Doxepin (Silenor) is a tricyclic antidepressant medicine used to treat anxiety, depression, chronic urticaria, and sleep-related problems.

Doxepin Antidepressant Uses:

• Depression and/or anxiety:

  • Treatment of psychoneurotic patients with depression and/or anxiety;
  • depression and/or anxiety associated with alcoholism;
  • depression and/or anxiety associated with the organic disease;
  • psychotic depressive disorders with associated anxiety, including involutional depression and manic-depressive disorders.

• Insomnia (Silenor only):

  •  Insomnia treatment characterized by difficulty with sleep maintenance.

• Off Label Use of Doxepin in Adults:

  • Chronic urticaria

Adult dose:

Doxepin Dose in the treatment of depression and/or anxiety:

• Initial: 25 to 50 mg as a single oral dose at bedtime or in divided doses; gradually increase the dose based on response and tolerability to a usual dose of 100 to 300 mg per day

Doxepin Dose in the treatment of Insomnia (Silenor):

• Oral: 3 to 6 mg once a day within 30 minutes of bedtime; maximum dose: 6 mg/day

Doxepin Dose in the treatment of Chronic urticaria (off-label):

• Oral: Adults: 10 mg 3 times a day (Greene 1985) or 10 mg to 30 mg once a day at bedtime.

• Discontinuation of therapy:

  • Antidepressant therapy can be discontinued by gradually tapering the dose to minimize the incidence of withdrawal symptoms and allowing for the detection of re-emerging symptoms.
  • Evidence supporting ideal taper rates is limited.
  • APA and NICE guidelines recommend tapering therapy over at least several weeks of times with consideration to the half-life of the drug; antidepressants with a shorter half-life may need to be tapered more conservatively.
  • In addition to long-term treated patients, WFSBP guidelines recommend tapering over a duration of 4 to 6 months.
  • If intolerable withdrawal symptoms occur after dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate.

MAO inhibitor recommendations:

• Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

  • 14 days of time should be allowed to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of doxepin.
  • 14 days of time should be allowed to elapse between discontinuing doxepin and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Dose in children:

Doxepin Antidepressant Dose:

Note:

• Controlled clinical trials have not shown tricyclic antidepressants to be superior to placebo for the treatment of depression in children and adolescents;
• not recommended as first-line medication;
• it may be beneficial for patients with comorbid conditions.

• Children 7 to 11 years:

  • 1 to 3 mg/kg per day in single or divided doses

• Children ≥12 years and Adolescents:

  • Initial: 25 to 75 mg/day oral at bedtime or in 2 to 3 divided doses; begin at the low end of the range and gradually titrate; select patients may respond to 25 to 50 mg per day; maximum single dose: 150 mg; maximum daily dose: 300 mg per day

• Discontinuation of therapy:

  • Antidepressant therapy can be discontinued by gradually tapering the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms.
  • Evidence supporting ideal taper rates is limited.
  • APA and NICE guidelines suggest tapering therapy over at least several weeks of time with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively.
  • In addition to long-term treated patients, WFSBP guidelines recommend tapering over a duration of 4 to 6 months. If intolerable withdrawal symptoms occur after a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate

MAO inhibitor recommendations:

• Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

  • 14 days should be allowed to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of doxepin.
  • 14 days should be allowed to elapse between discontinuing doxepin and initiation of an MAO inhibitor intended to treat psychiatric disorders.

• Use with other MAO inhibitors (such as linezolid or IV methylene blue):

  • Do not prescribe doxepin to patients receiving linezolid or IV methylene blue; consider other interventions for a psychiatric condition.
  • If treatment with linezolid or IV methylene blue is urgently desired in a patient who is on doxepin already and potential benefits outweigh potential risks, promptly discontinue doxepin and administer linezolid or IV methylene blue.
  • Monitor for serotonin syndrome for 14 days or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first.
  • May resume doxepin 1 day after the last dose of linezolid or IV methylene blue.

Pregnancy Risk Factor C

• In animal reproduction studies, adverse events were noted.
• Tricyclic antidepressants can cause irritability, jitteriness and convulsions in neonates.
• ACOG recommends that treatment for depression during pregnancy should be individualized; it should include the clinical expertise of the mental healthcare provider, primary care provider, and pediatrician.
• According to the American Psychiatric Association, medication treatment risks must be weighed against untreated depression and other options.
• Women who have stopped taking antidepressant medication during pregnancy or who are at high risk of postpartum depression can resume their medications after delivery.
• The ACOG and APA have developed treatment algorithms for women with depression before and during pregnancy.

