Antidepressant Warnings

Health Canada and the U.S. Food and Drug Administration (FDA) have issued warnings about antidepressant drugs.

Click here to read the warnings about antidepressants and suicidality.

Click here to read the warnings about antidepressants and birth defects.

Antidepressants and Suicidality

Health Canada

May 2004

Example of letter sent to manufacturers of SSRIs and other newer antidepressants

Subject: Stronger WARNING for SSRIs and other newer antidepressants regarding the potential for behavioural and emotional changes, including risk of self-harm. For paroxetine, this replaces the interim contraindication.

Dear Healthcare professional:

GlaxoSmithKline Inc. (GSK), following discussions with Health Canada, would like to inform you of important safety information regarding the possibility that selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants may be associated with behavioural and emotional changes, including risk of self-harm.

The new Class warning incorporated in the product monograph of paroxetine is provided below.

Please note this warning replaces the interim contraindication for Paxil (paroxetine) issued in July 2003 for patients under 18 years of age with major depressive disorder.

POTENTIAL ASSOCIATION WITH THE OCCURRENCE OF BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicide ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Adult and pediatrics: Additional data

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Discontinuation symptoms

Patients currently taking paroxetine should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue a SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt disruption is recommended.

It should be noted that a causal role of SSRIs and other newer antidepressants in inducing self-harm or harm to others has not been established. The possibility of a suicide attempt is inherent in depression and other psychiatric disorders, and may persist until remission occurs. Therefore, high-risk patients should be closely supervised throughout therapy with appropriate consideration to the possible need for hospitalization. The updated warnings inform practitioners that all patients being treated with SSRIs and other newer antidepressants should be rigorously monitored for clinical worsening, or onset/worsening of agitation-type adverse events, or other indicators of potential for suicidal behaviour.

Paroxetine is not indicated for use in the pediatric population, and controlled clinical studies with paroxetine in children and adolescents under 18 years of age with major depressive disorder fail to demonstrate efficacy.

New Information Added to the Consumer Information Section

The Consumer Information Section of the product monograph has been updated to reflect this new Class warning, and to advise patients that treatment with SSRIs and other newer antidepressants is most safe and effective when there is good communication with the treating physician about how the patient is feeling.

Background

In February 2004, a scientific advisory panel set up by Health Canada was asked to provide the clinical practice perspective on the pediatric clinical trial safety data, and the spontaneous post-marketing reports for SSRIs and other newer antidepressants. The panel agreed that a contraindication was not warranted for these medications, and supported Health Canada’s recommendation for stronger warnings, while providing suggestions and comments.

FDA News Release

May 2, 2007

FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young Adults Who Take Antidepressant Medications

The U.S. Food and Drug Administration (FDA) today proposed that makers of all antidepressant medications update the existing “black box” warning on their products' labeling to include warnings about increased risks of suicidal thinking and behavior, known as suicidality, in young adults ages 18 to 24 during initial treatment (generally the first one to two months).

The proposed labeling changes also include language stating that scientific data did not show this increased risk in adults older than 24, and that adults ages 65 and older taking antidepressants have a decreased risk of suicidality. The proposed warning statements emphasize that depression and certain other serious psychiatric disorders are themselves the most important causes of suicide.

"Today's actions represent FDA's commitment to a high level of post-marketing evaluation of drug products," said Steven Galson, M.D., MPH, director of FDA's Center for Drug Evaluation and Research. "Depression and other psychiatric disorders can have significant consequences if not appropriately treated. Antidepressant medications benefit many patients, but it is important that doctors and patients are aware of the risks."
People currently prescribed antidepressant medications should not stop taking them. Those who have concerns should notify their healthcare providers.

The proposed labeling changes apply to the entire category of antidepressants. Results of individual placebo-controlled scientific studies are reasonably consistent in showing a slight increase in suicidality for patients taking antidepressants in early treatment for most of the medications. Available data are not sufficient to exclude any single medication from the increased risk of suicidality.

