FDA Safety Labeling Changes: Vesanoid, Kaletra, Axid, Enbrel

Yael Waknine

January 05, 2005

Jan. 5, 2005 -- The U.S. Food and Drug Administration (FDA) approved in October 2004 revisions to safety labeling to advise healthcare professionals of the following changes: use of tretinoin is associated with a 25% risk of toxic syndrome in patients with promyelocytic leukemia; drug interactions between lopinavir/ritonavir and phosphodiesterase-5 inhibitors may result in adverse events; nizatidine should not be used by patients with allergies to acid reducers; etanercept use may be associated with an increased risk of lymphoma.

Tretinoin (Vesanoid) Associated with Risk of Toxic Syndrome

On Oct. 5, the FDA approved revisions to the safety labeling for tretinoin (Vesanoid capsules, made by Roche), warning of the risk of a toxic syndrome associated with its use.

The FDA warns that patients with acute promyelocytic leukemia (APL) are generally at high risk and can have severe adverse reactions to the tretinoin therapy. Tretinoin should only be administered to patients with APL under the strict supervision of a clinician experienced in the management of APL, in a facility with laboratory and supportive services capable of monitoring drug tolerance, and protecting and maintaining patients adversely affected by drug toxicity, including respiratory compromise.

According to the FDA, retinoic acid-APL (RA-APL) syndrome occurs in approximately 25% of APL patients receiving tretinoin. It is characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. Multi-organ failure has resulted in several fatalities.

RA-APL syndrome may present with impaired myocardial contractility and episodic hypertension. Progressive hypoxemia has required intubation and mechanical ventilation in some patients.

The syndrome generally occurs within the first month of treatment, in some cases following the first dose of tretinoin. Tretinoin should only be used in patients for whom the possible benefit outweighs the risk of these adverse events.

The FDA recommends administration of 10 mg dexamethasone every 12 hours for 3 days (or to symptom resolution) at the first sign of RA-APL. Such signs include unexplained fever, dyspnea, and/or weight gain, abnormal chest ascultatory findings or radiographic abnormalities. Tretinoin therapy may be temporarily suspended in patients with moderate to severe symptoms.

The FDA warns that concomitant use of drugs known to cause pseudotumor cerebri/intracranial hypertension (such as tetracyclines) may increase the risk of RA-APL syndrome.

Use of tretinoin is contraindicated in patients with known hypersensitivities to tretinoin, other retinoids, or any of its components.

Tretinoin capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia (APL) who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated.

Lopinavir/Ritonavir (Kaletra) Drug Interaction With Phosphodiesterase-5 Inhibitors

On Oct. 19, the FDA approved changes to the safety labeling for lopinavir plus ritonavir capsules and oral solution (Kaletra, made by Abbott), warning of a possible drug interaction with sildenafil, tadalafil, and vardenafil.

According to the FDA, coadministration of these drugs with lopinavir/ritonavir is expected to substantially increase their concentrations and the risk of associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV infection.

Allergy Alert for Nizatidine (Axid AR)

On Oct. 26, the FDA approved changes to the safety labeling for nizatidine 75-mg tablets (Axid AR, made by Wyeth Consumer Healthcare), advising that the product not be used by patients with allergies to nizatidine or other acid reducers.

Nizatidine should not be used in patients experiencing difficult or painful swallowing, vomiting with blood, or bloody or tarry stools. These may be signs of a serious condition and should be evaluated by a physician. The FDA notes that nizatidine should not be used concurrently with other acid reducers.

Nizatidine is indicated for the treatment of duodenal and gastric ulcers, esophagitis, heartburn due to gastroesophageal reflux disease (GERD), and maintenance of healed duodenal ulcers.

Etanercept (Enbrel) May Be Associated With Increased Risk of Lymphoma

The FDA approved in October changes to the safety labeling for etanercept (Enbrel, made by Immunex Corporation), advising of the risk of lymphoma associated with its use and discouraging concurrent therapy with anakinra.

During controlled trials of 3 to 24 months' duration, three lymphomas were observed among 4509 patients receiving etanercept, compared with 0 in 2040 patients administered placebo. In controlled and open-label clinical trials, lymphomas occurred in 9 of 5723 patients receiving etanercept during approximately 11201 patient-years of therapy.

According to the FDA, the risk of lymphoma in patients receiving etanercept is three-fold higher than that expected in the general population.

Etanercept is indicated in the treatment of rheumatoid arthritis, polyarticular-course juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.

Reviewed by Gary D. Vogin, MD


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