Nortriptyline (Pamelor) is a tricyclic antidepressant (TCA) medicine used in the treatment of patients with depression, neuropathic pain, and nocturnal enuresis

Nortriptyline Uses:

• Unipolar Major depression:

  • Used in the treatment of symptoms of unipolar major depression

• Off Label Use of Nortriptyline in Adults:

  • Chronic pain;
  • Diabetic neuropathy;
  • Myofascial pain;
  • Orofacial pain;
  • Postherpetic neuralgia;
  • Smoking cessation

 

Nortriptyline Dose in Adults

Nortriptyline Dose in the treatment of Unipolar Major depression:

• Oral: Initial: 25 mg once a day (APA 2010).
• Adjust dose based on response and tolerability to a usual dose of 25 mg 3 to 4 times per day.
• Total daily doses may be given once a day.
• Maximum: 150 mg per day.

Nortriptyline Dose in the treatment of Chronic pain (off-label):

• Oral: Initial: 10 to 25 mg once a day at bedtime; may increase as tolerated as soon as every 3 days up to 150 mg/day.
• Patients with neuropathic pain and an inadequate response to nortriptyline alone may benefit from a combination with gabapentin.

Nortriptyline Dose in the treatment of Diabetic neuropathy (off-label):

• Oral: Initial: 10 to 25 mg per day; may gradually increase based on response and tolerability to a target dose of 25 to 100 mg per day.
• Additional data may be necessary to further define the role of nortriptyline in this condition.

Nortriptyline Dose in the treatment of Myofascial pain (off-label):

• Oral: Initial: 12.5 mg once a day at bedtime;
• may increase as tolerated up to 35 mg/day.
• If after 4 weeks at 25 to 35 mg per day there is no change in pain intensity, then consider alternative therapy.

Nortriptyline Dose in the treatment of Orofacial pain (off-label):

• Oral: Initial: 10 to 30 mg once a day at bedtime; gradually titrated up to 100 mg/day as tolerated.

Nortriptyline Dose in the treatment of Postherpetic neuralgia (off-label):

• Oral: Initial: 10 to 20 mg once a day at bedtime; may increase as needed every 3 to 5 days in 10 mg once a day increments up to 160 mg per day.

Nortriptyline Dose in the treatment of Smoking cessation (off-label):

• Oral: Initial: 25 mg once a day began 10 to 28 days prior to the selected “quit” date.

Titrate dose to 75 to 100 mg per day; continue therapy for ≥12 weeks after “quit” day.

Discontinuation of therapy:

• When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms.
• Reasons for a slower titration (eg, over 4 weeks) include the use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants.
• If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate.
• Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months.
• Evidence supporting ideal taper rates is limited.

MAO inhibitor recommendations:

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

• Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of nortriptyline.
• Allow 14 days to elapse between discontinuing nortriptyline and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Nortriptyline Dose in Childrens

Nortriptyline Dose in the treatment of Attention-deficit hyperactivity disorder (ADHD):

Note:

• Should not be used first-line.

Use should be reserved for cases where other therapies have failed or not tolerated.

Children ≥6 years and Adolescents:

• Oral: Initial: 0.5 mg/kg/day; may increase by 0.5 mg/kg/day increments at weekly intervals.
• Maximum daily dose: 2 mg/kg/day up to 100 mg/day.
• In one trial, the daily dose was divided twice a day with a dose administered before school and a dose after dinner;
• reported mean effective dose: 1.8 mg/kg/day.

Nortriptyline Dose in the treatment of Enuresis:

Note:

• TCAs are considered a third-line treatment for enuresis, due to the risk of serious side effects (eg, arrhythmias, heart block, seizures).
• May consider use in patients who have failed all other therapies; high relapse rate when discontinued.
• Administer dose 30 minutes before bedtime.
• Usual treatment duration: ≤3 months.

Children ≥6 years and Adolescents:

• Oral: General dosing: Initial: 10 to 20 mg per day.
• Titrate up to the maximum daily dose of 40 mg per day (Kliegman 2007).

Nortriptyline Dose in the treatment of Depression: Oral:

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.
• May be beneficial for patients with comorbid conditions (ADHD enuresis).

Children 6 to 12 years: Limited data available:

• 1 to 3 mg/kg/day in 4 divided doses.
• Maximum daily dose: 150 mg per day (Kliegman 2007).

