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 patients with psychoneurotic disorders who have depression or anxiety, as well as depression or anxiety linked to alcoholism, organic disease, or psychotic depressive disorders with related anxiety, such as 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: Depending on response and tolerance, gradually raise the amount to a typical dose of 100 to 300 mg per day, either as a single oral dose before bedtime or in divided doses.

Doxepin Dose in the treatment of Insomnia (Silenor):

• Oral: 30 minutes prior to bedtime, 3 to 6 mg once daily; daily maximum: 6 mg

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

• Oral: Adults: 10 mg three times daily (Greene 1985) or 10 mg to 30 mg at bedtime each day.

• Discontinuation of therapy:

  • Antidepressant therapy can be stopped by gradually reducing the dosage to reduce the likelihood of withdrawal symptoms and make it possible to spot any symptoms that reappear.
  • There is little data to support appropriate taper rates.
  • According to APA and NICE recommendations, therapy should be reduced over the course of at least several weeks while taking the drug's half-life into account; antidepressants with a shorter half-life may need to be tapered more gradually.
  • In addition to individuals who have been receiving long-term treatment, WFSBP recommendations suggest tapering over a period 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:

  • It is recommended to wait 14 days before starting doxepin after stopping an MAO inhibitor used to treat psychiatric problems.
  • It is recommended to wait 14 days before starting an MAO inhibitor after stopping doxepin.

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:

  • Single or split doses of 1 to 3 mg/kg per day

• Children ≥12 years and Adolescents:

  • Initial: Select persons may react to 25 to 50 mg per day; 25 to 75 mg/day oral at bedtime or in 2 to 3 divided doses; start at the low end of the range and progressively titrate; Limit single dose is 150 mg, while the daily maximum is 300 mg.

• Discontinuation of therapy:

  • To reduce the likelihood of withdrawal symptoms and enable the detection of re-emerging symptoms, antidepressant therapy can be stopped by gradually reducing the dose.
  • There is little data to support appropriate taper rates.
  • According to APA and NICE recommendations, therapy should be reduced over at least a few weeks while taking the antidepressant's half-life into account. Antidepressants having a shorter half-life may need to be tapered more gradually.
  • 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:

  • .It is recommended to wait 14 days before starting doxepin after stopping an MAO inhibitor used to treat psychiatric problems.
  • Doxepin should be stopped for at least 14 days before starting an MAO inhibitor used to treat psychiatric disorders.

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

  • If a patient is taking linezolid or IV methylene blue, do not prescribe doxepin; instead, think about alternate treatments for their psychiatric illness.
  • If a patient who is already taking doxepin needs therapy with linezolid or IV methylene blue urgently and potential advantages outweigh potential dangers, stop taking doxepin right away and start giving linezolid or IV methylene blue.
  • For 14 days, or until 24 hours after the final dosage of linezolid or IV methylene blue, whichever comes first, keep an eye out for serotonin syndrome.
  • can start taking doxepin again after one day.

Pregnancy Risk Factor C

• In animal reproduction studies, adverse events were noted.
• Tricyclic antidepressants can cause irritability, jitteriness and convulsions in neonates.
• The American College of Obstetricians and Gynecologists (ACOG) advises that therapy for depression during pregnancy be customised and incorporate the clinical know-how of the mental healthcare practitioner, primary care physician, and paediatrician.
• 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 need to be given advice regarding activities requiring mental awareness, such operating machinery or operating a vehicle.

• 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 is possible (risk is moderate compared to other antidepressants); individuals at high risk or those who cannot tolerate brief hypotensive episodes should use cautiously.

• 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

  • Doxepin may be an agent that can exacerbate myocardial dysfunction, according to the American Heart Association, thus patients with a history of cardiovascular illness (MI, stroke, or conduction abnormalities) should exercise caution.

• 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
• Anxiety
• social dysfunction
• panic attacks
• Heart rate
• 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 recommended oral dosage for the entire day should be taken once daily or in divided doses.
• For those who take it once a day, the maximum suggested daily dose is 150 mg at bedtime.
• Only for maintenance purposes; not for therapeutic use.

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 powerful H/H receptor antagonist activity is assumed to be the reason for its effectiveness in treating chronic urticaria off-label.

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:

• Meals that are high in fat can make a drug more bioavailable and push out the peak plasma concentration by up to three 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.