Wednesday, November 29, 2006

FDA Safety Changes: Paxil and Paxil CR CME/CE

(Check out the definition of younger adults 18-30)

"Although all cases of suicidal behavior in adult patients with MDD involved nonfatal suicide attempts, the majority of these events (8/11) occurred in younger adults aged 18 to 30 years, suggesting that the risk for suicidality across psychiatric disorders in younger adults may extend beyond the age of 24 years."

 
FDA Safety Changes: Paxil and Paxil CR  CME/CE

News Author: Yael Waknine
CME Author: Yael Waknine


Disclosures

To earn CME credit, read the news brief along with the CME information that follows and answer the test questions.

Release Date: November 22, 2006Valid for credit through November 22, 2007


This activity is part of an ongoing CME/CE initiative to provide information on label changes reported by the FDA. Activities of this nature will be posted by Medscape on a weekly basis.

November 22, 2006 — On August 22, the FDA approved safety labeling revisions for paroxetine HCl tablets/oral suspension and controlled-release tablets (Paxil and Paxil CR, made by GlaxoSmithKline). Paroxetine is approved only for use in adults. The tablet and oral solution formulations are indicated for the treatment of major depressive, obsessive-compulsive, panic, social anxiety, generalized anxiety, and posttraumatic stress disorders. Paroxetine extended-release tablets may be used in the treatment of major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder.

Use of Paroxetine (Paxil, Paxil CR) in Late Pregnancy Linked to Risk for PPHN in Newborns

The FDA has approved safety labeling changes to warn of potential risks associated with both continuation and discontinuation of paroxetine HCl therapy during pregnancy.

Data from a retrospective case-control study of 1213 women suggests that continued use of selective serotonin reuptake inhibitors (SSRIs) past the 20th week of pregnancy is linked to a 6-fold increased risk for persistent pulmonary hypertension (PPHN) in newborns. PPHN normally occurs in 1 or 2 per 1000 births and often involves severe respiratory tract failure requiring immediate treatment.

The FDA notes that although the study was too small to compare individual drugs and the risk has thus far not been investigated by other studies, the potential risk for PPHN adds to growing concerns regarding use of SSRIs during pregnancy.

Newborn adverse events previously reported in association with prenatal exposure include irritability, difficulty feeding, and rare cases of difficulty breathing. In addition, use of paroxetine during the first trimester has been epidemiologically linked to an increased risk for cardiac birth defects.

Women receiving antidepressant therapy who are pregnant or considering becoming pregnant should consult with their healthcare professional prior to discontinuing or continuing antidepressant therapy. Such a decision should be made only after careful consideration of individual treatment-related risks and benefits.

The FDA notes that patients who elect to discontinue SSRI therapy should be closely monitored for depression relapse. According to results from a prospective longitudinal study of 201 women, those who discontinue antidepressant therapy are 5 times more likely to have a relapse during pregnancy compared with those who continue treatment.

Concomitant Use of Paroxetine (Paxil, Paxil CR) and Triptans Linked to Risk for Serotonin Syndrome

The FDA has approved safety labeling changes to advise that concomitant use of selective serotonin reuptake inhibitors (SSRIs), such as paroxetine HCl, with serotonergic drugs (including 5-hydroxytryptamine-receptor agonists [triptans]) or drugs that impair serotonin metabolism (including monoamine oxidase inhibitors [MAOIs]), yields an additive effect on serotonin levels that can lead to potentially life-threatening serotonin syndrome.

Concurrent treatment with paroxetine and MAOIs is therefore contraindicated. Concomitant use of other SSRIs, serotonin/norepinephrine reuptake inhibitors, or the serotonin precursor tryptophan is not recommended. Caution is advised when using paroxetine in combination with other drugs or agents that can affect serotonergic neurotransmitter systems, such as the antibiotic linezolid (a reversible nonselective MAOI), lithium, tramadol, St. John's Wort, and triptans.

According to the FDA, rare postmarketing cases of serotonin syndrome have been reported with use of SSRIs and triptans. Potential symptoms include changes in mental status (eg, agitation, hallucinations, and coma), autonomic instability (eg, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg, hyperreflexia and incoordination), and/or gastrointestinal tract symptoms, such as nausea, vomiting, and diarrhea.

Careful monitoring is advised for paroxetine-treated patients for whom concomitant triptan therapy is clinically warranted, particularly during initiation of therapy, dose increases, or the addition of another serotonergic drug.

Triptans are used to treat migraines. The drug class includes naratriptan HCl (Amerge, made by GlaxoSmithKline), almotriptan malate (Axert, made by Ortho-McNeil Pharmaceutical, Inc), frovatriptan succinate (Frova, made by Endo Pharmaceuticals), sumatriptan/sumatriptan succinate (Imitrex, made by GlaxoSmithKline), rizatriptan benzoate (Maxalt and Maxalt-MLT, made by Merck and Co, Inc), eletriptan HBr (Relpax, made by Pfizer, Inc), and zolmitriptan (Zomig and Zomig ZMT, made by AstraZeneca Pharmaceuticals LP).

Paroxetine (Paxil, Paxil CR) Linked to Increased Risk for Suicidality in Young Adults

The FDA has approved safety labeling changes to warn of the potential increased risk for suicidal behavior in paroxetine-treated patients. Careful monitoring is warranted for all patients regardless of the disorder being treated and may be of particular importance for young adults and those with improving depression.

The warning was based on data from a recent meta-analysis of suicidal behavior and ideation in placebo-controlled clinical trials of paroxetine in adults with psychiatric disorders, such as major depressive disorder (MDD), as well as other depression and nondepression disorders. The trials included 8958 paroxetine-treated patients and 5953 patients who received placebo.

Study results showed that paroxetine therapy was linked to an increased frequency of suicidal behavior in young adults aged 18 to 24 years (2.19% vs placebo, 0.92%). Although not statistically significant, the increase occurred in patients with depressive and nondepressive conditions alike. The FDA notes that no such increase was observed among adults aged 25 years and older.

Paroxetine therapy was also linked to a significantly increased frequency of suicidal behavior among adults of all ages with MDD (0.32% vs placebo, 0.05%). Despite the statistical significance of the finding, the FDA advises that it be interpreted with caution because of the small absolute number and incidence of events.

Although all cases of suicidal behavior in adult patients with MDD involved nonfatal suicide attempts, the majority of these events (8/11) occurred in younger adults aged 18 to 30 years, suggesting that the risk for suicidality across psychiatric disorders in younger adults may extend beyond the age of 24 years.

The FDA notes that the potential increased risk for suicidal behavior in MDD patients was observed despite substantial evidence for efficacy in those receiving paroxetine, as determined using standardized disease-specific instruments, such as the Hamilton Depression and Montgomery-Asberg Depression rating scales. Most patients had an identified social stressor at the time of the event.


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