Doxepin can be used during breastfeeding

• Breast milk contains Doxepin (Frey 1999; Kemp 1985).
• A nursing infant who had taken doxepin from its mother experienced symptoms such as vomiting, drowsiness, poor feeding, and muscle hypotonia.
• After discontinuing breast milk, symptoms began to improve within 24 hours.
• A nursing infant who was given doxepin by its mother for depression has also been noted to have experienced drowsiness or apnea.
• If the product is being administered to a nursing mother, it is recommended that caution be taken.

Renal dose:

Doxepin Antidepressant Dose in Kidney disease:

• There are no dosage adjustments provided in the drug manufacturer’s labeling.

DoxepinDose in Liver disease:

• Silenor: Initial: 3 mg once a day

Side effects of Doxepin antidepressant:

• Cardiovascular:

  • Hypertension
  • Edema
  • Flushing
  • Hypotension
  • Tachycardia

• Central Nervous System:

  • Sedation
  • Dizziness
  • Ataxia
  • Chills
  • Confusion
  • Disorientation
  • Drowsiness
  • Extrapyramidal Reaction
  • Fatigue
  • Hallucination
  • Headache
  • Numbness
  • Paresthesia
  • Seizure
  • Tardive Dyskinesia

• Dermatologic:

  • Alopecia
  • Diaphoresis (Excessive)
  • Pruritus
  • Skin Photosensitivity
  • Skin Rash

• Endocrine & Metabolic:

  • Altered Serum Glucose
  • Change In Libido
  • Galactorrhea
  • Gynecomastia
  • SIADH
  • Weight Gain

• Gastrointestinal:

  • Nausea
  • Gastroenteritis
  • Anorexia
  • Aphthous Stomatitis
  • Constipation
  • Diarrhea
  • Dysgeusia
  • Dyspepsia
  • Vomiting
  • Xerostomia

• Genitourinary:

  • Breast Hypertrophy
  • Testicular Swelling
  • Urinary Retention

• Hematologic & Oncologic:

  • Agranulocytosis
  • Eosinophilia
  • Leukopenia
  • Purpura
  • Thrombocytopenia

• Hepatic:

  • Jaundice

• Neuromuscular & Skeletal:

  • Tremor
  • Weakness

• Ophthalmic:

  • Blurred Vision

• Otic:

  • Tinnitus

• Respiratory:

  • Upper Respiratory Tract Infection
  • Exacerbation Of Asthma

Contraindications to Doxepin antidepressant:

• Hypersensitivity/Allergy To Doxepin, Dibenzoxepins, Or Any Component of the Formulation
• Glaucoma
• Urinary retention
• Use MAO inhibitors within 14 Days
• There is not much evidence of cross-reactivity between tricyclic antidepressants and allergenic tricyclic antidepressants. 
• Cross-sensitivity is possible due to the same chemical structure as the pharmacologic actions.

Canadian labeling: Additional contraindications not in the US labeling

• Following myocardial injury, the acute recovery phase;
• Acute congestive heart failure
• History of blood dyscrasias
• Grave hepatic disease
• Use in children

Warnings and precautions

• Anticholinergic effects

  • Anticholinergic effects can cause constipation, xerostomia and blurred vision.
  • Patients with reduced GI motility, paralytic ileus or urine retention, BPHs, xerostomia or visual problems should be cautious.
  • This agent produces a high anticholinergic blockade relative to other antidepressants.

• Depression in the CNS:

  • It can lead to depression in the central nervous system. This can then impair mental and physical abilities.
  • Patients must be counselled about tasks that require mental alertness, such as operating machinery or driving.

• CNS effects

  • Unpredictability may be a factor in anxiety, psychosis, or other neuropsychiatric symptoms.

• Fractures

  • Antidepressant treatment has been shown to be associated with bone fractures.
  • A patient taking antidepressants may experience a fragility fracture when they have undiagnosed bone pain, tenderness, swelling or bruising.

• Ocular effects

  • Mild pupillary dilation may occur. This can cause narrow-angle glaucoma in those who are susceptible.
  • Patients who have not undergone an iridectomy to reduce narrow-angle glaucoma risks should be evaluated.

• Orthostatic hypotension

  • Orthostatic hypotension may occur (risk is moderate relative other antidepressants); caution should be exercised in patients at high risk or those who cannot tolerate transient hypotensive episodes.

