Paroxetine

Oral
Obsessive compulsive disorder

Oral
Generalised anxiety disorder

Oral
Premenstrual dysphoric disorder

Oral
Posttraumatic stress disorder

Oral
Social anxiety disorder

Oral
Major depressive disorder

Oral
Panic disorder with or without agoraphobia

Oral
Moderate to severe vasomotor symptoms associated with menopause

Pharmacogenomics:

Paroxetine is extensively metabolised by CYP2D6 isoenzyme to form glucuronide or sulfate conjugates. CYP2D6 polymorphisms may influence the metabolism, clinical efficacy, and safety of paroxetine.

CYP2D6 allele frequencies among individuals of different populations and ethnic backgrounds may be a considering factor that may cause potential uncertainty in genotyping and phenotype predictions. For example, CYP2D6*10 is common in Asians and CYP2D6*17 is common in people of Sub-Saharan African ancestry, while these alleles have considerably lower prevalence in other ethnic groups such as Caucasians of European ancestry. Moreover, Asian populations were also found to carry CYP2D6*14A allele. Thus, the alleles that should be tested may considerably vary for a given population.

CYP2D6 ultrarapid metabolisers
Carriers of duplications of functional alleles e.g. *1/*1xN, *1/*2xN, *2/*2xN. May have increased paroxetine metabolism as compared with extensive metabolisers, resulting in lower or undetectable plasma levels and increased risk of pharmacotherapy failure.
Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends selecting an alternative drug not primarily metabolised or to a lesser extent by CYP2D6 (e.g. citalopram, sertraline).

CYP2D6 extensive metabolisers
Carriers of 2 normal function alleles, or 2 decreased function alleles, or 1 normal function and 1 no function allele, or 1 normal function and 1 decreased function allele e.g. *1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2, *41/*41. May have normal paroxetine metabolism.
CPIC recommends initiating treatment with the recommended starting dose.

CYP2D6 intermediate metabolisers
Carriers of 1 decreased function and 1 no function allele e.g. *4/*10, *4/*41, *5/*9. May have reduced paroxetine metabolism as compared with extensive metabolisers, resulting in higher plasma concentrations and increased risk of adverse effects (e.g. insomnia, headache, sexual or gastrointestinal dysfunction).
However, CPIC considers initiating treatment with the recommended starting dose.

CYP2D6 poor metabolisers
Carriers of no functional alleles e.g. *3/*4, *4/*4, *5/*5, *5/*6. May have greatly reduced paroxetine metabolism as compared with extensive metabolisers, resulting in higher plasma concentrations and increased risk of adverse effects (e.g. insomnia, headache, sexual or gastrointestinal dysfunction).
CPIC recommends selecting an alternative drug not primarily metabolised by CYP2D6 (e.g. citalopram, sertraline). If paroxetine use is warranted, may consider 50% dose reduction of the recommended initial dose and titrate according to response.

Major depressive disorder; Obsessive compulsive disorder; Panic disorder with or without agoraphobia; Social anxiety disorder; Generalised anxiety disorder; Posttraumatic stress disorder; Premenstrual dysphoric disorder:

CrCl (mL/min)	Dosage
<30	Use the lower end of the dosage range.

Major depressive disorder; Obsessive compulsive disorder; Panic disorder with or without agoraphobia; Social anxiety disorder; Generalised anxiety disorder; Posttraumatic stress disorder; Premenstrual dysphoric disorder: Use the lower end of the dosage range.

May be taken with or without food. May be taken w/ meals to minimise GI upset.

Pregnancy (as paroxetine mesilate cap). Concurrent use with or within 14 days after discontinuation of MAOIs (including linezolid and IV methylene blue). Concomitant use with pimozide, thioridazine.

Patients with history of suicide-related events or pre-existing suicidal ideation, bipolar disorder, history of mania, pre-existing seizure disorder or conditions predisposing to seizures (e.g. brain damage, alcoholism), narrow-angle glaucoma or history of glaucoma, CV disease (e.g. recent history of MI, unstable heart disease), history of bleeding disorders or other conditions predisposing to bleeding, diabetes mellitus, volume depletion. Paroxetine mesilate cap: Not indicated for the treatment of any psychiatric conditions. Oral susp: Patients with high gastric pH or achlorhydria. Concomitant electroconvulsive therapy. Avoid abrupt withdrawal. Severe renal (CrCl <30 mL/min) and hepatic impairment. Debilitated patients. Elderly. Pregnancy and lactation. CYP2D6 ultrarapid and poor metabolisers.

Significant: Suicidal thoughts and behaviour, worsening of depression, mania or hypomania, akathisia or psychomotor restlessness, seizures, bleeding abnormalities (e.g. ecchymoses, purpura, epistaxis, haematomas, petechiae), anticholinergic effects, bone fractures, mild pupillary dilation, sexual dysfunction (e.g. impotence, ejaculatory disorder), withdrawal symptoms. Rarely, hyponatraemia (primarily in elders).
Cardiac disorders: Sinus tachycardia. Rarely, bradycardia.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Blurred vision.
Gastrointestinal disorders: Nausea, constipation, dry mouth, vomiting, diarrhoea.
General disorders and administration site conditions: Asthenia, fatigue, malaise, lethargy.
Investigations: Weight gain, increased cholesterol levels, transient changes in blood pressure. Rarely, elevated hepatic enzymes.
Metabolism and nutrition disorders: Decreased appetite.
Musculoskeletal and connective tissue disorders: Rarely, myalgia, arthralgia.
Nervous system disorders: Headache, dizziness, tremor, impaired concentration.
Psychiatric disorders: Insomnia, somnolence, agitation, abnormal dreams, aggression.
Renal and urinary disorders: Urinary retention or incontinence.
Respiratory, thoracic and mediastinal disorders: Yawning.
Skin and subcutaneous tissue disorders: Sweating, rashes, pruritus.
Vascular disorders: Postural hypotension.
Potentially Fatal: Serotonin syndrome, neuroleptic malignant syndrome (NMS)-like events, haemorrhage (e.g. gastrointestinal or gynaecological haemorrhage). Rarely, anaphylactoid reactions and angioedema.