Adolescents:

• 30 to 50 mg per day in 3 to 4 divided doses or as a single daily dose.
• Maximum daily dose: 150 mg per day.

Nortriptyline Dose in the treatment of Neuropathic pain in children and adolescents (Oral):

• Usual Range: 0.05 to 1 mg/kg/dose at bedtime.
• Begin at the lower end of the dosing range and titrate every 3 days to effect.
• The analgesic effects of TCAs are typically observed at a lower dose compared to TCA doses for depression.
• Maximum daily dose: 3 mg/kg/day or 150 mg/day, whichever is less.

Discontinuation of therapy:

• Upon discontinuation of antidepressant therapy, gradually taper 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 with consideration to the half-life of the antidepressant.
• Antidepressants with a shorter half-life may need to be tapered more conservatively.
• WFSBP guidelines recommend tapering over 4 to 6 months, in addition to long-term treated patients.
• If intolerable withdrawal symptoms occur following 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:

• Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of nortriptyline.
• Allow 14 days to elapse between discontinuing nortriptyline and initiation of an MAO inhibitor intended to treat psychiatric disorders.

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

• Do not initiate nortriptyline in patients receiving linezolid or IV methylene blue.
• Consider other interventions for psychiatric conditions.
• If urgent treatment with linezolid or intravenous methylene blue is required in a patient already receiving nortriptyline and potential benefits outweigh potential risks, discontinue nortriptyline promptly and administer linezolid or IV methylene blue.
• Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first.
• May resume nortriptyline 24 hours after the last dose of linezolid or IV methylene blue.

Nortriptyline Pregnancy Risk Category: C

• Nortriptyline, along with its metabolites, crosses the human placenta. It can be detected in cordblood.
• Tricyclic antidepressants can cause irritability, jitteriness and convulsions in neonates.
• ACOG recommends that treatment for depression during pregnancy is individualized.
• The treatment should include the clinical expertise of the mental, obstetric, primary, and pediatric health care providers.
• The American Psychiatric Association states that medication treatment can have risks, but should 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 (APA 2010).
• The ACOG and APA have developed treatment algorithms for women suffering from depression during pregnancy and before conception.

Use Nortriptyline while breastfeeding

• Breast milk contains Nortriptyline.
• Based on the highest breastmilk concentration and a comparison to a maternal dose of 125mg per day, the relative infant dose (RID), of nortriptyline was 3.4%.
• When the RID of medication falls below 10%, breastfeeding is generally acceptable.
• Some sources mention that breastfeeding is only recommended if the RID for psychotropic drugs is less than 5%.
• The RID of nortriptyline was calculated with a milk concentration 0.404 mcg/mL. This gives an estimated daily infant dose via breastmilk of 60.6 mg/kg/day.
• The milk concentration was determined after the mother received nortriptyline (125 mg) daily starting at delivery. Samples were taken 6 days later.
• Note that the actual milk concentrations for tricyclic antidepressants in milk are usually related to maternal serum concentrations and can vary depending on the breast milk fat content. Assay methods can have a wide range of results.
• Most studies that have been done so far have focused on infant serum levels rather than breast milk nortriptyline concentrations.
• Some infants who were breastfed nortriptyline have had their serum tested for the E-10-hydroxynortriptyline, Z-10hydroxynortriptyline, and other metabolites.
• Negative events have not been reported.
• Mothers who use psychotropic medication should monitor their infants daily for any changes in sleep, feeding, or behavior.
• Tricyclic antidepressants for depression are not recommended.
• Nortriptyline, however, is the best agent to use when a TCA is required.
• If a woman is already on TCA during pregnancy, she may continue to take it while breastfeeding.
• Pregnancy-induced pharmacokinetic differences can alter the clearance of nortriptyline. Therefore, it is important to monitor maternal serum levels immediately after birth to avoid toxic effects.

