|Systematic (IUPAC) name|
|Trade names||Paxil, Pexeva, Brisdelle, Rexetin|
|Licence data||US FDA:|
|Pregnancy cat.||D (AU) D (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Bioavailability||Extensively absorbed from the GI tract, but extensive first-pass metabolism in the liver|
|Metabolism||Extensive, hepatic (mostly CYP2D6-mediated)|
|Excretion||Renal (64%; 2% unchanged and 62% as metabolites), Faecal (36%; <1% unchanged)|
|(what is this?)|
Paroxetine (also known by the trade name Paxil among others) is an antidepressant drug of the SSRI type. Paroxetine is used to treat major depression, obsessive-compulsive disorder, panic disorder, social anxiety, posttraumatic stress disorder, generalized anxiety disorder and vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause in adult outpatients.
Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline. Generic formulations have been available since 2003 when the patent expired. As with all antidepressants there may be an increased risk of suicidality in patients receiving paroxetine, although the only solid evidence regarding this is with regard to children and young adults under the age of 25.
Differences between newer antidepressants are usually fairly subtle and mostly confined to side effects. It shares the common side effects and contraindications of other SSRIs, with high rates of nausea, sleepiness, and sexual side effects. Paroxetine is associated with weight gain. Discontinuing paroxetine is associated with a high risk of withdrawal syndrome. Paroxetine is the only SSRI proven to be associated with an increased risk of birth defects.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 7 Formulations
- 8 Society and culture
- 9 Research
- 10 References
- 11 External links
Paroxetine is primarily used to treat major depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder (GAD), social phobia/social anxiety disorder, premenstrual dysphoric disorder (PMDD) and menopausal hot flashes.
Paroxetine was the first antidepressant formally approved in the United States for the treatment of panic attacks.
A variety of meta analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior or equivalent to placebo and that it is equivalent to or inferior to other antidepressants.
Menopausal hot flashes
On June 28, 2013 U.S. FDA approved low dose paroxetine – for the treatment of moderate-to-severe vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause. Randomized controlled trials have shown modest relief in such cases. Side effect such as nausea and weakness are however relatively common.
The American College of Obstetricians and Gynecologists recommends that for pregnant women and women planning to become pregnant, "treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized and paroxetine use among pregnant women or women planning to become pregnant be avoided, if possible." According to the prescribing information "epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant." These conclusions are supported by multiple systematic reviews and meta-analyses that found that, on average, the use of paroxetine during pregnancy is associated with about 1.5–1.7-fold increase in congenital birth defects, in particular, heart defects.
Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses): nausea 26%(9%), diarrhoea 12% (8%), constipation 14% (9%), dry mouth 18% (12%), somnolence 23% (9%), insomnia 13% (6%), headache 18% (17%), hypomania 1% (0.3%), blurred vision 4%(1%), loss of appetite 6% (2%), nervousness 5% (3%), paraesthesia 4% (2%), dizziness 13% (6%), asthenia (weakness; 15% (6%)), tremor 8% (2%), sweating 11% (2%) and sexual dysfunction (≥10% incidence). Most of these adverse effects are transient and go away with continued treatment. Excess 5-HT2 receptor stimulation in the brain results in the increased anxiety, insomnia, reduced libido and irritability. Excess 5-HT2receptor stimulation in the spinal cord results in the physical (as opposed to psychological, namely reductions in libido) aspects of sexual dysfunction such as erectile dysfunction, ejaculatory delay and anorgasmia (trouble achieving orgasm). Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment. Compared to other SSRIs it has a lower incidence of diarrhoea, a higher incidence of anticholinergic effects (e.g. dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects and weight gain.
Sexual side effects often include difficulty becoming aroused, lack of interest in sex, and anorgasmia. Genital anaesthesia, loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months or years after the drug has been completely withdrawn.
On 9 December 2004, the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) informed patients, prescribers, and parents that paroxetine should not be prescribed to children. CHMP also gave a warning to prescribers recommending close monitoring of adult patients at high risk of suicidal behaviour and/or suicidal thoughts. CHMP does not prohibit use of paroxetine with high risk adults but urges extreme caution. Due to reports of adverse withdrawal reactions upon terminating treatment, CHMP recommends to reduce gradually over several weeks or months if the decision to withdraw is made. See also Discontinuation syndrome (withdrawal).
Mania or hypomania may occur in 1% of patients with depression and up to 12% of patients with bipolar disorder. This side effect can occur in individuals with no history of mania but it may be more likely to occur in those with bipolar or with a family history of mania. Cases of akathisia and activation syndrome have been observed during paroxetine treatment. Rarely serotonin syndrome, a severe adverse effect may occur. Paroxetine is associated with an increased risk of hyperacusis as compared with some similar medications.
Paroxetine may increase the risk of suicidal ideation and suicidal behaviour in children and adolescents. Because suicide is rare, it is difficult to test its relationship with the use of paroxetine. Some studies instead analyze suicidality, which generally refers to suicidal ideation and suicidal behaviour. The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004, finding an increase in "suicidality" and ideation as compared to placebo; the trend for increased "suicidality" was observed in both trials for depression and for anxiety disorders. A University of North Carolina review of SSRIs found the average risk of suicide among adolescents was 4%, versus 2% on placebo, and among all patients "the greatest risk of self-harm was among paroxetine users."
Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Evidence has shown that paroxetine has among the highest incidence rates and severity of withdrawal syndrome of any medication of its class. Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as crying and anxiety. Liquid formulation of paroxetine is available and allows a very gradual decrease of the dose, which may prevent discontinuation syndrome. Another recommendation is to temporarily switch to fluoxetine, which has a longer half-life and thus decreases the severity of discontinuation syndrome.
In addition, The Lancet published an analysis of World Health Organization data showing SSRIs taken during pregnancy may cause withdrawal symptoms, including convulsions, in newborn children: among "93 suspected cases of SSRI-induced neonatal withdrawal syndrome...64 were associated with paroxetine, 14 with fluoxetine, nine with sertraline, and seven with citalopram."
Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of paroxetine may be measured to monitor therapeutic administration, confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Plasma paroxetine concentrations are generally in a range of 40–400 μg/L in persons receiving daily therapeutic doses and 200–2000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1–4 mg/L in acute lethal overdose situations. It is usually considered, along with the other SSRIs, sertraline and fluoxetine to be a low-risk drug in cases of overdose.
- The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with PAXIL, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists.
The prescribing information states that paroxetine should "not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI", and should not be used in combination with pimozide, thioridazine, tryptophan, or warfarin.
- CYP2D6 for which it is both a substrate and a potent inhibitor. Its interaction with the CYP2D6 substrate (which is activated by CYP2D6 into its pharmacologically active form) and breast cancer medication, tamoxifen, is so great that the risk of mortality from breast cancer is increased by 24–91% (depending on the time and extent of coexposure) in patients coadministered paroxetine during tamoxifen treatment.
- CYP2B6 (strong) inhibitor.
- CYP3A4 (weak) inhibitor.
- CYP1A2 (weak) inhibitor.
- CYP2C9 (weak) inhibitor.
- CYP2C19 (weak) inhibitor.
Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI). It also binds to the allosteric site of the serotonin transporter, similarly, but less potently than escitalopram. This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects. Paroxetine inhibits the reuptake of norepinephrine more than the other SSRIs, just as sertraline inhibits the reuptake of dopamine more than the other SSRIs.
- SERT (Ki = 0.08 nM)
- NET (Ki = 56.7 nM)
- DAT (Ki = 573.7 nM)
- The following muscarinic acetylcholine receptors (mAChRs):
- α1 adrenoceptor (Ki>100,000 nM)
- Histamine H1 receptor (Ki=22,000 nM)
Paroxetine has been shown to have antimicrobial activity against several groups of microorganisms, mainly Gram positive microorganisms. It also shows synergistic activity when combined with some antibiotics against several bacteria. Additionally, paroxetine has demonstrated antifungal activity, being most potent against the hypersusceptible Candida albicans strain DSY1204.
Paroxetine CR (controlled release) was shown to be associated with a lower rate of nausea during the first week of treatment than paroxetine immediate release. However, the rate of treatment discontinuation due to nausea was not significantly different.
Society and culture
GlaxoSmithKline has paid substantial fines, paid settlements in class action lawsuits, and become the subject of several highly critical books in relation to its marketing of paroxetine, in particular the off-label marketing of paroxetine to children, the suppression of negative research results relating to its use in children, and allegations that it failed to warn consumers of substantial withdrawal effects associated with use of the drug.
In 2002 the U.S. FDA published a warning regarding "severe" discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, bad dreams, and dizziness. The Agency also warned of case reports describing agitation, sweating, and nausea. In connection with a Glaxo spokesperson's statement that withdrawal reactions occur only in 0.2% of patients and are "mild and short-lived", the International Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the Federation's codes of practice.
The suppression of unfavorable research findings on Paxil by GSK — and the legal discovery process that uncovered it — is the subject of Alison Bass's 2008 book Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial.
Off-label marketing to children
In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million. The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavorable Paxil research results. One of GSK's internal documents had said, "It would be commercially unacceptable to include a statement that efficacy [in children] had not been demonstrated, as this would undermine the profile of paroxetine".
In 2012 the U.S. Justice Department announced that GSK had agreed to plead guilty and pay a $3 billion fine, in part for promoting the use of Paxil for children.
In 2007, paroxetine was ranked 94th on the list of bestselling drugs, with over $1 billion in sales. In 2006, paroxetine was the fifth-most prescribed antidepressant in the United States retail market, with more than 19.7 million prescriptions. In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.
In 1999 paroxetine was the second SSRI (after fluvoxamine) to be approved in Japan. Paroxetine became the first and non-hormonal prescription therapy for menopausal hot flashes approved by FDA.
Several studies have suggested that paroxetine can be used in the treatment of premature ejaculation. In particular, intravaginal ejaculation latency time (IELT) was found to increase with 6–13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram). However, paroxetine taken acutely ("on demand") 3–10 hours before coitus resulted only in a "clinically irrelevant and sexually unsatisfactory" 1.5-fold delay of ejaculation and was inferior to clomipramine, which induced a fourfold delay.
Emerging evidence shows that antipsychotics can be used as a supplement or alternative to paroxetine in patients with generalised anxiety disorder.
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