PO: D, Z (Birth defects (e.g. cardiac) in early pregnancy use. Postpartum haemorrhage, persistent pulmonary hypertension in infant, neonatal withdrawal/toxicity in late pregnancy use. Monitor closely.)

This drug may impair judgment, thinking or motor skills, if affected, do not drive or operate machinery.

Perform pregnancy tests for female patients prior to treatment initiation. Monitor renal function at baseline and as clinically indicated, LFTs, CBC as clinically indicated; serum Na in at-risk patients. Closely monitor for signs and symptoms of serotonin syndrome, clinical worsening, suicidality, or unusual behavioural changes especially at the start of therapy or during dose adjustments.

Symptoms: Somnolence, dizziness, nausea, tremor, tachycardia, confusion, vomiting, fever, involuntary muscle contractions, ECG changes, mydriasis, convulsions, ventricular dysrhythmias, hypertension, aggressiveness, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, hepatic dysfunction, manic reactions, myoclonus, acute renal failure, urinary retention, serotonin syndrome and coma. Management: Symptomatic and supportive treatment. Ensure adequate airway, oxygenation, and ventilation. Administer 20-30 g activated charcoal within a few hours of ingestion to decrease absorption. Frequently monitor cardiac rhythm and vital signs.

Increased risk of bleeding with aspirin, NSAIDs including COX-2 inhibitors, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. clozapine). May increase risk of hyponatraemia with diuretics. May increase blood glucose levels with pravastatin. May reduce plasma concentration and efficacy of endoxifen (active metabolite of tamoxifen). May reduce absorption of paroxetine oral susp with antacids, histamine H₂-receptor antagonists, PPIs. Decreased plasma levels with fosamprenavir/ritonavir. Increased plasma levels of procyclidine, certain TCAs (e.g. clomipramine, nortriptyline, desipramine), phenothiazines (e.g. perphenazine), risperidone, atomoxetine, certain class 1C antiarrhythmics (e.g. propafenone, flecainide), metoprolol. May increase plasma concentrations with cimetidine.
Potentially Fatal: Increased risk of serotonin syndrome with other serotonergic agents (e.g. triptans, TCAs, fentanyl, lithium, tramadol, pethidine, buspirone, amphetamines, tryptophan) and agents which impair metabolism of serotonin (e.g. MAOIs including linezolid, IV methylene blue). Increased plasma levels of thioridazine and pimozide thus increasing the risk of QTc interval prolongation.

Increased risk of serotonin syndrome with St. John’s wort.

Description:
Mechanism of Action: Paroxetine selectively inhibits serotonin reuptake from the brain synapse, thereby stimulating serotonin activity in the brain.
Onset: Depression: Within 1 week; Anti-obsessional and anti-panic effects: Up to several weeks.
Pharmacokinetics:
Absorption: Readily and completely absorbed from the gastrointestinal tract. Increased peak concentration with food. Time to peak plasma concentration: 5.2-8.1 hours (immediate-release tab, susp); 6 hours (range: 3-8 hours [cap]); 6-10 hours (modified-release tab).
Distribution: Widely distributed throughout body tissues. Crosses placenta and enters breast milk. Volume of distribution: 8.7 L/kg (3-28 L/kg). Plasma protein binding: Approx 93-95%.
Metabolism: Undergoes extensive first-pass metabolism in the liver mainly via oxidation and methylation by CYP2D6 isoenzyme to form polar glucuronide and sulfate conjugates.
Excretion: Mainly via urine (approx 64% as metabolites, 2% as unchanged drug); faeces (approx 36% as metabolites, <1% as unchanged drug). Elimination half-life: Approx 21 hours (immediate release tab); 15-20 hours (modified-release tab).

Source: National Center for Biotechnology Information. PubChem Database. Paroxetine, CID=43815, https://pubchem.ncbi.nlm.nih.gov/compound/Paroxetine (accessed on Apr. 28, 2020)

Modified-release tab; cap: Store between 20-25°C. Protect from light and humidity. Conventional tab: Store between 15-30°C. Oral susp: Store ≤25°C.

Thuốc chống trầm cảm / Thuốc giải lo âu

N06AB05 - paroxetine ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

Hicks JK, Bishop JR, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacology and Therapeutics. 2015 Aug;98(2):127-134. doi: 10.1002/cpt.147. Accessed 14/10/2019. PMID: 25974703

Hicks JK, Bishop JR, Sangkuhl K et al. Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of SSRIs. CPIC Guidelines. Accessed 14/10/2019

Annotation of CPIC Guideline for Paroxetine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 14/10/2019.

Annotation of DPWG Guideline for Paroxetine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 14/10/2019.

Anon. Paroxetine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 14/10/2019.

Brisdelle Capsule (Sebela Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 14/10/2019.

Buckingham R (ed). Paroxetine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/10/2019.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 14/10/2019.

Joint Formulary Committee. Paroxetine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 14/10/2019.

Paxil - Tablet, Film Coated; Suspension (Apotex Corp). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 14/10/2019.

Paxil CR - Tablet, Film Coated, Extended Release (Apotex Corp). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 14/10/2019.

Pexeva Tablet, Film Coated (Sebela Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 14/10/2019.