The proposed labeling update follows similar labeling changes made in 2005 that warned of a suicidality risk in children and adolescents who use antidepressants. At that time, FDA asked manufacturers to add a “black box” warning to the labeling of all antidepressants to describe this risk and to emphasize the need for appropriate monitoring and close observation, particularly for younger patients taking these medications. In addition, FDA directed manufacturers to develop Medication Guides, FDA-approved user-friendly information for patients, families and caregivers, that could help improve monitoring. Medication Guides are intended to be distributed at the pharmacy with each prescription or refill of a medication.

Also in 2005, FDA began a comprehensive review of 295 individual antidepressant trials that included over 77,000 adult patients with major depressive disorder (MDD) and other psychiatric disorders, to examine the risk of suicidality in adults who are prescribed antidepressants.

In December 2006, FDA's Psychopharmacologic Drugs Advisory Committee agreed that labeling changes were needed to inform health care professionals about the increased risk of suicidality in younger adults using antidepressants. Additionally, the committee noted product labeling needed to reflect the apparent beneficial effect of antidepressants in older adults and to remind health care professionals that the disorders themselves are the most important cause of suicidality.

FDA has been developing language to revise product labeling and update the Patient Medication Guides for these products. Manufacturers of antidepressants will now have 30 days to submit their revised product labels and revised Medication Guides to FDA for review.

Products involved in today's action include:

• Anafranil (clomipramine)
• Asendin (amoxapine)
• Aventyl (nortriptyline)
• Celexa (citalopram hydrobromide)
• Cymbalta (duloxetine)
• Desyrel (trazodone HCl)
• Elavil (amitriptyline)
• Effexor (venlafaxine HCl)
• Emsam (selegiline)
• Etrafon (perphenazine/amitriptyline)
• Fluvoxamine maleate
• Lexapro (escitalopram hydrobromide)
• Limbitrol (chlordiazepoxide/amitriptyline)
• Ludiomil (maprotiline)
• Marplan (isocarboxazid)
• Nardil (phenelzine sulfate)
• Nefazodone HCl
• Norpramin (desipramine HCl)
• Pamelor (nortriptyline)
• Parnate (tranylcypromine sulfate)
• Paxil (paroxetine HCl)
• Pexeva (paroxetine mesylate)
• Prozac (fluoxetine HCl)
• Remeron (mirtazapine)
• Sarafem (fluoxetine HCl)
• Seroquel (quetiapine)
• Sinequan (doxepin)
• Surmontil (trimipramine)
• Symbyax (olanzapine/fluoxetine)
• Tofranil (imipramine)
• Tofranil-PM (imipramine pamoate)
• Triavil (perphenazine/amitriptyline)
• Vivactil (protriptyline)
• Wellbutrin (bupropion HCl)
• Zoloft (sertraline HCl)
• Zyban (bupropion HCl)

FDA Public Health Advisory

June 30, 2005

Suicidality in Adults Being Treated with Antidepressant Medications

Several recent scientific publications suggest the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medications. Even before these reports became available, the FDA began a complete review of all available data to determine whether there is an increased risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. It is expected that this review will take a year or longer to complete. In the meantime, FDA is highlighting that:

Adults being treated with antidepressant medications, particularly those being treated for depression, should be watched closely for worsening of depression and for an increased suicidal thinking or behavior. Close watching may be especially important early in treatment, or when the dose is changed, either increased or decreased.

Adults whose symptoms worsen while being treated with antidepressant drugs, including an increase in suicidal thinking or behaviour, should be evaluated by their healthcare professional.

