Paroxetine

Article Author:
Prabina Shrestha
Article Editor:
Sara Abdijadid
Updated:
1/26/2019 9:43:55 PM
PubMed Link:
Paroxetine

Indications

Paroxetine is a selective serotonin reuptake inhibitor (SSRI). It is used to treat several diseases including major depressive disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and premenstrual dysphoric disorder. It is used in the treatment of hot flashes and night sweats that are associated with menopause. Side effects that are most common include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping and delayed ejaculation. It is believed to be associated with a slightly increased risk of birth defects. The rate of withdrawal symptoms in young people may be higher with paroxetine than other SSRIs and selective norepinephrine serotonin reuptake inhibitors (SNRIs). Paroxetine is associated with suicidal thinking and behavior in children and adolescents.

FDA Approved Indications

Paroxetine is an antidepressant approved by the FDA for the following disorders:

  • Major depressive disorder[1]
  • Generalized anxiety disorder
  • Obsessive-compulsive disorder
  • Panic disorder
  • Social anxiety disorder (social phobia)
  • Posttraumatic stress disorder
  • Premenstrual dysphoric disorder

It has shown to increase the risk of suicidal ideation in children, adolescent, and young adults. Therefore, it is not FDA approved in use of children and adolescents less than 18 years of age.

Off-Label Use in Children and Adolescents

  • Obsessive-compulsive disorder
  • Social anxiety disorder

Mechanism of Action

Paroxetine falls under the umbrella of SSRIs, so it inhibits the serotonin reuptake pump. It also desensitizes serotonin receptors, in particular, the 1A autoreceptor. In a radioligand study, paroxetine has also shown little affinity for muscarinic, alpha1, alpha2, beta-adrenergic, dopamine (D2), 5-HT2, and H1 receptors.[2]

Metabolism

The steady state mean values of T1/2 is 21 hours. Paroxetine is metabolized by P450 2D6. 2% is excreted by the urine, 62% metabolized over a 10-day post-dosing period, 36% excreted in the feces. Paroxetine inhibits CYP2D6 and its metabolism.[3]

Protein Binding

Ninety-five percent to 93% of paroxetine is bound to plasma protein.

Patients with liver and renal disease: Patients have increased the plasma concentration of paroxetine. Lower dosages to be used when treating patients with renal or hepatic disease.

Administration

Paroxetine is administered orally. The medication should be titrated based on the patient symptoms and tolerance to dosage. The medication can be taken with or without food. In addition to regular tablets, it is available in controlled-release tablet as well as liquid form. Paroxetine is given once daily at bedtime. However, it may be administered any time of the day depending on toleration.

For Major Depression

Immediate-release formulas

  • Adults: start with 20 mg by mouth (PO) daily and increase by 10 mg weekly with a max of 50 mg per day
  • Geriatric adults: start with 10 mg PO daily and then increase by 10 mg weekly with a max dose of 40 mg per day PO

Controlled-release formulas:

  • Adults: Start with 25 mg PO daily then increase by 12.5 mg weekly with a max of 62.5
  • Geriatrics: Start with 12.5 mg PO once daily then increase to 12.5 if needed weekly

Generalized Anxiety Disorder

Immediate release formulas

  • Adults: 20 mg PO once daily. Titrate the dose by 10 mg per day at weekly intervals if needed with a max dose to 60 mg per day
  • Geriatric Adults: 10 mg PO once daily and titrate 10 mg per day at weekly intervals. Usually effective at 20 mg PO daily but can increase up to 40 mg per day

Premenstrual Dysphoric Disorders

Controlled-release tablet

  • Adult Females: 12.5 mg per day PO. Effective doses were between 12.5 to 25 mg per day

Immediate-release formulation

  • Adult females: 5 mg per day to 30 mg per day

Vasomotor Disorder Secondary to Menopause

Controlled release tablets: 12.5 mg PO daily and titrated to 25 mg PO weekly

Obsessive-Compulsive Disorder

Immediate release formulation

  • Adult: 20 mg once daily and increase by 10 mg per day weekly intervals if tolerated. Titrate the dose include 40 mg PO once daily with a max of 60 mg per day
  • Geriatric: 10 mg once daily. If needed increase to 10 mg per day at weekly intervals with a max dose of 40 mg per day
  • Children and adolescents 7 years and older: 10 to 50 mg PO; 10 mg per day increase at intervals of a week with a max of 50 mg per day 

