Amitriptyline

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Amitriptyline
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]

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Black Box Warning

Suicidality and Antidepressant Drugs
See full prescribing information for complete Boxed Warning.
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Amitriptyline hydrochloride is not approved for use in pediatric patients.

Overview

Amitriptyline is a Tricyclic antidepressant that is FDA approved for the {{{indicationType}}} of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include M.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition 1

  • Dosing Information
(Dosage)

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition 1

  • Developed by: American Association
  • Class of Recommendation: Class 1(Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Condition 1

  • Dosing Information
  • There is limited information about Off-Label Non–Guideline-Supported Use of Amitriptyline in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

  • Dosing Information
(Dosage)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

  • Developed by: (Organization)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Condition 1

  • Dosing Information
  • There is limited information about Off-Label Non–Guideline-Supported Use of Amitriptyline in pediatric patients.

Contraindications

Warnings

Suicidality and Antidepressant Drugs
See full prescribing information for complete Boxed Warning.
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Amitriptyline hydrochloride is not approved for use in pediatric patients.

Condition 1

(Description)

Adverse Reactions

Clinical Trials Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Postmarketing Experience

Central Nervous System

(list/description of adverse reactions)

Cardiovascular

(list/description of adverse reactions)

Respiratory

(list/description of adverse reactions)

Gastrointestinal

(list/description of adverse reactions)

Hypersensitive Reactions

(list/description of adverse reactions)

Miscellaneous

(list/description of adverse reactions)

Drug Interactions

  • An increase in plasma concentrations of the drug to be seen.
  • It can reduce the antihypertensive effects of this drug.
  • May exacerbate each other's anticholinergic effects, causing paralytic ileus and tachycardia.
  • Interfere with hepatic metabolism of amitriptyline, increasing steady-state concentrations of the drug.
  • The potential for the development of delirium
  • May increase the risks associated with this treatment
  • Antithyroid medications
  • Thyroid hormones
  • May increase adverse effects such as CNS stimulation and arrhythmias.
  • May increase in seizure risk.
  • Medications that are subject to gastric inactivation (e.g. levodopa)
  • Amitriptyline delays gastric emptying and reduce intestinal motility
  • Medications that may be subject to increased absorption given more time in the small intestine (e.g. anticoagulants)
  • Serotoninergic agents such as the SSRIs and triptans

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Amitriptyline in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amitriptyline in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Amitriptyline during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Amitriptyline in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Amitriptyline in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Amitriptyline in geriatric settings.

Gender

There is no FDA guidance on the use of Amitriptyline with respect to specific gender populations.

Race

There is no FDA guidance on the use of Amitriptyline with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Amitriptyline in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Amitriptyline in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Amitriptyline in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Amitriptyline in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Amitriptyline Administration in the drug label.

Monitoring

There is limited information regarding Amitriptyline Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Amitriptyline and IV administrations.

Overdosage

The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of serotonin syndrome and adverse cardiac effects. The British National Formulary notes that amitriptyline can be particularly dangerous in overdose,[2] thus it and other tricyclic antidepressants are no longer recommended as first line therapy for depression. Alternative agents, SSRIs and SNRIs are safer in overdose, though they are no more efficacious than TCAs. English folk singer, Nick Drake, died from an overdose of Tryptizol in 1974.

The possible symptoms of amitriptyline overdose include:[3]

The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose.[3] Activated charcoal may reduce absorption if given within 1-2 hours of ingestion.[3] If the affected person is unconscious or have an impaired gag reflex a nasograstic tube may be used to deliver the activated charcoal in the stomach.[3] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[3] Body temperature should be regulated with measures such as heating blankets if necessary.[3] Likewise cardiac arrhythmias can be treated with propanolol and should heart failure occur digitalis may be used.[3] Cardiac monitoring is advised for at least five days after the overdose.[3] Other measures include the use of inhalation anaesthetics or diazepam for convulsions and barbiturates should be avoided if possible due to the potential for additive CNS depression (that is, on top of the CNS depression caused by the amitriptyline).[3] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[3]

Pharmacology

Template:Px
Template:Px
Amitriptyline
Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine
Identifiers
CAS number 50-48-6

549-18-8 (hydrochloride)
ATC code N06AA09
PubChem 2160
DrugBank DB00321
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 277.403 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 30–60% due to first pass metabolism
Protein binding 96%[4][5][3][1]
Metabolism Hepatic (CYP2D6)[4][5][3][1]
Half life 22.4 hr (26 hr for active metabolite, nortriptyline)[4][5][3][1]
Excretion Renal[4][5][3][1]
Therapeutic considerations
Licence data

US

Pregnancy cat.