Dose in Kidney Disease:

• In the manufacturer’s labeling there are no dosage adjustments provided
• Nortriptyline is eliminated renally; use cautiously

Nortriptyline Dose in Liver Disease:

• In the manufacturer’s labeling there are no dosage adjustments provided
• Nortriptyline is eliminated renally; use with cautiously

Side effects of Nortriptyline:

• Cardiovascular:

  • Acute Myocardial Infarction
  • Cardiac Arrhythmia
  • Cerebrovascular Accident
  • Edema
  • Flushing
  • Heart Block
  • Hypertension
  • Hypotension
  • Palpitations
  • Tachycardia

• Central Nervous System:

  • Agitation
  • Anxiety
  • Ataxia
  • Confusion
  • Delusion
  • Disorientation
  • Dizziness
  • Drowsiness
  • Drug Fever
  • EEG Pattern Changes
  • Extrapyramidal Reaction
  • Fatigue
  • Hallucination
  • Headache
  • Hypomania
  • Insomnia
  • Nightmares
  • Numbness
  • Panic
  • Peripheral Neuropathy
  • Psychosis (Exacerbation)
  • Restlessness
  • Seizure
  • Tingling Of Extremities
  • Tingling Sensation
  • Withdrawal Symptoms

• Dermatologic:

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

• Endocrine & Metabolic:

  • Decreased Libido
  • Decreased Serum Glucose
  • Galactorrhea Not Associated With Childbirth
  • Gynecomastia
  • Increased Libido
  • Increased Serum Glucose
  • SIADH
  • Weight Gain
  • Weight Loss

• Gastrointestinal:

  • Abdominal Cramps
  • Anorexia
  • Constipation
  • Diarrhea
  • Epigastric Distress
  • Melanoglossia
  • Nausea
  • Paralytic Ileus
  • Parotid Gland Enlargement
  • Stomatitis
  • Sublingual Adenitis
  • Unpleasant Taste
  • Vomiting
  • Xerostomia

• Genitourinary:

  • Breast Hypertrophy
  • Impotence
  • Nocturia
  • Testicular Swelling
  • Urinary Hesitancy
  • Urinary Retention
  • Urinary Tract Dilation

• Hematologic & Oncologic:

  • Agranulocytosis
  • Eosinophilia
  • Petechia
  • Purpuric Disease
  • Thrombocytopenia

• Hepatic:

  • Abnormal Hepatic Function Tests
  • Cholestatic Jaundice

• Neuromuscular & Skeletal:

  • Asthenia
  • Tremor

• Ophthalmic:

  • Accommodation Disturbance
  • Blurred Vision
  • Eye Pain
  • Mydriasis

• Otic:

  • Tinnitus

• Renal:

  • Polyuria

Contraindications to Nortriptyline:

• Hypersensitivity to nortriptyline or similar chemical classes dibenzazepines, and any component of the formulation
• Use in patients during acute recovery phases of MI.
• MAO inhibitors are used to treat psychiatric disorders. They can be used concurrently or within 14-days of stopping nortriptyline.
• Initiation to nortriptyline for a patient who has received intravenous methyleneblue or linezolid.

Warnings and precautions

Anticholinergic effects

• Possible anticholinergic side effects: constipation, xerostomia and blurred vision.
• Patients with reduced gastrointestinal motility, paralytic and ileus, urinary retentions, BPH, xerostomia, and visual impairments should be cautious.
• This antidepressant produces a moderate degree of anticholinergic blocking.

Depression in the CNS:

• CNS depression can lead to mental or physical impairment.
• It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.
• The level of sedation is moderate to low in comparison to other antidepressants.

Fractures

• Antidepressant treatment has been shown to be associated with bone fractures.
• If an antidepressant-treated person presents with unresolved bone pain or tenderness, swelling, swelling, or bruising, there may be a fragility fracture.

Hematologic effects

• Rarely, TCAs can cause bone marrow suppression.
• If you notice any symptoms of infection, monitor your body and get CBC.

Ocular effects

• Mild pupillary dilation may occur, which can in some cases lead to narrow-angle glaucoma.
• Patients who have not undergone an iridectomy to reduce the risk of narrow-angle glaucoma should be evaluated.

Orthostatic hypotension

• Orthostatic hypotension may occur (risk is low in comparison to other antidepressants).
• Patients at high risk for this effect and those who cannot tolerate temporary hypotension (cerebrovascular disease or cardiovascular disease), should be cautious.

Serotonin syndrome

• Serotonin syndrome (SS), which can be life-threatening, has been reported with serotonergic drugs (eg SSRIs, SNRIs), especially when combined with other serotonergic medications (eg triptans TCAs, fentanyls, buspirones, fentanyls, lithium, tramadols, buspirones, St John wort and tryptophan) or agents that impair serotonin metabolism (eg MAO inhibitors to treat psychid, intravenous methyleneblue blue and linezolid]
• Watch out for signs and symptoms of SS in patients, such as mental changes (eg. agitation, hallucinations or coma); autonomic stability (eg. tachycardias, labile pressure, diaphoresis); neuromuscular disorders (eg. tremors, rigidity, myoclonus); GI symptoms like nausea, vomiting, diarrhea; and/or seizures.
• If you notice any signs or symptoms, discontinue treatment.

