doxepin (systemic)

Absorption: Well absorbed from the GI tract, although much is metabolized on first pass through the liver.

Distribution: Widely distributed to tissues.

Metabolism/Excretion: Metabolized by the liver by the CYP2C19 and CYP2D6 isoenzymes; the CYP2C19 isoenzyme exhibits genetic polymorphism; 15–20% of Asian patients and 3–5% of White and Black patients may be poor metabolizers of CYP2C19 and may have significantly ↑ doxepin concentrations and an ↑ risk of adverse effects; the CYP2D6 isoenzyme also exhibits genetic polymorphism; ∼7% of population may be poor metabolizers of CYP2D6 and may have significantly ↑ doxepin concentrations and an ↑ risk of adverse effects. Some conversion to active antidepressant compound. May re-enter gastric juice via secretion from enterohepatic circulation, where more absorption may occur.

Half-Life: 8–25 hr.

Time/Action Profile ⬆ ⬇

(antidepressant activity)

ROUTE	ONSET	PEAK	DURATION
PO	2–3 wk	up to 6 wk	days–weeks

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Concurrent use of MAO inhibitors;
Some products contain bisulfites and should be avoided in patients with known intolerance;
Untreated angle-closure glaucoma;
Severe urinary retention;
QT interval prolongation, HF, cardiac arrhythmia or recent history of MI;
Lactation: Lactation.

Use Cautiously in:

May ↑ risk of suicide attempt/ideation especially during early treatment or dose adjustment; this risk appears to be greater in adolescents or children
;
Pre-existing cardiovascular disease (↑ risk of adverse reactions);
Prostatic enlargement (more susceptible to urinary retention);
Seizures;
OB: Neonates exposed during late 3rd trimester at ↑ risk for complications at birth (prolonged hospitalization, respiratory support, tube feeding); use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Safety and effectiveness not established in children;
Geri: Appears on Beers list. ↑ risk of adverse reactions in older adults, including falls secondary to sedative and anticholinergic effects and orthostatic hypotension. Avoid use of dose >6 mg/day in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension, arrhythmias

Derm: photosensitivity, rash

EENT: blurred vision, ↑intraocular pressure

GI: constipation, dry mouth, hepatitis, nausea, paralytic ileus

GU: ↓libido, urinary retention

Hemat: blood dyscrasias

Metab: ↑appetite, weight gain

Neuro: fatigue, sedation, agitation, confusion, hallucinations, SUICIDAL THOUGHTS/BEHAVIORS

Misc: hypersensitivity reactions

Interactions ⬆ ⬇

Drug-drug:

CYP2D6 inhibitors, including cimetidine, quinidine, amiodarone, and ritonavir, may ↑ levels and risk of toxicity.
May cause hypotension, tachycardia, and potentially fatal reactions when used with MAO inhibitors; avoid concurrent use; discontinue 2 wk prior to doxepin.
Concurrent use with SSRIs may ↑ risk of serotonin syndrome; avoid concurrent use (fluoxetine should be stopped 5 wk before).
Clonidine may ↑ risk of hypertensive crisis and should be avoided.
Concurrent use with levodopa may delay/↓ absorption of levodopa or ↑ risk of hypertension.
Rifamycins may ↓ levels and effectiveness.
↑risk of CNS depression with other CNS depressants, including alcohol, antihistamines, clonidine, opioid analgesics, and sedative/hypnotics.
Barbiturates may alter levels and effects.
Adrenergic and anticholinergic side effects may be ↑ with other agents having these properties.
Phenothiazines or hormonal contraceptives may ↑ levels and risk of toxicity.
Smoking may ↓ levels and effectiveness.

Drug-Natural Products:

Kava-kava, valerian, or chamomile can ↑ risk of CNS depression.
↑anticholinergic effects with jimson weed and scopolia.

Route/Dosage ⬆ ⬇

PO (Adults ): Antidepressant/antianxiety: 25 mg 3 times daily; may ↑ as needed (up to 150 mg/day in outpatients or 300 mg/day in inpatients; some patients may require only 25–50 mg/day). Once stabilized, entire daily dose may be given at bedtime. Antipruritic: 10 mg at bedtime initially; may ↑ up to 25 mg at bedtime. Insomnia: 6 mg at bedtime (should not exceed 3 mg/day if concurrently taking cimetidine).
PO Geriatric Patients ): Antidepressant: 25–50 mg/day initially; may ↑ as needed. Insomnia: 3 mg at bedtime; may ↑ as needed to 6 mg at bedtime (should not exceed 3 mg/day if concurrently taking cimetidine).

