mixture of cis- and trans-isomers
Systematic (IUPAC) name
Clinical data
Trade names Sinequan, Zonalon
AHFS/ monograph
MedlinePlus a682390
Pregnancy cat. C(AU) Not recommended.
Animal studies have shown embryotoxic properties.
Legal status Prescription only
Routes Oral, IM, IV
Pharmacokinetic data
Bioavailability Absolute: 25%
When main metabolite desmethyldoxepin is included: 31%
Metabolism Hepatic
Half-life Doxepin 17 hours, main metabolite Desmethyldoxepin 51 hours
Excretion Renal
CAS number 1668-19-5 YesY
ATC code N06AA12
PubChem CID 3158
DrugBank APRD00398
ChemSpider 3046 YesY
KEGG D07875 YesY
Chemical data
Formula C19H21NO 
Mol. mass 279.376 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Doxepin (play /ˈdɒksɨpɪn/ dok-sə-pin) is a psychotropic agent with tricyclic antidepressant and anxiolytic properties, known under many brand-names such as Aponal, the original preparation by Boehringer-Mannheim, now part of the Roche group; Adapine, Doxal (Orion), Deptran, Sinquan and Sinequan (Pfizer). As doxepin hydrochloride, it is the active ingredient in cream-based preparations (Zonalon and Xepin) for the treatment of dermatological itch. Doxepin is also used for the treatment of sleep maintenance, and the tradename of doxepin for this indication is Silenor.


Medical uses

Doxepin is used to treat depression, anxiety disorders, and as a second line treatment of chronic idiopathic urticaria.[1]

  • Insomnia[2]
  • low dose doxepin (3 to 6 mg) is an FDA approved use in the treatment of insomnia[3]

Pregnancy and lactation

If Doxepin is used chronically during pregnancy, the newborn may show a withdrawal syndrome with agitation, impaired cardio-respiratory functions, disturbed urination and defecation. Caution should be exerted in treating pregnant women on a regular basis.

Doxepin is found in significant amounts in the milk of lactating women. If therapy is necessary, breastfeeding should be interrupted during treatment. In order to maintain supply, the mother may pump and discard the milk during her treatment.


  • known hypersensitivity to doxepin or other dibenzazepines or other ingredients of the drug
  • acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
  • acute delirium tremens
  • untreated closed angle glaucoma
  • hypertrophy of the prostate with urine retention
  • paralytic ileus
  • hypertrophy of the prostate without urine retention
  • reduced function of the bone marrow
  • organic brain disorders
  • increased risk of seizures, preexisting epilepsy
  • preexisting cardiac damage, particular some arrhythmias (e.g. sinoatrial blockage)
  • other forms of preexisting cardiac damage (other arrhythmias, insufficience)
  • MAOIs of the irreversible type (tranylcypromine among others) : These drugs should normally be stopped at least 2 weeks before therapy with doxepin is started.

Children under 12 years of age should not be treated, because no sufficient clinical experience exists for this group of age.

Tricyclic antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction time, and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, doxepin should be administered with extreme caution to patients with a history of cardiovascular disease, those with circulatory lability, and elderly patients. In such cases, treatment should be initiated with low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels.

Since tricyclic agents are known to reduce the seizure threshold, doxepin should be used with caution in patients with a history of convulsive disorders. Concurrent administration of ECT and doxepin may be hazardous and, therefore, such treatment should be limited to patients for whom it is essential.

Close supervision is required when doxepin is given to hyperthyroid patients or those receiving thyroid medication because of the possibility of cardiovascular toxicity. At doses above 150 mg/day, it may block the antihypertensive effect of guanethidine and related compounds.

Before initiation of treatment a complete and differentiated blood count should be taken. If any value is pathologic, the blood count should be monitored closely under therapy with doxepin. If values are normal, blood counts should be taken during therapy in regular intervals (recommended: weekly during first month of therapy, monthly during the next 2 months, every 3 months afterwards).

Liver-function studies should be performed periodically.

Side effects

  • Central Nervous System : fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side-effects (rarely), abuse in patients with polytoxikomania (rarely), tinnitus
  • Anticholinergic : dry mouth, constipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma
  • Antiadrenergic : hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, av-blockade)
  • Allergic/toxic : skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)
  • Others : frequently increased appetite, weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely).
  • May increase or decrease liver function in some patients.[4]

Suicidal patients

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Doxepin. Perhaps, the decision is made to hospitalize high-risk patients until remission or to prescribe an additional sedating drug like a benzodiazepine or chlorprothixene for 2–4 weeks of initial treatment with Doxepin (until significant remission). At least, the smallest amount of Doxepin should be prescribed at one time to minimize the risk of deliberate overdose.

Drug abuse and dependence

Doxepin has an extremely low potential for abuse and psychological dependence (mostly noted with polytoxicomaniacs, possibly due to the strong anxiolytic action of Doxepin).

Withdrawal symptoms frequently seen when treatment with doxepin is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) can be avoided by reducing the daily dose of Doxepin gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Other remarks

Doxepin may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

With Zonalon and Xepin; in most countries an external form (cream) is available for the treatment of itching skin disease; the effect is probably due to the affinity of doxepin for H1 and H2 receptors and action on muscarinic receptors. Doxepin is the most anxiolytic of all the tricyclic antidepressants.


  • Irreversible MAOIs: agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. potentially fatal. N.B. Treatment-resistant hospitalized patients may be treated concomitantly with an MAO-inhibitor, if they are closely monitored by an expert and the initial dose of both drugs is low.
  • Increased drug actions:
  • other antidepressants, barbiturates, narcotics, sedating antihistaminics, anticonvulsive drugs, alcohol - resulting in increased central depression
  • anticholinergics (antiparkinsonian agents, tri- and tetracyclic antidepressants) - resulting in increased anticholinergic action (dry mouth, obstipation etc.)
  • Cimetidine: impairs the excretion of Doxepin - increased central depression and anticholinergic effects
  • Sympathomimetics (also those used in local anesthetics like Noradrenaline): sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc.)
  • Nitrates and Antihypertensives (e.g. Beta-Blockers) - increased antihypertensive action with pronounced fall in blood pressure
  • Decreased drug actions:
  • Guanethidine, Reserpine, Guanfacine: antihypertensive effects decreased
  • Clonidine: antihypertensive effects decreased and risk of (massive) rebound hypertension.


If overdose is suspected, local poison control centers or emergency departments can provide advice. United States residents can call the US national poison hotline at 1-800-222-1222. Other worldwide poison centers can be found at the World directory of poisons centers.

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.


Doxepin inhibits the reuptake of serotonin and norepinephrine. Its actions of the reuptake of dopamine are negligible. Doxepin also has antagonistic effects at a variety of receptors:


Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology.

See also


  1. ^ "Doxepin". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  2. ^ Hajak G, Rodenbeck A, Voderholzer U et al. (2001). "Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study". J Clin Psychiatry 62 (6): 453–63. doi:10.4088/JCP.v62n0609. PMID 11465523. 
  3. ^ "Phase 3 Data Show New Insomnia Drug, Silenor(R), Effective Without Side Effects". Medical News Today. 2006-04-12. Retrieved 2008-02-01. 
  4. ^ Lippincot"nursing 2007 drug handbook" LWW press. 2007