The Healthcare Professional and Patient Information Sheets for the antidepressant indications will be updated to add this information within the week for the following drugs:

• Celexa (citalopram)
• Cymbalta (duloxetine)
• Effexor (venlafaxine)
• Lexapro (escitalopram)
• Fluvoxamine
• Paxil (paroxetine)
• Prozac (fluoxetine)
• Remeron (mirtazapine)
• Serzone (nefazodone)
• Wellbutrin (bupropion)
• Zoloft (sertraline)

FDA is working closely with the manufacturers of all marketed antidepressants to fully evaluate the risk of suicidality in adults treated with these drugs. The FDA has asked these manufacturers to identify all placebo-controlled trials conducted in adults in their development programs for their antidepressant products, regardless of the indication studied, and to provide information from these trials to FDA. Manufacturers are being asked to use a similar approach to assembling this information as was used in evaluating the risk of suicidality in placebo-controlled trials in pediatric patients treated with antidepressant medications.

FDA’s comprehensive review will involve many hundreds of individual clinical trials and many thousands of adult patients. It is expected that this review will require a year or more to complete because of the large number of trials and the thousands of adverse events that must be checked for possible evidence of suicidality. The FDA will make the results of its review available to the public once its analyses are complete, and will update this advisory in the meantime if more definitive information becomes available.

FDA News

October 15, 2004

FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated with Antidepressant Medications

The Food and Drug Administration (FDA) today issued a Public Health Advisory announcing a multi-pronged strategy to warn the public about the increased risk of suicidal thoughts and behavior (“suicidality”) in children and adolescents being treated with antidepressant medications.

The agency is directing manufacturers to add a “black box” warning to the health professional labeling of all antidepressant medications to describe this risk and emphasize the need for close monitoring of patients started on these medications. FDA has also determined that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs to advise them of the risk and precautions that can be taken, is appropriate, and is in the process of developing one.

“Today’s actions represent FDA’s conclusions about the increased risk of suicidal thoughts and the necessary actions for physicians prescribing these antidepressant drugs and for the children and adolescents taking them. Our conclusions are based on the latest and best science. They reflect what we heard from our advisory committee last month, as well as what many members of the public have told us,” said Dr. Lester M. Crawford, Acting FDA Commissioner.

In letters issued today, FDA directed the manufacturers of all antidepressant medications to add a “black box” warning that describes the increased risk of suicidality in children and adolescents given antidepressant medications and notes what uses the drugs have been approved or not approved for in these patients. FDA’s letters to the manufacturer also discuss other labeling changes designed to include additional information about pediatric studies of these drugs. These labeling changes are applicable to the entire category of antidepressant medications because the currently available data are not adequate to exclude any single medication from the increased risk of suicidality.

Prozac is currently the only medication approved to treat depression in children and adolescents. The analyses of the placebo controlled trials in children and adolescents summarized in the revised labeling are based on studies of five selective serotonin reuptake inhibitors (SSRIs) (Celexa, Prozac, Luvox, Paxil and Zoloft) and four “atypical” antidepressants (Wellbutrin, Remeron, Serzone and Effexor XR). In these studies, there was no reported case of a suicide.

A “black box” warning is the most serious warning placed in the labeling of a prescription medication. Advertisements that serve to remind healthcare professionals of a product’s availability (so called “reminder ads”) are not allowed for products with “black box” warnings. Until now, only ten drug products approved for children contained a “black box” warning about their use in children. The new warning language does not prohibit the use of antidepressants in children and adolescents. Rather, it warns of the risk of suicidality and encourages prescribers to balance this risk with clinical need.

FDA recognizes that depression and other psychiatric disorders in pediatric patients can have significant consequences if not appropriately treated. The new warning language recognizes this need but advises close monitoring of patients as a way of managing the risk of suicidality.

The second element of the agency’s strategy is a Patient Medication Guide (MedGuide), FDA-approved user-friendly information for patients. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication. FDA will work with the manufacturers of antidepressant medications to make the MedGuides available as soon as possible.

In addition, FDA intends to work with manufacturers to implement “Unit of Use” packaging for all antidepressants as a means of ensuring that patients receive a MedGuide with every prescription or refill. “Unit of Use” packaging is a method of preparing a medication in an original container, sealed and pre-labeled by the manufacturer, and containing sufficient medication for one normal course of therapy.