• Extension of QT

  • Could cause prolongation of the QT.

• SIADH and Hyponatremia

  • Hyponatremia and SIADH have been linked to antidepressant use, especially in older patients.
  • Other risk factors include volume loss, concurrent diuretics use, female gender and low body weight.
  • TCAs are less likely to cause hyponatremia than SSRIs.

• Activities that are sleep-related:

  • There is a higher risk of hazardous sleep-related activities like driving, cooking, eating, calling, or having sex while you sleep. Amnesia can also be a possibility.
  • Patients who have reported any sleep-related episode should stop receiving treatment.

• Cardiovascular disease

  • Patients with a history or cardiovascular disease should be cautious (MI, stroke, or conduction abnormalities)
  • The American Heart Association has determined that doxepin may be an agent that can potentiate myocardial dysfunction.

• Diabetes:

  • Patients with diabetes mellitus should exercise caution as it may affect glucose regulation.

• Hepatic impairment

  • Patients with hepatic impairment should exercise caution as higher doxepin concentrations can occur.

• Hypomania or mania:

  • Patients with bipolar disorder may experience a shift from mania to hypomania.
  • Patients with bipolar disorder must not be treated in monotherapy.
  • Patients with depressive symptoms need to be tested for bipolar disorder. This includes details about family history, suicide attempts, and depression.
  • Doxepin has not been approved by the FDA for treatment of bipolar disorder.

• Respiratory disease

  • Patients with sleep apnea or respiratory compromise should exercise caution.
  • Patients suffering from severe sleep apnea should not use Silenor.

• Seizure disorder

  • Patients at high risk of seizures should be cautious, especially those who have had seizures in the past, brain damage or head trauma.

Doxepin (systemic): Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Clinically indicated serum sodium for at-risk populations
• Assess your mental state
• Suicide ideation, especially at the beginning of therapy and when dosages are increased/ decreased
• Anxiety, social dysfunction, mania, panic attacks, or other unusual behavior changes;
• Heart rate, blood pressure, ECG, and heart rate in patients with preexisting or existing cardiac disease.
• Blood glucose
• Weight and BMI
• For therapeutic monitoring, blood levels can be used.
• If insomnia persists, you should reexamine your diagnosis.

How to administer Doxepin Antidepressant?

Depression and/or Anxiety:

• The total daily oral dosage should be administered in divided doses or on a once-a-day basis.
• The maximum recommended daily intake for those following the once-a-day schedule is 150 mg at bedtime.
• The 150 mg capsule is only for maintenance and not for treatment.

Insomnia:

• Oral: Take 30 minutes before you go to bed; don't take it within three hours.

Mechanism of action of Doxepin Antidepressant:

• It increases the synaptic concentrations of serotonin, norepinephrine in the CNS by inhibiting reuptake by presynaptic neural membranes; it also antagonizes sleep maintenance histamine receptors.
• Doxepin's efficacy in treating chronic urticaria off-label is thought to be due to its potent H/H receptor antagonist activity.

The beginning of action:

• Individual responses can vary. It may take 4-8 weeks to determine if someone with depression is responsive or not.
• Anxiolytic effects can take up to six weeks to manifest.

Absorption:

• High-fat meals can increase the bioavailability and delay peak plasma concentration by up to 3 hours.

Protein binding:

• ~80%

Metabolism:

• Hepatic via CYP2C19 and 2D6; primary metabolite is N-desmethyldoxepin (active)

Bioavailability:

• 27% (Hiemke 2018)

Half-life elimination:

• Adults: Doxepin: about ~15 hours; N-desmethyldoxepin: 31 to 51 hours

Time to peak, serum:

• Fasting: Silenor: 3.5 hours

Excretion:

• Urine (<3% as unchanged drug or N-desmethyldoxepin)

International Brands of Doxepin:

• Silenor
• NOVO-Doxepin
• SINEquan
• Adnor
• Anten
• Antidoxe
• Deptran
• Docsomniea
• Dofu
• Doneurin
• Doxal
• Doxe
• Doxecan
• Doxepia
• Doxetar
• Doxin
• Espadox
• Expan
• Flake
• Gilex
• Insomniax
• Li Ke Ning
• Lotroska
• Qualiquan
• Quitaxon
• Sagalon
• Silenor
• Sinequan
• Sinquan
• Slipaid
• Spectra

Doxepin Brand Names in Pakistan:

No Brands Available in Pakistan.