Doxepin hydrochloride, SILENOR®, SINEQUAN®

• SILENOR®
• SINEQUAN®

• Tricyclic Anti-depressants

• SILENOR: Tablets 3 and 6 mg
  

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• SINEQUAN: Capsules 10 mg and 25 mg

1. Major Depression Disorder 
2. Insomnia: (Hypnotic effect)

• Mechanism of Action: Antagonism of H1 receptor.
  

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• Pharmacodynamics: No effect on QT intervals in ECG in daily doses of 6 mg or 50 mg.

Pharmacokinetics:

• Absorption: Orally >>> Peak concentration: 3.5 hours >>> half life: 15.3 hours
• Distribution: 80% bound to plasma proteins, highly lipophilic and widely distributed throughout the body tissues.
• Metabolism: Primarily metabolized by hepatic cytochrome P450 (Isozymes CYP2C19 & CYP2D6)
• Excretion: Urine mainly

Insomnia (Hypnotic effect):

1. Adults: 6 mg/day >>> 3 mg/day for some patients
2. Elderly: (≥ 65 years old): 3 mg/day >>> 6 mg/day if clinically indicated
3. Hepatic Impairment: initiate with 3 mg/day

MDD: (Daily dose is usually administered tid)

1. Mild MDD:
   1. Initial dose: 30 mg/day, Optimum dose: good clinical response is obtained in 30-50 mg/day almost. Max dose: 150 mg/day
2. Moderate/Severe MDD:
   1. Initial dose: 75 mg daily in divided doses (Usually tid). Optimum dose: up to 150 mg/day. Max dose: 300 mg a day in divided doses.

Hepatic impairment & Elderlies: Dosage reduction may be required

• CNS Depressants
  

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• Sedating Antihistamines
  

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• Alcohol
  

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• Cimetidine (A maximum dose of 3 mg is recommended in adults and elderly whencimetidine is co-administered)
  

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• Selective Serotonin Reuptake Inhibitors
  

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• Medications inhibit Cytochrome P-450 (CYP2C19 and CYP2D6 Isoenzymes) >>> Enzyme inhibitor effect
  

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• Medications induce Cytochrome P-450 >>> Hepatic Enzyme Inducers: eg: Barbiturates, phenytoin, carbamazepine
  

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• Monoamine oxidase inhibitors (MAOIs)
  

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• Sympathomimetic Agents
  

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• Guanethidine and related agents
  

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• Tolazamide

Most Frequent:

• Somnolence
• Sedation
• Nausea
• Dizziness
• Dry mouth
• Upper respiratory tract infection

Less Common: (< 1%)

• Cardiac disorders: tachycardia.
• Ear and labyrinth disorders: hypoacusis, motion sickness, tinnitus.
• Eye disorders: blepharospasm, diplopia, eye pain, vision blurred, visual disturbance.
• Gastrointestinal disorders: abdominal pain upper, diarrhoea, gastrooesophageal reflux disease, gingival recession, toothache, tooth fracture.
• General disorders: fatigue, feeling abnormal, hangover, oedema peripheral, pitting oedema, sluggishness.
• Infections and infestations: bronchitis, eye infection, fungal infection, gastroenteritis viral, herpes zoster, infective tenosynovitis, influenza, laryngitis, lower respiratory tract infection, onychomycosis, sinusitis, tooth abscess, urinary tract infection, viral infection.
• Injury, poisoning and procedural complications: back injury, excoriation, foot fracture, hand fracture, skin laceration, upper limb fracture.
• Investigations: blood pressure decreased, electrocardiogram abnormal.
  Metabolism and nutrition disorders: decreased appetite, hypokalaemia, increased appetite.
• Musculoskeletal and connective tissue disorders: joint range of motion decreased, muscle cramp, myalgia, neck pain, pain in extremity.
• Neoplasm benign, malignant and unspecified (incl cysts and polyps): lung adenocarcinoma stage I, malignant melanoma.
• SILENOR Product Monograph Page 11 of 30
• Nervous system disorders: ageusia, ataxia, disturbance in attention, lethargy, migraine, sleep paralysis, tremor.
• Psychiatric disorders: depression, elevated mood, libido decreased, nightmare.
• Renal and urinary disorders:
• Reproductive system and breast disorders: breast cyst.
• Respiratory, thoracic and mediastinal disorders: cough, nasal congestion, nasopharyngeal disorder, pharyngolaryngeal pain, sinus congestion.
• Skin and subcutaneous tissue disorders: dermatitis contact, erythema, pruritus generalized, rash, rosacea, skin lesion.
• Vascular disorders: blood pressure inadequately controlled, haematoma.

