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Paroxetine

Clinical data
License data	US FDA: Paroxetine
Routes of administration	Oral
ATC code	N06AB05 (WHO)
Legal status
Legal status	US: WARNING In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	complete absorption from GI, but extensive first-pass-metabolization in the liver; max concentration 4.9 (with meals) to 6.4 hours (fasting)
Metabolism	extensive, probable hepatic
Elimination half-life	24 hours (range 3-65 hours)
Excretion	66% urine, 37% bile
Identifiers
IUPAC name (3S-trans)-3-((1,3-Benzodioxol-5-yloxy)methyl)- 4-(4-fluorophenyl)-piperidine
CAS Number	61869-08-7
PubChem CID	43815
DrugBank	APRD00364
CompTox Dashboard (EPA)	DTXSID3023425
ECHA InfoCard	100.112.096
Chemical and physical data
Formula	C19H20FNO3
Molar mass	374.8 g·mol

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Paroxetine or paroxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI) antidepressant. It was released in 1992 by the pharmaceutical company GlaxoSmithKline and has since become one of the most prescribed antidepressants on the market due to its efficacy in treating depression as well as a spectrum of anxiety disorders ranging from panic attacks to phobias.

Trade names

Paroxetine is marketed under several tradenames:

• Aropax or Oxetine in Australia, New Zealand, South Africa, Argentina and Brazil,
• Aroxat or Aroxat CR in Chile,
• Cebrilin in Latin America,
• Deroxat in Switzerland and France,
• Motivan in Spain,
• Optipar in Finland,
• Paroxat in Germany and Hungary,
• Paxil or Paxil CR in the United States, Canada, Mexico, Argentina, Brazil and Venezuela,
• Pondera in Brazil,
• Seroxat in Austria, Belgium, Finland, Sweden, Greece, Israel, The Netherlands, Poland, Portugal, Singapore, Spain, Turkey, the UK and China,
• Posivil in Chile,
• Pexot, Paraxyle and Plasare in Pakistan

Indications

Approved

Paroxetine is primarily used to treat the symptoms of depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder (GAD), social phobia/social anxiety disorder, and premenstrual dysphoric disorder (PMDD).

It was the first (and as of 2002, the only) antidepressant formally approved in the United States for the treatment of social anxiety disorder, causing it to be sometimes referred to (although inaccurately) as an anti-shyness drug.

Clinical Trials

Trials for Paxil CR have not lasted more than twelve months. The effectiveness of Paxil in major depressive disorders has been proven by two twelve week clinical trials in which the patients either had flexible doses or a placebo. Both of the studies concluded that Paxil is significantly more effective than the placebo control group. For another disorder, three 10-week studies were conducted to prove the effectiveness of Paxil CR on panic disorders. In the first and second studies, Paxil proved consistently better than the placebo. But the third trial Paxil CR failed to have any significant difference to the placebo. For social anxiety disorder, a 12-week trial for adult outpatients was conducted to show Paxil's effectiveness against the disease and prior information of Paxil's nature in the immediate release formulation. The study did not include adolescents with the disorder.

Unapproved/Off-label/Investigational

Paroxetine can also be used in the treatment of premature ejaculation, chronic headache, and bipolar disorder.

Paroxetine has not been found to significantly reduce the symptoms of diabetic neuropathy.

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling and hot flashes.

Pharmacology

Paroxetine is the most potent selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects.

Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α₁, α₂, β), dopaminergic, serotonergic (5HT₁, 5HT₂), or histamine receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine and noradrenaline receptors was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.

Paroxetine controlled release (CR)

Paroxetine controlled release contains a Geomatrix™ tablet that controls the absorption of the drug. Clinical studies show that controlled release tablet provides effective symptom relief with a lower number of patients stopping their treatment due to side effects.

However, the need for an extended release form of paroxetine has not been established, as the FDA indicated that the half-life for the original Paxil was ideal for once-daily dosing, and that a CR version was not needed.

Chemistry

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.

Formulations

Paxil / Seroxat (paroxetine) is available in 10, 20, 30, and 40 mg tablets.

