FDA Safety Labeling Changes: Requip, Lodine, Zestril

Yael Waknine

August 24, 2005

Aug. 24, 2005 — The U.S. Food and Drug Administration (FDA) approved in May revisions to safety labeling to advise that use of ropinirole for the treatment of moderate to severe restless legs syndrome is associated with risks of somnolence, syncope, and hypotension; use of etodolac is associated with an increased risk of serious gastrointestinal toxicity, particularly in elderly or debilitated patients and those with a prior history of peptic ulcer disease and/or gastrointestinal bleeding; and lisinopril therapy has been linked rarely to head/neck angioedema and hepatic failure.

Ropinirole (Requip) Linked to Somnolence, Syncope, Hypotension in RLS

On May 4, the FDA approved revisions to the safety labeling for ropinirole HCl (Requip capsules, made by SmithKline Beecham Corp.), warning of the risk of somnolence, and rarer risks of syncope, hypotension, and hallucinations associated with its use in patients with moderate to severe primary restless legs syndrome (RLS).

Ropinirole was recently approved for the treatment of RLS and is also used for the symptomatic treatment of idiopathic Parkinson's disease (PD).

The FDA has received reports of ropinirole-treated patients falling asleep while engaged in activities of daily living (ADLs), including the operation of motor vehicles. Some patients reported having been alert immediately prior to the episode, which occurred without warning.

In controlled clinical trials, somnolence was less common in patients with RLS compared with those with PD (12% vs up to 40%; placebo, 6%).

The FDA recommends that patients be advised of this potential risk prior to initiation of ropinirole therapy. Patients should also be questioned regarding potential exacerbating factors such as sleep disorders and concomitant use of sedating medications or other drugs that increase ropinirole plasma levels.

Ropinirole should be discontinued in patients reporting significant daytime sleepiness during ADLs, because it is unclear whether dose reduction will eliminate such episodes. Patients continuing therapy should be advised not to drive and to avoid other potentially dangerous activities.

As in PD patients, ropinirole therapy has also been linked to reports of syncope and orthostatic hypotension in patients with RLS. In a 12-week, phase 2/3 trial involving 496 RLS patients, these adverse events were reported in 1% and 0.8% of those receiving ropinirole vs 0.2% and 0.4%, respectively, of those receiving placebo.

In the study, no hallucinations were reported in ropinirole-treated patients (placebo, 0.2%). Long-term open-label studies revealed a 0.5% incidence of hallucinations that spontaneously resolved without discontinuation of ropinirole therapy.

Etodolac (Lodine) Associated With Risk of Serious Gastrointestinal Toxicity

On May 24, the FDA approved revisions to the safety labeling for etodolac (Lodine capsules and tablets, made by Wyeth Pharmaceuticals, Inc.) to warn of the risk of serious gastrointestinal (GI) toxicities associated with its use, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine.

These effects can occur at any time, with or without warning symptoms, in patients chronically treated with nonsteroidal anti-inflammatory drugs (NSAIDs) such as etodolac. To minimize this risk, the FDA advises use of the lowest effective NSAID dose for the shortest possible duration, and consideration of alternate therapies for high-risk patients.

Pharmacoepidemiological data have shown that patients with a prior history of peptic ulcer disease and/or GI bleeding have a 10-fold increased risk of developing NSAID-related GI bleeding. Extreme caution is advised in prescribing NSAIDs for this population.

Concomitant corticosteroid or anticoagulant therapy, increased duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status have also been linked to an increased risk of GI toxicity. Because most spontaneous reports of fatal GI events have occurred in elderly or debilitated patients, special care should be taken with their treatment.

NSAID therapy is not recommended in patients with advanced kidney disease; if treatment must be initiated, close monitoring of kidney function is advisable.

Etodolac is indicated for acute and long-term use in the management of signs and symptoms of osteoarthritis and rheumatoid arthritis, and for the management of acute pain.

Lisinopril (Zestril) Linked Rarely to Head/Neck Angioedema, Hepatic Failure

On May 24, the FDA approved revisions to the safety labeling for lisinopril (Zestril tablets, made by AstraZeneca Pharmaceuticals LP) to warn of the rare risk of head/neck angioedema and hepatic failure associated with its use.

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme (ACE) inhibitors such as lisinopril. This may occur at any time during treatment and has occurred more frequently in black vs nonblack patients.

Immediate discontinuation of lisinopril therapy is advised in patients presenting with angioedema; appropriate antihistamine/corticosteroid therapy and monitoring should be provided until complete and sustained resolution of all signs and symptoms has occurred.

The FDA notes that even patients presenting with swelling of the tongue only (in the absence of respiratory distress) may require prolonged observation, because treatment may not be sufficient. Very rarely, airway obstruction due to angioedema of the larynx or tongue has resulted in fatality.

Patients with involvement of the tongue, glottis, or larynx who are likely to experience airway obstruction (especially those with a history of airway surgery) should be treated with 0.3 to 0.5 mL of subcutaneous 1:1000 epinephrine solution and/or other measures to ensure patency.

ACE inhibitor therapy has also been associated rarely with a syndrome that initially presents as cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death.

Lisinopril tablets are indicated for the treatment of hypertension and may be used alone as initial therapy or concomitantly with other classes of antihypertensive agents.

Reviewed by Gary D. Vogin, MD

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