Hyponatremia and inappropriate antidiuretic hormone production:

• The development of hyponatremia and inappropriate antidiuretic hormone production has been linked to the use of antidepressants, mainly in elderly people.
• Other risk factors include volume loss, concurrent diuretics use, female gender and low body weight.
• TCAs are less likely to cause hyponatremia than SSRIs.

Cardiovascular disease

• Patients with a history or cardiovascular disease (including stroke, MI, or tachycardia) should be cautious.
• Patients with Brugada syndrome or suspected of it should be avoided.
• This agent has a moderate risk of conduction abnormalities compared to other antidepressants.

Diabetes:

• Patients with diabetes mellitus should be cautious as it can alter the glucose regulation.

Hepatic impairment

• Patients with hepatic impairment should be cautious.

Hypomania and mania:

• Patients with bipolar disorder can experience mania or hypomania.
• Monotherapy should not be used for bipolar disorder patients.
• Patients with depressive symptoms need to be tested for bipolar disorder. This includes details about family history, suicide attempts, bipolar disorder, depression, and other mental disorders.
• Nortriptyline has not been approved by the FDA for treatment of bipolar disorder.

Renal impairment

• Patients with impaired renal function should be cautious.

Seizure disorder

• Patients with seizures history should be cautious.

Nortriptyline: 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

Risk Factor C (Monitor therapy)
Acetylcholinesterase Inhibitors	May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors.
Ajmaline	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Alcohol (Ethyl)	CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Alpha1-Agonists	Tricyclic Antidepressants may enhance the therapeutic effect of Alpha1Agonists. Tricyclic Antidepressants may diminish the therapeutic effect of Alpha1-Agonists.
Alpha2-Agonists (Ophthalmic)	Tricyclic Antidepressants may diminish the therapeutic effect of Alpha2-Agonists (Ophthalmic).
Altretamine	May enhance the orthostatic hypotensive effect of Tricyclic Antidepressants.
Amantadine	May enhance the anticholinergic effect of Anticholinergic Agents.
Amezinium	May enhance the adverse/toxic effect of Tricyclic Antidepressants.
Amifampridine	Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.
Amphetamines	Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines.
Anticholinergic Agents	May enhance the adverse/toxic effect of other Anticholinergic Agents.
Antiemetics (5HT3 Antagonists)	May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.
Antipsychotic Agents	Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.
Beta2-Agonists	Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2Agonists.
Botulinum Toxin-Containing Products	May enhance the anticholinergic effect of Anticholinergic Agents.
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
CarBAMazepine	May decrease the serum concentration of Tricyclic Antidepressants.
Chloral Betaine	May enhance the adverse/toxic effect of Anticholinergic Agents.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
Cimetidine	May decrease the metabolism of Tricyclic Antidepressants.
Citalopram	Tricyclic Antidepressants may enhance the serotonergic effect of Citalopram. Tricyclic Antidepressants may increase the serum concentration of Citalopram. Citalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA and citalopram concentrations/effects.
CloBAZam	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
Cobicistat	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
CYP2D6 Inhibitors (Moderate)	May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors).
Darunavir	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Desmopressin	Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin.
Dexmethylphenidate	May enhance the adverse/toxic effect of Tricyclic Antidepressants. Dexmethylphenidate may increase the serum concentration of Tricyclic Antidepressants.
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Doxylamine	May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
DULoxetine	May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. DULoxetine may decrease the metabolism of Tricyclic Antidepressants.
Escitalopram	Tricyclic Antidepressants may enhance the serotonergic effect of Escitalopram. Escitalopram may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined.
Esketamine	May enhance the CNS depressant effect of CNS Depressants.
FluvoxaMINE	May enhance the serotonergic effect of Tricyclic Antidepressants. FluvoxaMINE may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined.
Gastrointestinal Agents (Prokinetic)	Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).
Glucagon	Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased.
Guanethidine	Tricyclic Antidepressants may diminish the therapeutic effect of Guanethidine.
HydrOXYzine	May enhance the CNS depressant effect of CNS Depressants.
Imatinib	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Itopride	Anticholinergic Agents may diminish the therapeutic effect of Itopride.
Kava Kava	May enhance the adverse/toxic effect of CNS Depressants.
Lumefantrine	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Magnesium Sulfate	May enhance the CNS depressant effect of CNS Depressants.
Metaxalone	May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.
Methylphenidate	May enhance the adverse/toxic effect of Tricyclic Antidepressants. Methylphenidate may increase the serum concentration of Tricyclic Antidepressants.
Methylphenidate	May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased.
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
MetyroSINE	May enhance the adverse/toxic effect of Tricyclic Antidepressants.
Mianserin	May enhance the anticholinergic effect of Anticholinergic Agents.
Minocycline	May enhance the CNS depressant effect of CNS Depressants.
Mirabegron	Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron.
Mirtazapine	CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
Nabilone	May enhance the CNS depressant effect of CNS Depressants.
Nicorandil	Tricyclic Antidepressants may enhance the hypotensive effect of Nicorandil.
Nitroglycerin	Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption.
Panobinostat	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Peginterferon Alfa-2b	May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Perhexiline	CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
Protease Inhibitors	May increase the serum concentration of Tricyclic Antidepressants.
QuiNINE	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Ramosetron	Anticholinergic Agents may enhance the constipating effect of Ramosetron.
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
Selective Serotonin Reuptake Inhibitors	CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.
Serotonin Modulators	May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid.