Panic Disorder

Immediate-release formulation

  • Adult: 10 mg PO once daily and increase the dose to 10 mg per day at weekly intervals with a target dose of 40 mg per day with a max dose of 60 mg per day
  • Geriatrics: 10 mg PO once daily and increase 10 mg per day at weekly intervals with a target dose of 40 mg per day. Max dose is 40 mg per day
  • Children and adolescents 7 years and older: 10 mg PO; Max dose 40 mg per day

Controlled-release tablets

  • Adults: 12.5 mg PO once daily and increase by 12.5 mg at weekly intervals. The effective dose range is 12.5 to 75 mg per day with a max dose of 75 mg per day
  • Geriatrics Adults: 12 mg PO daily and increase by 12.5 mg at weekly intervals. The effective dose is 12.5 to 75 mg per day. The recommended maximum dose is 50 mg per day

Post Traumatic Stress Disorder

Immediate-release formulation

  • Adults: 20 mg PO daily. Effective dose range from 20 to 50 mg per day. With a max dose of 60 mg per day
  • Geriatrics: 10 mg PO once daily and increase by 10 mg per day at a weekly interval. Max dose of 40 mg per day PO

Social Phobias

Immediate release formulation

  • Adult: 20 mg per day PO; Effective dose range is 20 to 60 mg per day; Titrate to 10 mg per day weekly; Max dose of 60 mg per day
  • Geriatric adults: 10 mg PO and titrate by 10 mg per day; Target the dose 20 mg per day with a max dose of 40 mg per day
  • Children and adolescents 8 years and older: 10 mg per day and titrate 10 mg per day at a weekly interval; The maximum dose of 50 mg per day PO

Controlled release formulation

  • Adult: 12.5 mg per day PO and titrate at intervals of at least one week and an increase of 12.5 mg per day; Max dose of 37.5 mg per day PO

Renal Impairment: Adults

For patients with renal impairment, the dosage is based on creatinine clearance as shown below.

  • If the CrCL is 30 to 60 ml per minute: No need to change the dosing
  • If CrCl less than 30 ml per minute:
    • Immediate release formulation: 10 mg per day; increase if needed by 10 mg per day increments at interval of at least a week; maximum dose: 40 mg per day
    • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at interval 1 week; maximum dose: 50 mg per day

Hepatic Impairment Adults

In hepatic impairment that plasma concertation is 2 times that is seen in normal function.

  • If mild to moderate: no change in dosage
  • If severe
    • Immediate release formulations: 10 mg per day and if needed increase by 10 mg per day at intervals of 1 week; maximum dose of 40 mg per day
    • Controlled release formulation: 12.5 mg per day; increase if needed by 12.5 mg per day increments at intervals of 1 week; Maximum dose of 50 mg per day

Adverse Effects

General Side Effects

Insomnia, anxiety, nausea, diarrhea, flatulence, and impotence.

The most common side effects in vasomotor symptoms include abdominal pain.

Other Adverse Effects

  • Psychiatric: Insomnia in more than 10%, hypomania or mania (1%). In children and adolescents and young adults (18-24 years of age) paroxetine increase the risk of suicide
  • Nervous system: Extrapyramidal symptoms, dizziness, headache, tremor
  • Metabolic: hyponatremia
  • Cardiovascular: Edema, chest pain, palpitations, tachycardia, vasodilation
  • Genitourinary: Decreased libido, ejaculation disturbances
  • Dermatologic: Alopecia, Eczema, photosensitivity, purities
  • Gastrointestinal: Constipation, diarrhea, dry mouth, nausea

Contraindications

Monoamine Oxidase Inhibitor (MOAI)

If the patient is taking MOAI patient need to look out for serotonin syndrome

Thioridazine

Paroxetine inhibits the metabolism of thioridazine because it inhibits CYP2D6.[4]

Cautions

  • TCA because paroxetine inhibits TCA metabolism
  • Drugs highly bound to plasma protein: Paroxetine has a high binding affinity to plasma protein. A patient who takes drugs that have a high binding affinity to plasma protein will increase the free concentration of the other drug.
  • Alcohol
  • Drugs affecting hepatic metabolism: Cimetidine, Phenobarbital, phenytoin

Paroxetine is not recommended for use during pregnancy or if breastfeeding. Based on epidemiological studies, infants exposed to paroxetine during the first trimester had an increased risk for cardiovascular malformations. Paroxetine is excreted in the breast milk.