Paxil CR (paroxetine extended release) is available in 12.5, 25, and 37.5 mg tablets.

Paxil, Seroxat and Paxil CR are manufactured by GlaxoSmithKline, however a generic is now available under the chemical name paroxetine.

Side effects

General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug. Almost all SSRIs are known to cause either one or more of these symptoms. A person receiving paroxetine treatment may experience a few, all, or none of the following side-effects, and most side-effects will disappear or lessen with continued treatment, though some may last throughout the duration.

• Nausea
• Teratogenicity: Pregnant women are advised not to take the drug due to possible fetal heart defects.
• Drowsiness
• Headache
• Changes in weight and appetite
• Changes in sexual behaviour
• Increased feelings of depression and anxiety (initially)
• Dry mouth
• Aggressive behavior (esp. in children)
• Possible suicidal behavior
• Possible congenital malformations
• Rash
• Restlessness or Akathisia
• Itch
• Sodium depletion
• Sweating
• Muscle weakness
• Uncharacteristic levels of aggression
• Serotonin syndrome

Individuals experiencing any of the following symptoms should contact their doctor immediately:

• Jaw, neck, and back muscle spasms
• Fever, chills, sore throat, or flu-like symptoms
• Yellowing of the skin or eyes
• Black, tarry stools (this can indicate upper GI bleeding)

Paroxetine and other SSRIs have been shown to cause sexual side effects in most patients, both males and females. Although usually reversible, these sexual side effects can sometimes last for months, years or possibly indefinitely even after the drug has been completely withdrawn. This disorder is known as Post SSRI Sexual Dysfunction.

Discontinuation syndrome

While any psychoactive medication (from caffeine to anti-psychotics) can cause withdrawal symptoms upon discontinuation from acute administration, anecdotal evidence suggests that paroxetine has a higher incidence rate and severity of SSRI discontinuation syndrome than other SSRIs and psychoactive medications. For those experiencing extreme and unusual difficulty discontinuing paroxetine, it is recommended that an SSRI with a longer half-life, such as fluoxetine, be administered for approximately two weeks, then discontinued, to lessen symptoms.

Suicidal ideation is a frequently reported experience in those withdrawing from SSRIs. Withdrawal from paroxetine or any other SSRI should be medically supervised.

Warning for nursing mothers

Pregnant women and those who might become pregnant should avoid taking the antidepressant Paxil because of a high risk of birth defects, according to a committee of obstetricians who published their opinion in the December issue of the journal Obstetrics & Gynecology.

The obstetric practice committee of the American College of Obstetricians and Gynecologists said pregnant women should not take Paxil because two previous studies found that the drug posed up to double the risk of heart defects in fetuses.

Nearly a year ago, the U.S. Food and Drug Administration (FDA) and GlaxoSmithKline -- which makes Paxil -- changed the warnings on the drug to include the results of the studies. The FDA then advised pregnant women to merely switch from Paxil to another SSRI drug, such as Prozac or Zoloft.

The FDA's enhanced warning on Paxil followed the results of a review of Sweden's birth registry that found pregnant women who took Paxil were 1.5 to 2 times more likely to give birth to a baby with heart defects than women who took other SSRIs or who did not take antidepressants at all.

Neonatal withdrawal symptoms from Paxil have also been documented from mothers taking Paxil during pregnancy.

Controversy

On Dec 22, 2006, US court decided in Hoorman, et al. v. SmithKline Beecham Corp that individuals who purchased Paxil(R) or Paxil CR(TM) (paroxetine) for a minor child may be eligible for benefits under a $63.8 million Proposed Settlement. The lawsuit won the argument that pharmaceutical maker GlaxoSmithKline (GSK) promoted Paxil(R) or Paxil CR(TM) for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors.

The lawsuit stemmed from a consumer advocate protest against Paroxetine manufacturer GSK. Since the FDA approved paroxetine in 1992, approximately 5,000 U.S. citizens – and thousands more worldwide – have sued GSK. Most of these people feel they were not sufficiently warned in advance of the drug's side effects and addictive properties. However, GSK certainly must have known of the drug's potential dangers since, in clinical trials, up to 50 percent of patients taking paroxetine experienced adverse withdrawals from the drug.