Availability ⬆ ⬇

(Generic available)

Tablets (Silenor): 3 mg; 6 mg
Capsules: 10 mg; 25 mg; 50 mg; 75 mg; 100 mg; 150 mg
Oral concentrate: 10 mg/mL

Assessment ⬆ ⬇

Monitor BP and HR prior to and during initial therapy. Patients taking high doses or with a history of cardiovascular disease should have ECG monitored prior to and periodically during therapy.
Assess for sexual dysfunction (↓ libido; erectile dysfunction).
Assess weight and BMI initially and during treatment. Obtain fasting blood glucose and cholesterol levels in overweight/obese individuals.
Geri: Assess falls risk and institute fall prevention strategies. Assess for anticholinergic effects.
Depression:
Assess mental status and mood changes (orientation, mood, behavior) frequently, especially during initial few months of therapy and during dose changes. Confusion, agitation, and hallucinations may occur during initiation of therapy and may require dose ↓. Assess for suicidal tendencies, especially during early therapy. Restrict amount of drug available to patient. Risk may be ↑ in children, adolescents, and adults ≤24 yr. Inform health care provider if patient demonstrates significant ↑ in signs of depression (depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, ↑ fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, suicide attempt or suicidal ideation). Restrict amount of drug available to patient.
Assess for serotonin syndrome (mental changes [agitation, hallucinations, coma], autonomic instability [tachycardia, labile BP, hyperthermia], neuromuscular aberrations [hyperreflexia, incoordination], or GI symptoms [nausea, vomiting, diarrhea]), especially in patients taking other serotonergic drugs (SSRIs, SNRIs, triptans).
Insomnia: Assess sleep patterns prior to and during therapy.
Anxiety: Assess degree and manifestations of anxiety prior to and during therapy.
Pain: Assess the type, location, and severity of pain prior to and periodically during therapy. Use pain scale to assess effectiveness of therapy.

Lab Test Considerations:

Monitor WBC and differential blood counts, hepatic function, and serum glucose periodically. May ↑ serum bilirubin and alkaline phosphatase levels. May cause bone marrow depression. Serum glucose may be ↑ or ↓.

Implementation ⬆ ⬇

Dose ↑ should be made at bedtime because of sedation. Dose titration is a slow process; may take weeks to months.
To avoid withdrawal, taper by 50% for 3 days and then 50% again for 3 days; then discontinue.
PO: Administer medication with or immediately following a meal to ↓ gastric irritation. Capsules may be opened and mixed with foods or fluids if patient has difficulty swallowing.
- Oral concentrate must be diluted in ≥120 mL of water, milk, or fruit juice. Do not mix with carbonated beverages or grape juice. Use calibrated measuring device to ensure accurate amount.
- Insomnia: Administer 30 min before bedtime. To minimize potential for next day effects, do not administer within 3 hr of a meal.

Patient/Family Teaching ⬆ ⬇

Inform patient that systemic side effects may occur with oral or topical use.
- May cause drowsiness and blurred vision. Caution patient to avoid driving and other activities requiring alertness until response to the medication is known.
- Orthostatic hypotension, sedation, and confusion are common during early therapy, especially in geriatric patients. Protect patient from falls. Institute fall precautions. Advise patient to change positions slowly.
- Advise patient to avoid alcohol or other CNS depressant drugs, including opioids, during and for ≥3–7 days after therapy has been discontinued.
- Inform patient that doxepin may cause getting up out of bed while not being fully awake and doing an activity that patient does not know they aredoing. The next morning, they may not remember they did anything during the night. May occur more frequently with alcohol or other sedatives. Advise patient to notify health care provider if this occurs.
- Instruct patient to notify health care provider if urinary retention occurs or if dry mouth or constipation persists. Sugarless candy or gum may diminish dry mouth, and an increase in fluid intake or bulk may prevent constipation. If symptoms persist, dose ↓ or discontinuation may be necessary. Consult health care provider if dry mouth persists for >2 wk.
- Advise patient to notify health care provider of medication regimen prior to treatment or surgery.
- May cause fetal harm. Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Monitor neonates who were exposed to doxepin in the 3rd trimester of pregnancy for poor neonatal adaptation syndrome. Monitor infants exposed to doxepin through breast milk for excess sedation, respiratory depression and hypotonia. May ↓ fertility.
PO: Instruct patient to take medication as directed. Take missed doses as soon as possible unless almost time for next dose; if regimen is a single dose at bedtime, do not take in the morning because of side effects. Advise patient that drug effects may not be noticed for ≥2 wk. Abrupt discontinuation may cause nausea, vomiting, diarrhea, headache, trouble sleeping with vivid dreams, and irritability.
- Advise patient, family, and caregivers to look for suicidality, especially during early therapy or dose changes. Notify health care provider immediately if thoughts about suicide or dying, attempts to commit suicide, new or worse depression or anxiety, agitation or restlessness, panic attacks, insomnia, new or worse irritability, aggressiveness, acting on dangerous impulses, mania, or other changes in mood or behavior.
- Advise patient and caregivers to immediately notify health care provider if symptoms of serotonin syndrome occur.
- Caution patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
- Inform patient that urine may turn blue-green in color.
- Inform patient of need to monitor dietary intake. ↑ in appetite is possible and may lead to undesired weight gain.
- Therapy for depression is usually prolonged. Emphasize the importance of follow-up exams to monitor effectiveness and side effects.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