FDA Safety Labeling Changes: Humira, Inderal LA, ProSom, and Others

Yael Waknine

September 15, 2004

Sept. 15, 2004 — The U.S. Food and Drug Administration (FDA) approved in June revisions to safety labeling to advise healthcare professionals of the following changes: adalimumab has been associated with a risk for malignancy, hypersensitivity reactions, and hematologic adverse events; hypersensitivity and cutaneous reactions have been associated with use of propranolol and propranolol/hydrochlorothiazide; estazolam interacts with CYP-3A4 inhibitors and inducers; mirtazapine may cause worsening of depression and suicidality; and metformin HCl is associated with a risk of lactic acidosis.

Adalimumab (Humira) Associated With Risk of Malignancy, Other Adverse Events

On June 18, the FDA approved revisions to the safety labeling for adalimumab (Humira, made by Abbot) to warn of the risk of malignancy, hypersensitivity reactions, and hematologic adverse events that may be associated with its use.

During a controlled-trial period of seven months, two lymphomas were observed among 1,380 adalimumab-treated patients with moderately to severely active rheumatoid arthritis (RA) compared with 0 malignancies among placebo-treated patients. In controlled and open-label studies, 10 lymphomas were observed in 2,468 patients over 4,870 patient-years of adalimumab therapy.

The FDA has also received rare postmarketing reports of anaphylaxis after adalimumab administration. Clinical trials have shown a 1% overall incidence rate of allergic reactions, including allergic rash, anaphylactoid reaction, fixed drug reaction, nonspecified drug reaction, and urticaria.

Tumor necrosis factor-α inhibitors such as adalimumab have been associated with rare reports of pancytopenia, including aplastic anemia. Adalimumab use has resulted in infrequent reports of hematologic adverse events, including medically significant cytopenia.

Adalimumab is indicated for reducing the signs and symptoms of RA, for inhibiting the progression of structural damage in RA, and for improving physical function in adult patients with moderately to severely active RA who have had inadequate response to one or more disease-modifying antirheumatic drugs.

Propranolol (Inderal LA) and Propranolol/Hydrochlorothiazide (Inderide) Linked With Hypersensitivity Reactions

On June 9, the FDA approved revisions to the safety labeling for propranolol HCl capsules and propranolol HCl/hydrochlorothiazide tablets (Inderal LA and Inderide, respectively, both made by Wyeth Pharmaceuticals, Inc.), warning of hypersensitivity and cutaneous reactions associated with their use.

Anaphylactic/anaphylactoid hypersensitivity reactions have been reported, in addition to cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria.

Propranolol is indicated for the management of hypertension, angina pectoris, and arrhythmias, and for the prevention of migraines and myocardial infarction. Propranolol/hydrochlorothiazide is indicated for the treatment of hypertension.

Estazolam (ProSom) Interacts With CYP-3A4 Inhibitors/Inducers

On June 4, the FDA approved revisions to the safety labeling for estazolam tablets (ProSom, made by Abbott), warning of a drug interaction with potent cytochrome P450 3A4 (CYP-3A4) inhibitors such as ketoconazole and itraconazole. Estazolam may be used in conjunction with less potent inhibitors, with appropriate reduction of dose.

Drugs known to inhibit the metabolism of related benzodiazepines via CYP-3A4 inhibition include nefazodone, diltiazem, fluvoxamine, cimetidine, isoniazid, and some macrolide antibiotics.

The FDA expects CYP-3A4 inducers such as carbamazepine, phenytoin, rifampin, and barbiturates to decrease estazolam concentrations, although this has not been confirmed by in vivo studies.

Estazolam is indicated for use as a hypnotic in the short-term management of severe insomnia.

Mirtazapine (Remeron, Remeron SolTabs) May Cause Worsening of Depression, Suicidality

On June 11, the FDA approved revisions to the safety labeling for mirtazapine tablets and mirtazapine orally disintegrating tablets (Remeron and Remeron SolTabs, made by Organon, USA, Inc.) to include the warning that adult and pediatric patients with major depressive disorder may be at risk of worsening depression and/or the emergence of suicidal ideation and behavior until significant remission occurs, regardless of whether antidepressants are being taken.

Although the causal role of antidepressants in inducing such behaviors has not been established, the FDA recommends that patients being treated with these medications be monitored carefully for clinical signs of worsening depression and suicidality, especially at the initiation of therapy and during dose changes.

Mirtazapine is indicated in the treatment of major depressive disorder.

Metformin (Riomet) Associated With Lactic Acidosis

On June 2, the FDA approved revisions to the safety labeling for metformin HCl oral solution (Riomet, made by Ranbaxy), warning of the risk of lactic acidosis associated with its use.

According to the FDA, the reported incidence of lactic acidosis in patients receiving metformin is low (approximately 0.03 cases and 0.015 fatal cases/1,000 patient-years). No cases of lactic acidosis were reported in more than 20,000 patient-years of clinical trials.

Metformin is indicated for use as an adjunct to diet and exercise in improving glycemic control in patients with type 2 diabetes aged 10 years and older.

Reviewed by Gary D. Vogin, MD


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