• Hypersensitivity to TCAs
  

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• Hepatic Impairment (Relative Contraindication- If no alternatives)
  

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• Renal Impairment (Relative Contraindication- If no alternatives)
  

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• SSRIs
  

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• CNS Depressants
  

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• Sedating Antihistamines
  

  ---

• Alcohol
  

  ---

• Cimetidine (A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co-administered)
  

  ---

• Selective Serotonin Reuptake Inhibitors
  

  ---

• Medications inhibit Cytochrome P-450 (CYP2C19 and CYP2D6 Isoenzymes) >>> Enzyme inhibitor effect
  

  ---

• Medications induce Cytochrome P-450 >>> Hepatic Enzyme Inducers: eg: Barbiturates, phenytoin, carbamazepine
  

  ---

• Monoamine oxidase inhibitors (MAOIs)
  

  ---

• Sympathomimetic Agents
  

  ---

• Guanethidine and related agents
  

  ---

• Tolazamide

• Pregnancy: No available category, No studies have done yet.
  

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• Lactation: Not recommended in nursing mother.

• Geriatrics (≥ 65 years of age): may cause confusionand over-sedation in elderly >>> use with caution.

• Pediatrics (< 18 years of age): Safety has not been evaluated.

• Complex sleep-related behaviours:
  1. Potentially dangerous behaviours >>> after taking a sedative- hypnotic >>> eg: Sleep-driving behaviours, not fully awake, preparing and eating food, making phone calls, leaving the house, having sex.
  2. Sleep-driving” may occur at therapeutic doses >>> Synergistic effect withAlcohol & other CNS depressants, Anti-histamins.
  3. Mental alertness: Use with caution in tasks requiring mental alertness >>> Avoid driving!

• Potential for Abuse: Caution!>>> Carefully evaluate patients for history of drug abuse.

• Administer with caution in patients with depression>>> Depression could be intensified >>> Suicide risk & suicidality & worsening of depression >>> Carefully monitor the patient.

• Patients with severe Sleep-apnea: Not recommended

• Administration time: within 30 minutesof bedtime >>> should confine their activities to those necessary to prepare for bed >>> should not be taken within 3 hours of a meal.

• Over dosage:

1. Symptoms: Excessive drowsiness, alterations of consciousness, unresponsiveness.
2. ECG: Q-T Prolongation >>> slow intravenous administration of physostigmine salicylatemay reverse most of the cardiovascular & CNS anticholinergic manifestations of tricyclic overdose.
3. Treatment: Symptomatic and supportive >>> No specific antidote.

• Caution in concomitant use with Monoamine oxidase inhibitors(MAOIs): >>> potentiate other drug effects >>> Serotonin syndrome! >>> At least 14 days should be elapsed before starting either medications.

• Caution in concomitant use with Selective Serotonin Reuptake Inhibitors >>> sufficient time should be elapsed >>>at least 5 weeks.

• Sympathomimetic Agents:Caution in co-administration nasal drops and local anaesthetics.

• Anticholinergic Agents: Caution in co-administration >>> Delirium, glaucomaattack, urinary retention or paralytic ileus.

• Caution in co administration with Guanethidine and related agents >>> Antihypertensive effect may reduce.

• Caution in co administration with Tolazamide: Severe hypoglycaemia.

• Hepatic &Renal Impairment: SINEQUAN should be used with caution.