FDA Safety Labeling Changes: CombiPatch, Antidepressants

Yael Waknine

March 23, 2005

March 23, 2005 — The U.S. Food and Drug Administration (FDA) approved in January revisions to safety labeling to advise healthcare professionals of the following changes: estradiol plus norethindrone acetate transdermal system is contraindicated for use in preventing cardiovascular disease and dementia and in pregnant women; use of drugs approved to treat major depressive disorder is associated with an increased risk of suicidality in children and adolescents.

Estradiol/Norethindrone Transdermal System (CombiPatch) Contraindicated for Prevention of CVD, Dementia and in Pregnancy

On Jan. 13, the FDA approved revisions to the safety labeling for an estradiol/norethindrone acetate transdermal system (CombiPatch, made by Novartis Pharmaceuticals Corp.) to reflect additional contraindications for its use.

Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. Estrogen therapy, alone or in combination with progestins, has been linked to an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism. In addition, estrogen-progestin therapy has been associated with an increased risk of probable dementia in postmenopausal women (risk compared with placebo, 2.05).

The patch should not be used in women with known or suspected pregnancy. The FDA notes that there is no indication for its use in pregnancy. Inadvertent use in early pregnancy of estrogens and progestins from contraceptives has not been linked to a significant increase in risk of birth defects.

The estradiol/norethindrone patch is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy associated with menopause. It is also indicated for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Antidepressant Use in Children, Adolescents Linked to Increased Risk of Suicidality

On Jan. 12, the FDA approved revisions to the safety labeling for all drugs approved to treat major depressive disorder (MDD), warning of the increased risk of suicidal thinking and behavior (suicidality) associated with their use in children and adolescents.

Pediatric patients with MDD may experience worsening of their depression and/or emergence of suicidal ideation and behavior or unusual changes in behavior until significant remission occurs — regardless of whether antidepressants are being taken.

The warning was based on an analysis of pooled data from 24 short-term, placebo-controlled trials of nine antidepressant drugs (selective serotonin reuptake inhibitors and others) in more than 4,400 children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders.

The analysis revealed that treatment with antidepressants significantly increased the mean risk of adverse events representing suicidality in this population compared with placebo (4% vs 2%) and that this risk was greater during the first few months of treatment. No suicides occurred in any of the trials.

Although considerable variation in risk was observed among the drugs, the FDA notes that a tendency toward increase was observed for almost all those studied. This trend occurred most consistently in the MDD trials, but it was also present in some trials for other psychiatric indications, including OCD and social anxiety disorder.

It is unknown whether the suicidality risk in pediatric patients extends to longer-term use (beyond several months) or to adults.

The FDA recommends that all pediatric patients being treated with antidepressants be monitored closely for clinical worsening, suicidality, and unusual changes in behavior — particularly during the initial few months of therapy and when dose changes.

Suchmonitoring should include weekly face-to-face contact with patients or their family members/caregivers during the first month of treatment, then every other week visits for the next month, then at three months, and thereafter as clinically indicated.

Similar monitoring is recommended for adults with MDD or comorbid depression in the setting of other psychiatric illness being treated with antidepressants. The FDA notes that consideration should be given to changing or discontinuing the therapeutic regimen in patients with persistently worsening depression or suicidality that is newly emergent, severe, or abrupt in onset.

The warning applies to safety labeling for clomipramine HCl tablets (Anafranil, made by Mallinkrodt, Inc.); nortriptyline HCl oral solution (Aventyl, made by Ranbaxy, Inc.); trazodone HCl tablets (Desyrel, made by Apothecon, a Bristol-Myers Squibb company); chlordiazepoxide plus amitriptyline HCl tablets (Limbitrol, made by Valeant Pharmaceuticals, Inc.); isocarboxazid tablets (Marplan, made by Oxford Pharmaceuticals, Inc.); desipramine HCl tablets (made by Aventis Pharmaceuticals, Inc.); nortriptyline HCl capsules and oral solution (Pamelor, made by Mallinkrodt, Inc.); tranylcypromine sulfate tablets (Parnate, made by GlaxoSmithKline), paroxetine HCl controlled-release tablets, tablets, and oral suspension (Paxil, made by GlaxoSmithKline).

It has also been included in the labeling for paroxetine mesylate tablets (Pexeva, made by Synthon Pharmaceuticals, Ltd.); mirtazapine orally disintegrating tablets and tablets (Remeron SolTab and Remeron, made by Organon, Inc.); nefazodone HCl tablets (Serzone, made by Bristol-Myers Squibb Co.); trimipramine maleate capsules (Surmontil, made by Odyssey Pharmaceuticals); imipramine pamoate capsules (Tofranil-PM, made by Mallinkrodt, Inc.); bupropion HCl tablets, sustained-release tablets, and extended-release tablets (Wellbutrin, Wellbutrin SR and Zyban, and Wellbutrin XL, made by GlaxoSmithKline).

Reviewed by Gary D. Vogin, MD

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