Today’s actions are consistent with the recommendations made at the September 2004 joint meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee and Pediatric Drugs Advisory Committee.

Antidepressants and Birth Defects

Health Canada Advisory

March 10, 2006

Newer Antidepressants Linked To Serious Lung Disorder in Newborns

OTTAWA - Health Canada is advising women who are taking antidepressants known as Selective Serotonin Reuptake Inhibitors (SSRI) and who are pregnant or intend to become pregnant to discuss the situation with their doctor due to potential risks to the baby.

Health Canada stresses that patients should not stop taking SSRI medication without first consulting their doctors, as they could experience serious side effects.

Generally, SSRI treatment should only be continued if the benefits to the individual patient are thought to outweigh the risks to the unborn child, while also considering the benefits and risks of switching to another treatment option or stopping treatment altogether. These precautions and the possibility of adverse health effects in newborns are mentioned in the current Canadian prescribing information and consumer information for SSRIs.
SSRIs and other newer antidepressants prescribed for the treatment of depression include the following drugs: Wellbutrin (bupropion), Celexa (citalopram), Cipralex (escitalopram), Prozac (fluoxetine), Luvox (fluvoxamine), Remeron (mirtazapine), Paxil (paroxetine), Zoloft (sertraline) and Effexor (venlafaxine), and Zyban (bupropion) for smoking cessation.

A study published recently in the New England Journal of Medicine suggests that use of SSRIs during the second half of pregnancy may be associated with a condition called persistent pulmonary hypertension of the newborn. Newborns with this rare but life-threatening condition do not receive enough oxygen in the blood and require intensive-care treatment to survive. According to the study, babies born with this condition were six times more likely than healthy babies to have been exposed to SSRIs. This information is considered to be preliminary at this time.

Numerous reports in Canada and abroad have already indicated that some children exposed to SSRIs and other newer antidepressants during pregnancy may develop serious complications at birth. An increase in the overall risk of major birth defects has also been associated with SSRI use.
The safety of these drugs is vigilantly monitored and Canadians will continue to be informed if new concerns arise. Health Canada advisories on other SSRI-related complications in newborns are available on the Health Canada website. Managing the adverse reactions of marketed health products depends on the active participation of both healthcare professionals and consumers in reporting these reactions. The spontaneous reporting of adverse reactions generally underestimates the risks associated with the use of marketed health products.

FDA Alert

July 2006

Increased Risk of Neonatal Persistent Pulmonary Hypertension

A recently published case-control study has shown that infants born to mothers who took selective serotonin reuptake inhibitors (SSRIs) after the 20th week of pregnancy were 6 times more likely to have persistent pulmonary hypertension (PPHN) than infants born to mothers who did not take antidepressants during pregnancy (see SSRI drug names at the bottom of this sheet). The background risk of a woman giving birth to an infant affected by PPHN in the general population is estimated to be about 1 to 2 infants per 1000 live births. Neonatal PPHN is associated with significant morbidity and mortality. The FDA is updating the prescribing information for all SSRIs with this new information. The FDA is also accruing data from additional sources pertaining to the potential association between SSRIs and neonatal PPHN. The FDA will provide additional information when it becomes available. In the interim, the FDA recommends that physicians carefully consider and discuss with patients the potential risks and benefits of SSRI treatment throughout pregnancy, including late pregnancy.
Considerations

Physicians should consider the benefits and risks of treating pregnant women with SSRIs, alternative treatments, or no treatment late in pregnancy.

