FDA Safety Labeling Changes: Arthrotec, NuvaRing, Pravachol

Yael Waknine

October 19, 2005

Oct. 19, 2005 — The U.S. Food and Drug Administration (FDA) approved safety labeling revisions in July to advise that use of diclofenac sodium plus misoprostol tablets is contraindicated in pregnancy; etonogestrel plus ethinyl estradiol vaginal rings are contraindicated for use in patients having valvular heart disease with thrombogenic complications and may cause breakthrough bleeding or spotting; treatment with pravastatin sodium tablets is contraindicated in patients with active liver disease or unexplained, persistent elevations of serum transaminase levels and has been linked rarely to myopathy.

Diclofenac Sodium/Misoprostol (Arthrotec) Contraindicated in Pregnancy

On July 8, the FDA approved safety labeling revisions for diclofenac sodium plus misoprostol (Arthrotec tablets, made by Pfizer, Inc.) to warn that its use is contraindicated in pregnancy due to the abortifacient nature of the misoprostol component. Women who are pregnant or who become pregnant during therapy should discontinue use of the combination drug.

Misoprostol may cause abortion (sometimes incomplete), premature labor, or birth defects when administered to pregnant women. Uterine rupture has been reported in women treated with misoprostol to induce labor or to induce abortion beyond the eighth week of pregnancy.

Oral and/or vaginal use of misoprostol during pregnancy has also been linked to reports of amniotic fluid embolism resulting in maternal and fetal death, severe vaginal bleeding, retained placenta, shock, fetal bradycardia, and pelvic pain.

The FDA notes that the diclofenac sodium component of the drug may inhibit uterine contractions and affect the fetal cardiovascular system, causing premature closure of the ductus arteriosus.

Diclofenac sodium plus misoprostol tablets are indicated to treat signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing gastric and duodenal ulcers and their complications related to nonsteroidal anti-inflammatory drugs.

Etonogestrel Plus Ethinyl Estradiol Vaginal Ring (NuvaRing) May Cause Breakthrough Bleeding

On July 29, the FDA approved safety labeling revisions for etonogestrel plus ethinyl estradiol vaginal ring (NuvaRing, made by Organon, Inc.) to advise of a new contraindication and warning associated with its use.

Because of the increased risk of thromboembolic and thrombotic disease associated with use of the vaginal ring, it should not be used in women with valvular heart disease and thrombogenic complications.

The FDA also warned that breakthrough bleeding and spotting may occur with use of the ring. In a large (n = 1,177) U.S. and Canadian study, 7.2% to 11.7% of women experienced breakthrough bleeding/spotting during cycles 1 to 13. In two non-U.S. studies, these values ranged from 2.6% to 6.4% and 2.0% to 8.7% (n = 1,145 and 512, respectively). In all three studies, 0.3% to 3.8% of women using the vaginal ring did not have withdrawal bleeding in a given cycle.

The FDA notes that severe or persistent abnormal bleeding should be investigated to rule out the possibility of organic pathology or pregnancy, and appropriate treatment should be initiated if necessary.

Amenorrhea or oligomenorrhea may occur upon therapy discontinuation, particularly if the condition was preexisting. In the event of amenorrhea, pregnancy should be ruled out.

The etonogestrel plus ethinyl estradiol vaginal ring is indicated for the prevention of pregnancy.

Pravastatin Sodium (Pravachol) Linked Rarely to Myopathy

On July 6, the FDA approved safety labeling revisions for pravastatin sodium (Pravachol tablets, made by Bristol-Myers Squibb Co.) to advise of a contraindication and warning associated with its use.

Pravastatin is contraindicated for use in patients with active liver disease or unexplained, persistent elevations of serum transaminase levels. Caution should be exercised when pravastatin is administered to patients with a recent history or with current symptoms suggestive of liver disease, or heavy consumers of alcohol.

The FDA also warned that myopathy (defined as muscle aching/weakness) in conjunction with elevation of creatine phosphokinase (CPK) levels to greater than 10 times the upper limit of normal was observed rarely (< 0.1%) in pravastatin clinical trials.

The FDA advises that myopathy be considered when evaluating patients who present with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK levels. Treatment should be discontinued if myopathy is diagnosed or suspected, or if markedly elevated CPK levels occur.

Pravastatin is indicated for the treatment of dyslipidemia to reduce the risk of coronary and cardiovascular events.

Reviewed by Gary D. Vogin, MD


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