Sertraline	May enhance the serotonergic effect of Tricyclic Antidepressants. Sertraline may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined.
Sodium Phosphates	Tricyclic Antidepressants may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure and/or loss of consciousness may be increased in patients with significant sodium phosphate induced fluid/electrolyte abnormalities.
Sulfonylureas	Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas.
Tedizolid	May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.
Tetrahydrocannabinol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Thiazide and Thiazide-Like Diuretics	Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics.
Thyroid Products	May enhance the arrhythmogenic effect of Tricyclic Antidepressants. Thyroid Products may enhance the stimulatory effect of Tricyclic Antidepressants.
Tobacco (Smoked)	May decrease the serum concentration of Nortriptyline.
Topiramate	Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate.
Trimeprazine	May enhance the CNS depressant effect of CNS Depressants.
Valproate Products	May increase the serum concentration of Tricyclic Antidepressants.
Vitamin K Antagonists (eg, warfarin)	Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists.
Yohimbine	Tricyclic Antidepressants may increase the serum concentration of Yohimbine.
Risk Factor D (Consider therapy modification)
Abiraterone Acetate	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity.
Alpha-/Beta-Agonists (Direct-Acting)	Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Management: Avoid, if possible, the use of direct acting alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist.
Alpha2-Agonists	Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Exceptions: Apraclonidine; Brimonidine (Ophthalmic); Lofexidine.
Asunaprevir	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors).
Barbiturates	May increase the metabolism of Tricyclic Antidepressants.
Blonanserin	CNS Depressants may enhance the CNS depressant effect of Blonanserin.
Buprenorphine	CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.
Chlormethiazole	May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
Cinacalcet	May increase the serum concentration of Tricyclic Antidepressants. Management: Seek alternatives when possible. If these combinations are used, monitor closely for increased effects/toxicity and/or elevated serum concentrations (when testing is available) of the tricyclic antidepressant.
CYP2D6 Inhibitors (Strong)	May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors).
Dacomitinib	May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index.
Droperidol	May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Flunitrazepam	CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
HYDROcodone	CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Iohexol	Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants.
Iomeprol	Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants.
Iopamidol	Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants.
Linezolid	May enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this combination whenever possible. If clinically acceptable, wait at least 2 weeks after tricyclic antidepressants (TCA) discontinuation to initiate linezolid.
Linezolid	May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely.
Lithium	May enhance the neurotoxic effect of Tricyclic Antidepressants. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome.
Lofexidine	Tricyclic Antidepressants may diminish the therapeutic effect of Lofexidine. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA.
Methotrimeprazine	CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.
Metoclopramide	May enhance the adverse/toxic effect of Tricyclic Antidepressants. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with tricyclic antidepressants for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome.
Opioid Agonists	CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
OxyCODONE	CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Perampanel	May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.
Pramlintide	May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract.
QuiNIDine	Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may increase the serum concentration of Tricyclic Antidepressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Secretin	Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin.
Sodium Oxybate	May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated.
St John's Wort	May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased.
Suvorexant	CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended.
Tapentadol	May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
Terbinafine (Systemic)	May increase the serum concentration of Nortriptyline. Management: Monitor for increased effects/toxicity of nortriptyline during concomitant administration with terbinafine. Reduced dosages of nortriptyline may be needed.
Zolpidem	CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.
Risk Factor X (Avoid combination)
Aclidinium	May enhance the anticholinergic effect of Anticholinergic Agents.
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bromopride	May enhance the adverse/toxic effect of Tricyclic Antidepressants.
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
Cimetropium	Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium.
Dapoxetine	May enhance the adverse/toxic effect of Serotonin Modulators.
Dronedarone	Tricyclic Antidepressants may enhance the arrhythmogenic effect of Dronedarone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Eluxadoline	Anticholinergic Agents may enhance the constipating effect of Eluxadoline.
Glycopyrrolate (Oral Inhalation)	Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation).
Glycopyrronium (Topical)	May enhance the anticholinergic effect of Anticholinergic Agents.
Iobenguane Radiopharmaceutical Products	Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose.
Ipratropium (Oral Inhalation)	May enhance the anticholinergic effect of Anticholinergic Agents.
Levosulpiride	Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride.
Methylene Blue	Tricyclic Antidepressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome.
Methylene Blue	May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome.
Monoamine Oxidase Inhibitors	May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxatomide	May enhance the anticholinergic effect of Anticholinergic Agents.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
Paraldehyde	CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
Pitolisant	Tricyclic Antidepressants may diminish the therapeutic effect of Pitolisant.
Potassium Chloride	Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride.
Potassium Citrate	Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate.
Revefenacin	Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.
Tiotropium	Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.
Umeclidinium	May enhance the anticholinergic effect of Anticholinergic Agents.