Data Summary

A retrospective case-control study published on February 9, 2006, in the New England Journal of Medicine assessed the risk for persistent pulmonary hypertension of the newborn (PPHN) following exposure to SSRIs during pregnancy. 377 women whose infants were born with PPHN and 836 women whose infants were healthy were enrolled in the study in four United States metropolitan areas between 1998 and 2003. The study showed that infants born to mothers who took SSRIs after the completion of the 20th week of gestation were 6 times more likely to have PPHN than infants who were not exposed to antidepressants during pregnancy. 14 infants with PPHN and 6 healthy control infants had been exposed to an SSRI after the 20th week of gestation. There were too few cases of PPHN with each individual SSRI to compare risks for PPHN with individual SSRIs. The study did not find an association between exposure to SSRIs during the first 20 weeks of gestation and PPHN.

Exposure to non-SSRI antidepressants did not appear to be associated with an increased risk of PPHN, although the number of infants with exposure to non-SSRI antidepressants was too small to permit a reliable risk estimate or comparison with the risk observed for SSRIs.

In weighing the risks and benefits of treatment with SSRIs and other antidepressants during pregnancy for individual patients, physicians should also note the recent publication of a prospective longitudinal study of 201 pregnant women with a history of major depression in the February 1, 2006, issue of JAMA. In this study, women who discontinued antidepressant medication during pregnancy had a higher risk of relapse of major depression during pregnancy (68%) than women who maintained antidepressant medication throughout pregnancy (26%).

• SSRI Drug Names
• Celexa (citalopram)
• Fluvoxamine
• Lexapro (escitalopram)
• Paxil (paroxetine)
• Prozac (fluoxetine)
• Symbyax (olanzepine/fluoxetine)
• Zoloft (sertraline)

FDA News

December 8, 2005

FDA Advising of Risk of Birth Defects with Paxil: Agency Requiring Updated Product Labeling

The Food and Drug Administration today is alerting health care professionals and patients about early results of new studies for Paxil (paroxetine) suggesting that the drug increases the risk for birth defects, particularly heart defects, when women take it during the first three months of pregnancy.  Paxil is approved for the treatment of depression and several other psychiatric disorders.  FDA is currently gathering additional data and waiting for the final results of the recent studies in order to better understand the higher risk for birth defects that has been seen with Paxil. 

FDA is advising health care professionals to discuss the potential risk of birth defects with patients taking Paxil who plan to become pregnant or are in their first three months of pregnancy.  Health care professionals should consider discontinuing Paxil (and switching to another antidepressant if indicated) in these patients.  In some patients, the benefits of continuing Paxil may be greater than the potential risk to the fetus.  FDA is advising health care professionals not to prescribe Paxil in women who are in the first three months of pregnancy or are planning pregnancy, unless other treatment options are not appropriate.

FDA is advising patients that this drug should usually not be taken during pregnancy, but for some women who have already been taking Paxil, the benefits of continuing may be greater than the potential risk to the fetus.  Women taking Paxil who are pregnant or plan to become pregnant should talk to their physicians about the potential risks of taking the drug during pregnancy.  Women taking Paxil should not stop taking it without first talking with their physician.

The early results of two studies showed that women who took Paxil during the first three months of pregnancy were about one and a half to two times as likely to have a baby with a heart defect as women who received other antidepressants or women in the general population. Most of the heart defects reported in these studies were atrial and ventricular septal defects (holes in the walls of the chambers of the heart). In general, these types of defects range in severity from those that are minor and may resolve without treatment to those that cause serious symptoms and may need to be repaired surgically.

In one of the studies, the risk of heart defects in babies whose mothers had taken Paxil early in pregnancy was about 2 percent, compared to a 1 percent risk in the whole population. In the other study, the risk of heart defects in babies whose mothers had taken Paxil in the first three months of pregnancy was 1.5 percent, compared to 1 percent in babies whose mothers had taken other antidepressants in the first three months of pregnancy.
FDA has asked the manufacturer, Glaxo Smith Kline (GSK), to change the pregnancy category from C to D, a stronger warning. Category D means that studies in pregnant women (controlled or observational) have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risks to the fetus.
Based on results of the preliminary data, GSK updated the drug's labeling in September 2005 to add data from one study. As additional data have become available, the label has now been changed to reflect the latest data from the two studies and to change the pregnancy category.