Side Effects of Sinequan (doxepin)

Sinequan (doxepin) is a tricyclic antidepressant (TCA) used primarily to treat depression and anxiety. 

Depression is an all-pervasive sense of sadness and gloom. In some patients with depression, an imbalance in levels of neurotransmitters in the brain may be the cause of the depression. Neurotransmitters are chemicals that nerves use to communicate with each other. 

Neurotransmitters affected by doxepin include serotonin, norepinephrine, acetylcholine, and histamine. Sinequan may elevate mood by raising the levels of serotonin and norepinephrine. It also blocks the activity of acetylcholine and histamine. The brand name Sinequan is discontinued. 

Common side effects of Sinequan include

• drowsiness,
• blurred vision,
• urinary retention,
• dry mouth,
• constipation,
• weight changes,
• low blood pressure when rising from a sitting position (orthostatic hypotension),
• rash,
• hives,
• rapid or irregular heart rates,
• seizures, and
• hepatitis.

Serious side effects of Sinequan include

• elevated pressure in the eyes of some patients with glaucoma,
• dilated pupils which may trigger an angle closure attack in a patient with angle closure glaucoma, and
• increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depression and other psychiatric disorders.

If antidepressants, including Sinequan, are discontinued abruptly, withdrawal symptoms may include

• dizziness,
• headache,
• nausea, and
• changes in mood.

Drug interactions of Sinequan include monoamine oxidase inhibitors (MAOIs) or other drugs that inhibit monoamine oxidase such as linezolid and intravenous methylene blue. Such combinations may lead to

• confusion,
• high blood pressure,
• tremor,
• hyperactivity,
• coma, and
• death.

Sinequan should not be administered for at least 14 days after stopping.

Drugs that affect heart rhythm such as amiodarone, bepridil, and disopyramide should not be combined with Sinequan since it also affects heart rhythm. Cimetidine increases the breakdown of Sinequan by the liver and can increase Sinequan blood levels, possibly causing side effects from Sinequan. 

There are no adequate studies of Sinequan use in pregnant women. It is unknown if Sinequan is secreted in breast milk. Consult your doctor before breastfeeding.

The most common side effect of doxepin is drowsiness. Drowsiness improves as therapy continues. Other side effects associated with doxepin include:

• blurred vision,
• urinary retention (difficulty urinating),
• dry mouth,
• constipation,
• weight gain or loss,
• low blood pressure when rising from a sitting position (orthostatic hypotension),
• rash,
• hives,
• rapid or irregular heart rates,
• seizures, and
• hepatitis.

Doxepin also can cause elevated pressure in the eyes of some patients withglaucoma. Doxepin may dilate pupils which may trigger an angle closure attack in a patient with angle closure glaucoma.

If antidepressants, including doxepin, are discontinued abruptly, symptoms may include:

• dizziness,
• headache,
• nausea, and
• changes in mood.

Such symptoms of withdrawal may occur even when a few doses of antidepressant are missed. Therefore, it is recommended that the dose of antidepressant be reduced gradually when therapy is discontinued.

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of any antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thinking or behavior, and unusual changes in behavior.

NOTE: Some of the adverse reactions noted below have not been specifically reported with Sinequan use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing Sinequan (doxepin HCl).

Anticholinergic Effects

• Dry mouth, blurred vision, constipation, and urinary retention have been reported. If they do not subside with continued therapy, or become severe, it may be necessary to reduce the dosage.

Central Nervous System Effects

• Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued.
• Other infrequently reported CNS side effects are
  • confusion,
  • disorientation,
  • hallucinations,
  • numbness,
  • paresthesias,
  • ataxia,
  • extrapyramidal symptoms,
  • seizures,
  • tardive dyskinesia, and
  • tremor.

Cardiovascular

• Cardiovascular effects including
  • hypotension,
  • hypertension, and
  • tachycardia have been reported occasionally.

Allergic

• Skin rash, edema, photosensitization, and pruritus have occasionally occurred.

Hematologic

• Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura.

Gastrointestinal

• Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis have been reported. (See Anticholinergic Effects.)

Endocrine

• Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration.

Other

• Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects.

Withdrawal Symptoms

• The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged Sinequan administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms.

Drugs Metabolized by P450 2D6

• The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7–10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available.
• Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses.
• Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
• In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.
• The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.
• The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.
• Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other.
• Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
• Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug.
• Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required.
• It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
• Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly.
• The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated.

MAO Inhibitors

• Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors.
• Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Sinequan.
• The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.

Cimetidine

• Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants.
• Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated.
• Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine.
• In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects.
• Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional Sinequan overdosage. This is especially important in patients who may use alcohol excessively.

Tolazamide

• A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).