Monitoring Parameters:

• Serum sodium in at-risk populations
• Blood pressure, heart  rate & ECG in older adults & patients with preexisting cardiac disease
• Blood glucose
• Weight and BMI
• Therapeutic blood levels (as clinically indicated)
• Suicide ideation (especially at the beginning of therapy or when doses are increased or decreased).

How to administer Nortriptyline?

Oral:

• May administer without regard to food.
• In pediatric patients, the timing of doses dependent upon use.
• For nocturnal enuresis and neuropathic pain, doses administered at bedtime.
• For ADHD, daily doses may be administered once a day in the morning or some have divided doses twice a day.

Mechanism of action of Nortriptyline:

• It has been believed that serotonin and/or nephrine can be increased in synaptic concentrations by inhibiting their reuptake at the presynaptic neural membrane.
• It blocks the activity of histamine and 5-hydroxytryptamine.
• It enhances the pressure effect of norepinephrine, but it blocks the phenethylamine's pressor response.
• Additional receptor effects were found to include desensitization and downregulation beta-adrenergic receptors and downregulation serotonin receptors.

The onset of action: Depression:

• Individual responses may vary; however, 4 to 8 weeks of treatment are needed before determining if a patient with depression is partially or non-responsive.

Absorption: Oral:

• Rapid

Protein binding:

• Extensively bound to plasma proteins

Metabolism:

• Primarily hepatic; extensive first-pass effect

Bioavailability:

• 46% to 70%

Half-life elimination:

• Adults: 14 to 51 hours (mean: 26 hours)
• Elderly: 23.5 to 79 hours (mean 45 hours)

Time to peak, serum:

• 4 to 9 hours

Excretion:

• Urine (as metabolites and small amounts of the unchanged drug)

International Brands of Nortriptyline:

• Pamelor
• APO-Nortriptyline
• Aventyl
• Nortriptyline-25
• PMS-Nortriptyline
• TEVA-Nortriptyline
• Allegron
• Altilev
• Ateben
• Avelin
• Aventyl
• Noritren
• Norline
• Norpress
• Norterol
• Nortilin
• Nortip
• Nortrilen
• Nortrilin
• Nortyl
• Nortylin
• Nortyline
• NotriTABS
• Ortrip
• Pamelor
• Paxtibi
• Sensaval
• Sensival
• Vividyl

Nortriptyline Brand Names in Pakistan:

Nortriptyline Hydrochloride Tablets 25 mg
Notrilin	Usawa Pharmaceuticals
Sensival	Pharmedic (Pvt) Ltd.

Nortriptyline hydrochloride Tablets 75 mg
Sensival	Pharmedic (Pvt) Ltd.