypoglycemia reported when doxepin added to tolazamide therapy in diabetic patients 1

Special Population Considerations

Elderly Patients

  • Start at low doses and observe closely due to increased risk of confusion and oversedation 1
  • More likely to have decreased hepatic, renal, or cardiac function requiring cautious dose selection 1
  • In comparative studies, elderly patients experienced fewer total side effects with fluoxetine than doxepin, with doxepin causing more dry mouth, drowsiness/sedation, constipation, and dizziness/lightheadedness 5

Cardiac Patients

  • Doxepin was poorly tolerated in patients with preexisting left ventricular impairment, ventricular arrhythmias, or conduction disease, with 41% overall dropout rate 3
  • Despite historical recommendations, doxepin should not be considered safer than other tricyclics for cardiac patients 3, 4

Withdrawal and Discontinuation

  • Withdrawal symptoms can develop upon abrupt cessation after prolonged administration 1
  • These symptoms are not indicative of addiction 1
  • Gradual withdrawal is recommended to avoid discontinuation symptoms 1

Suicide Risk and Monitoring

  • Close supervision is required during early therapy as suicide risk remains until significant improvement occurs 1
  • Prescriptions should be written for the smallest feasible amount 1

Low-Dose Formulation (1-6 mg for Insomnia)

  • At low doses used for insomnia, doxepin shows minimal adverse effects with sedation/sleepiness and headache at mainly placebo levels 6
  • No signal for tolerance, psychomotor impairment, residual sedation, rebound insomnia, or discontinuation symptoms in trials up to 3 months 6

References

3
Research

Is doxepin a safer tricyclic for the heart?

The Journal of clinical psychiatry, 1991

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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