FDA Safety Changes: Allegra, Cymbalta, Concerta


FDAJanuary 3, 2007 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise that administration of fexofenadine HCl products with fruit juice may decrease therapeutic efficacy; concomitant use of duloxetine HCl therapy with other drugs that affect the serotonergic system may increase the risk for serotonin syndrome; and use of central nervous system stimulants may increase the risk for sudden death in patients with serious heart conditions, may cause or exacerbate psychiatric symptoms in certain patients, and may cause temporary growth suppression.

Fexofenadine HCl (Allegra) Taken With Fruit Juices May Reduce Therapeutic Efficacy

On October 13, 2006, the FDA approved safety labeling revisions for fexofenadine HCl tablets and oral suspension (Allegra, made by Sanofi-Aventis US, LLC) to warn that exposure to fexofenadine may be reduced by their administration with fruit juices.

The warning was based on data from 3 clinical studies, showing that the size and flare of histamine-induced skin wheals were significantly increased by administration of fexofenadine with grapefruit or orange juice rather than water. A population pharmacokinetics analysis of the combined data from these studies and a bioequivalence study further revealed that the bioavailability of fexofenadine was reduced by 36%.

The FDA notes that literature reports suggest that these findings can be extrapolated to other fruit juices, such as apple juice. Although the clinical significance of these findings remains unclear, fexofenadine should be taken with water for maximized therapeutic effect.

Fexofenadine oral solution is indicated for treatment of seasonal allergic rhinitis in children aged 2 to 11 years and of uncomplicated chronic idiopathic urticaria in those aged 6 months to 11 years. The tablets are approved for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria in adults and children aged 6 years and older.

Concomitant Use of Duloxetine HCl (Cymbalta) With Triptans Linked to Risk for Serotonin Syndrome

On September 20, 2006, the FDA approved safety labeling revisions for duloxetine HCl delayed-release capsules (Cymbalta, made by Eli Lilly and Co, Inc) to advise of the potential increased risk for serotonin syndrome in patients receiving concomitant treatment with other serotonergic drugs (including 5-hydroxytryptamine-receptor agonists [triptans]) or drugs that impair serotonin metabolism (including monoamine oxidase inhibitors [MAOIs]). Duloxetine is classified as a serotonin/norepinephrine reuptake inhibitor (SNRI).

Potential symptoms of serotonin syndrome 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.

Concomitant use of duloxetine with MAOIs for the treatment of depression is therefore contraindicated, and use of serotonin precursors (eg, tryptophan) is not recommended.

Caution is advised when using duloxetine 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. Patients for whom concurrent use of an SNRI and a triptan is clinically warranted should be carefully monitored, particularly during treatment initiation and dose increases.

Triptans are a class of drug used to treat migraines and include 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).

Duloxetine delayed-release capsules are indicated for the treatment of major depressive disorder and the management of pain associated with diabetic peripheral neuropathy.

Methylphenidate HCl Extended-Release Tablets (Concerta) Linked to Multiple Risks

On September 7, 2006, the FDA approved safety labeling revisions for methylphenidate HCl extended-release tablets (Concerta, made by Alza Corp) to warn of the increased risk for sudden death associated with their use in patients with serious heart conditions. The drug also increased the potential for exacerbation of preexisting psychiatric disorders and the emergence of treatment-related psychotic/manic symptoms and the risk for temporary growth suppression.

The revisions are associated with an FDA class-labeling initiative for all central nervous system (CNS) stimulants. The first warning was based in part on reports of sudden death associated with use of CNS stimulants at normal doses in children and adolescents with structural cardiac abnormalities or other serious heart conditions. Because of their potential increased vulnerability to sympathomimetic effects, stimulant therapy should be avoided in pediatric patients with these defects.

The FDA notes that while a causative role for the drug remains unclear, serious cardiovascular events (eg, sudden death, stroke, and myocardial infarction) have also been reported in adults receiving stimulant drugs at usual doses.

Because stimulant therapy can exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorders, pretreatment screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Methylphenidate extended-release tablets should be used with caution in patients with comorbid bipolar disorder because of the potential risk for induction of a mixed/manic episode.

However, treatment-emergent psychotic/manic symptoms (eg, hallucinations, delusional thinking, and mania) have also been reported in children and adolescents without prior history of these conditions who have received normal doses of CNS stimulants. Data from a pooled analysis of multiple short-term studies have revealed an increased incidence of these events in patients receiving methylphenidate or amphetamines for several weeks, relative to placebo (0.1% vs 0%). A potential causal role for the stimulant should be considered in patients who develop symptoms of psychosis or mania, and discontinuation of therapy may be indicated.

The FDA notes that although there is no systematic evidence that stimulants cause aggressive behavior or hostility, such symptoms are often observed in children and adolescents with attention-deficit/hyperactivity disorder and have been reported in clinical trial and postmarketing data of some attention-deficit/hyperactivity disorder drugs. Patients should therefore be monitored for the appearance of or worsening of aggressive behavior or hostility during initial therapy.

Growth rate monitoring is also advised for pediatric patients receiving chronic stimulant therapy. The measure is based on data from a careful follow-up of weight and height in children aged 7 to 10 years randomized to receive either methylphenidate or nonmedication treatment for 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children aged 3 years or older to 10 or 13 years.

Study results suggested that children receiving chronic therapy every day for a year experience a temporary slowing in growth rate (mean, 2 cm less in growth height and 2.7 kg less in weight for 3 years) without evidence of growth rebound during this period. The FDA notes that interruption of therapy may be required in children who are not growing or gaining height or weight as expected.

Methylphenidate extended-release tablets are indicated for the treatment of attention-deficit/hyperactivity disorder in children and adolescents.



Pearls for Practice

  • Administration of fexofenadine tablets or oral solution with grapefruit or orange juice has been linked to decreased bioavailability and therapeutic efficacy. Although the clinical significance of these findings remains unclear, these effects may extend to other juices (eg, apple). Fexofenadine should therefore be taken with water to maximize its therapeutic effect.
  • Concomitant treatment with serotonin/norepinephrine reuptake inhibitors, such as duloxetine extended-release capsules, together with serotonergic drugs or those that impair serotonin metabolism can have an additive effect potentially resulting in serotonin syndrome. Concomitant use of duloxetine with monoamine oxidase inhibitors is contraindicated, and use of serotonin precursors (eg, tryptophan) is not recommended. Caution is advised when using fluoxetine in combination with the antibiotic linezolid, lithium, tramadol, St. John's Wort, and triptans.
  • Use of central nervous system stimulants, such as methylphenidate extended-release tablets, should be avoided in children and adolescents with structural cardiac abnormalities or other serious heart conditions.
©2007 Medscape