Monitoring

Patients on paroxetine should be observed closely and monitored for worsening clinical symptoms (serotonin syndrome), behavior changes (mania, social function, anxiety) or suicidal ideations.

Labs should include serum sodium concentration.

Liquid chromatography detected at 295/30nm PAR[5]

Monitor for serotonin syndrome, which can occur with the combination of different serotonergic agents such as triptans, TCA, lithium or tramadol. Other agents include MAOIs. The signs of serotonin symptoms include a change in mental status, autonomic instability and neuromuscular changes, gastrointestinal symptoms, as well as hyperreflexia and myoclonus. The treatment includes discontinuing the medication.[6]

The use of diuretic along with the medication increase the risk for the syndrome of inappropriate antidiuretic hormone secretion (SIAH) and hyponatremia.[7]

Toxicity

Though it is rarely lethal in overdose by itself, it is possible for patients to develop somnolence, nausea, tremor, heart rhythm disturbances, confusion, vomiting, dizziness, and mydriasis. During toxicity, a patient’s airway, oxygenation, and ventilation should be assessed first. The treatment for overdose includes symptomatic supportive treatment. Activated charcoal should be administered as well. There is no specific treatment for paroxetine toxicity.[8]

Enhancing Healthcare Team Outcomes

Inter-professionalism can impact a patients outcome in a positively. The increase in communication between the various department such as pharmacy and psychiatry can overall benefit the patient.[9] Each department acknowledges what the patients' needs and implement the plan. The pharmacist can provide the dosing for the patient and monitor toxicity levels. Each patient is unique, some may require a different dosage because of renal of hepatic dysfunction. This allow the patient to have a correct dosage based on their co-morbid conditions. The psychiatrist can monitor the patient at the clinical aspect for improvement or if needed changes in the medication. Besides this there is support from both sides of the team. 


References

[1] Monden R,Roest AM,van Ravenzwaaij D,Wagenmakers EJ,Morey R,Wardenaar KJ,de Jonge P, The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews. Journal of affective disorders. 2018 Aug 1     [PubMed PMID: 29677603]
[2] van Harten J, Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clinical pharmacokinetics. 1993 Mar     [PubMed PMID: 8384945]
[3] Uttamsingh V,Gallegos R,Liu JF,Harbeson SL,Bridson GW,Cheng C,Wells DS,Graham PB,Zelle R,Tung R, Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine. The Journal of pharmacology and experimental therapeutics. 2015 Jul     [PubMed PMID: 25943764]
[4] Dean L, Thioridazine Therapy and {i}CYP2D6{/i} Genotypes null. 2012     [PubMed PMID: 28520378]
[5] Magalhães P,Alves G,Llerena A,Falcão A, Therapeutic Drug Monitoring of Fluoxetine, Norfluoxetine and Paroxetine: A New Tool Based on Microextraction by Packed Sorbent Coupled to Liquid Chromatography. Journal of analytical toxicology. 2017 Sep 1     [PubMed PMID: 28873974]
[6] Fitzgerald KT,Bronstein AC, Selective serotonin reuptake inhibitor exposure. Topics in companion animal medicine. 2013 Feb     [PubMed PMID: 23796482]
[7] Koide T,Wakabayashi T,Matsuda T,Horiike S,Watanabe K, Hyponatremia associated with paroxetine induced by sodium-restricted diet and hypotonic saline. Pharmacy world     [PubMed PMID: 20013054]
[8] Calisto V,Ferreira CI,Oliveira JA,Otero M,Esteves VI, Adsorptive removal of pharmaceuticals from water by commercial and waste-based carbons. Journal of environmental management. 2015 Apr 1     [PubMed PMID: 25617872]
[9] Pontefract SK,Coleman JJ,Vallance HK,Hirsch CA,Shah S,Marriott JF,Redwood S, The impact of computerised physician order entry and clinical decision support on pharmacist-physician communication in the hospital setting: A qualitative study. PloS one. 2018     [PubMed PMID: 30444894]