According to the Paxil Protest website, http://www.paxilprotest.com, hundreds more lawsuits have been filed against GSK. The Paxil Protest website was launched August 8, 2005 to offer both information about the protest and information on Paxil previously unavailable to the public. Just three weeks after its launch, the site received more than a quarter of a million hits.

Footnotes

1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
2. Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005). "Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology". Journal of Psychopharmacology. 19 (6): 567–596. PMID 16272179.{{cite journal}}: CS1 maint: multiple names: authors list (link)
3. D Baldwin, J Bobes, DJ Stein, I Scharwachter and M Faure (1999). "Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled study. Paroxetine Study Group". The British Journal of Psychiatry. 175: 120–126. PMID 10627793.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. Yonkers KA, Gullion C, Williams A, Novak K, Rush AJ. (1996). "Paroxetine as a treatment for premenstrual dysphoric disorder". Journal of Clinical Psychopharmacology. 16 (1): 3–8. PMID 8834412.{{cite journal}}: CS1 maint: multiple names: authors list (link)
5. Waldinger MD, Hengeveld MW, Zwinderman AH. (1994). "Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study". The American Journal of Psychiatry. 151 (9): 1377–1379. PMID 8067497.{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. Foster CA, Bafaloukos J. (1994). "Paroxetine in the treatment of chronic daily headache". Headache. 34 (10): 587–589. PMID 7843954.
7. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF (2002). "A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers". Journal of Clinical Psychiatry. 63 (6): 508–512. PMID 12088162.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. Vieta E, Martinez-Aran A, Goikolea JM, Torrent C, Colom F, Benabarre A, Reinares M (1999). "The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms". Pain. 42 (2): 135–144. PMID 2147235.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. Kim SW, Grant JE, Adson DE, Shin YC, Zaninelli R (2002). "A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling". Journal of Clinical Psychiatry. 63 (6): 501–507. PMID 12088161.{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. Weitzner MA, Moncello J, Jacobsen PB, Minton S. (2002). "A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer". Journal of Pain and Symptom Management. 23 (4): 337–345. PMID 11997203.{{cite journal}}: CS1 maint: multiple names: authors list (link)
11. Golden RN, Nemeroff CB, McSorley P, Pitts CD, Dube EM. (2002). "Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression". Journal of Clinical Psychiatry. 63 (7): 577–584. PMID 12143913.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. FDA Warning on Birth defects
13. Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord 2006;91:27-32. PMID 16430968.
14. Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf. 24 (3): 183–97. PMID 11347722.
15. Quitpaxil.org - Information for persons suffering from Paxil withdrawal syndrome
16. Yerevanian B, Koek R, Feusner J, Hwang S, Mintz J (2004). "Antidepressants and suicidal behaviour in unipolar depression". Acta Psychiatr Scand. 110 (6): 452–8. PMID 15521830.{{cite journal}}: CS1 maint: multiple names: authors list (link)
17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17138801&query_hl=2&itool=pubmed_docsum PMID = 17138801
18. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16166193&query_hl=6&itool=pubmed_docsum
19. Paxil® Pediatric Settlement Web site
20. National Paxil Protest invites antidepressant drugs victims to join public outcry against GlaxoSmithKline September 06, 2005

External links

• Paroxetine.com - The official paroxetine site
• paxilprogress.org - Paxil Discussion Board
• Paxil Information from Drugs.com
• Paxil Patient Information leaflet, Paxil Patient Information leaflet
• Paxil CR Patient Information leaflet, Paxil CR Patient Information leaflet
• Detailed Paroxetine Consumer Information: Uses, Precautions, Side Effects from medlibrary.org
• The Secrets of Seroxat, BBC Panorama investigation
• Antidepressant Use in Children Soars Despite Efficacy Doubts, Washington Post, April 18, 2004
• Dependence on Antidepressants & Halting SSRIs - protocol for withdrawal
• NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
• NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
• one persons story of how they overcome their battle with Seroxat (Fluoxetine)

• Selective serotonin reuptake inhibitors