C(AU) C(US)

Legal status

Prescription Only (S4)(AU) ?(CA) POM(UK) [[Prescription drug|Template:Unicode-only]](US)

Routes Oral, intramuscular

Mechanism of Action

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter.[6][7] It has negligible influence on the dopamine transporter and therefore does not affect dopamine reuptake, being nearly 1,000 times weaker on it than on serotonin.[7] It is metabolised to nortriptyline — a more potent and selective norepinephrine reuptake inhibitor — which may hence compliment its effects on norepinephrine reuptake.[3]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[8] H4,[9][10] and mACh receptorantagonist, and σ1 receptor agonist.[11][12][13][14] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[15] Amitriptyline inhibits sodium channels, L-type calcium channels, and Kv1.1, Kv7.2, and Kv7.3 voltage-gated potassium channels, and therefore acts as a sodium, calcium, and potassium channel blocker as well.[16][17]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[18] It promotes the heterodimerization of these proteins in the absence of NGF and has potent neurotrophic activity both in-vivo and in-vitro in mouse models.[18][19] These are the same receptors BDNF activates, an endogenous neurotrophin with powerful antidepressant effects, and as such this property may contribute significantly to its therapeutic efficacy against depression. Amitriptyline also acts as FIASMA (functional inhibitor of acid sphingomyelinase).[20]

Structure

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Pharmacodynamics

There is limited information regarding Amitriptyline Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Amitriptyline Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Amitriptyline Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Amitriptyline Clinical Studies in the drug label.

How Supplied

There is limited information regarding Amitriptyline How Supplied in the drug label.

Storage

There is limited information regarding Amitriptyline Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Amitriptyline |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Amitriptyline |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Amitriptyline Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Amitriptyline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Amitriptyline Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Amitriptyline Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Invalid <ref> tag; no text was provided for refs named EMC
  2. ↑ Invalid <ref> tag; no text was provided for refs named BNF
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Invalid <ref> tag; no text was provided for refs named TGA
  4. ↑ 4.0 4.1 4.2 4.3 Invalid <ref> tag; no text was provided for refs named DM
  5. ↑ 5.0 5.1 5.2 5.3 Invalid <ref> tag; no text was provided for refs named MSR
  6. ↑ "Potency of antidepressants to block noradrenaline reuptake". CNS Forum. Retrieved 2013-02-16.
  7. ↑ 7.0 7.1 Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
  8. ↑ Albert Ellis; Gwynn Pennant Ellis (1 January 1987). Progress in Medicinal Chemistry. Elsevier. p. 56. ISBN 978-0-444-80876-9. Retrieved 27 November 2011.
  9. ↑ Nguyen T, Shapiro DA, George SR; et al. (March 2001). "Discovery of a novel member of the histamine receptor family". Molecular Pharmacology. 59 (3): 427–33. PMID 11179435.
  10. ↑ D. Sriram & P. Yogeeswari (1 September 2010). Medicinal Chemistry. Pearson Education India. p. 299. ISBN 978-81-317-3144-4. Retrieved 27 November 2011.
  11. ↑ Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". J. Pharmacol. Exp. Ther. 283 (3): 1305–22. PMID 9400006.
  12. ↑ Alan F. Schatzberg, Charles B. (2006). Essentials of clinical psychopharmacology. American Psychiatric Pub. p. 7. ISBN 978-1-58562-243-6.
  13. ↑ Rauser L, Savage JE, Meltzer HY, Roth BL (October 2001). "Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor". J. Pharmacol. Exp. Ther. 299 (1): 83–9. PMID 11561066.
  14. ↑ Werling LL, Keller A, Frank JG, Nuwayhid SJ (October 2007). "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Exp. Neurol. 207 (2): 248–57. doi:10.1016/j.expneurol.2007.06.013. PMID 17689532.
  15. ↑ Sills MA, Loo PS (July 1989). "Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate". Mol. Pharmacol. 36 (1): 160–5. PMID 2568580.
  16. ↑ Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C (January 1998). "Inhibition of neuronal Na+ channels by antidepressant drugs". J. Pharmacol. Exp. Ther. 284 (1): 208–14. PMID 9435180.
  17. ↑ Punke MA, Friederich P (May 2007). "Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels". Anesthesia and Analgesia. 104 (5): 1256–1264. doi:10.1213/01.ane.0000260310.63117.a2. PMID 17456683.
  18. ↑ 18.0 18.1 Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K (June 2009). "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chem. Biol. 16 (6): 644–56. doi:10.1016/j.chembiol.2009.05.010. PMC 2844702. PMID 19549602.
  19. ↑ "Pharmaceutical Information - AMITRIPTYLINE". RxMed. Retrieved 2013-02-16.
  20. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). Riezman, Howard, ed. "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE. 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365.

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