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FDA Safety Labeling Changes: Nubain and Zocor

  • Authors: News Author: Yael Waknine
    CME Author: Yael Waknine
  • CME Released: 11/30/2005; Reviewed and Renewed: 11/30/2006
  • Valid for credit through: 11/30/2007
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Target Audience and Goal Statement

This article is intended for primary care physicians, obstetricians and gynecologists, neonatologists, cardiologists, endocrinologists, and other specialists who care for women during labor and delivery, newborn infants, and patients with dyslipidemias, hypertension, and diabetes.

The goal of this activity is to provide the latest medical news to physicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Describe the risks associated with use of nalbuphine during labor and delivery.
  • Identify drug interactions that increase the risk for myopathy in patients receiving simvastatin.
  • Recognize appropriate clinical dosing options for simvastatin in combination with drugs that increase the risk for myopathy.


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  • Yael Waknine

    Yael Waknine is a freelance writer for Medscape.


    Disclosure: Yael Waknine has disclosed no relevant financial relationships.


  • Gary Vogin, MD

    Senior Medical Editor, Medscape


    Disclosure: Gary Vogin, MD, has disclosed no relevant financial relationships.

CME Author(s)

  • Yael Waknine

    Yael Waknine
    is a freelance writer for Medscape.


    Disclosure: Yael Waknine has disclosed no relevant financial relationships.

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FDA Safety Labeling Changes: Nubain and Zocor

Authors: News Author: Yael Waknine CME Author: Yael WaknineFaculty and Disclosures

CME Released: 11/30/2005; Reviewed and Renewed: 11/30/2006

Valid for credit through: 11/30/2007


Nov. 30, 2005 — The U.S. Food and Drug Administration (FDA) approved in the August safety labeling revisions to advise that use of nalbuphine HCl injection during labor and delivery is associated with a risk for serious fetal and neonatal adverse events; and simvastatin therapy is linked to a dose-dependent risk for myopathy that is increased by concurrent use of potent cytochrome P-450 3A4 inhibitors, gemfibrozil, and other lipid-lowering drugs (including niacin at doses of 1 g/d or higher), cyclosporine, danazol, amiodarone, or verapamil.

Nalbuphine Injection (Nubain) Linked to Risk for Fetal Adverse Events

On Aug. 23, the FDA approved safety labeling revisions for nalbuphine injection (Nubain, made by Endo Pharmaceuticals, Inc) to warn of the risk for serious fetal and neonatal adverse events associated with its use during labor and delivery.

The placental transfer of nalbuphine is high, rapid, and variable, with a maternal to fetal ratio ranging from 1:0.37 to 1:6. Fetal and neonatal adverse events have included reports of fetal bradycardia, respiratory depression at birth, apnea, cyanosis, and hypotonia. Some of these events have been life-threatening.

Although maternal administration of naloxone during labor has normalized these effects in some cases, severe prolonged fetal bradycardia has occurred, and in some cases, resulted in permanent neurologic damage. Nalbuphine has also been linked to reports of sinusoidal fetal heart pattern.

The FDA advises that nalbuphine be used during labor and delivery only if clearly indicated and the potential benefit outweighs the risk to the infant. Newborns exposed to maternal nalbuphine should be monitored for respiratory depression, apnea, bradycardia, and arrhythmias.

Nalbuphine injection is indicated for the relief of moderate to severe pain.

Simvastatin (Zocor) Drug Interactions Linked to Increased Risk for Myopathy

On Aug. 31, the FDA approved safety labeling revisions for simvastatin (Zocor tablets, made by Merck & Company, Inc) to advise of the risk for myopathy and/or rhabdomylosis associated with its use and of drug interactions that may increase this risk.

As with other 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin is associated with a dose-related risk for myopathy that presents as muscle pain, tenderness, or weakness, with creatine kinase levels more than 10 times the upper limit of normal. Myopathy may also take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria. Rare fatalities have occurred.

In a clinical trial database of 41,050 simvastatin-treated patients, with 60% of patients treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08%, and 0.43% at 20, 40, and 80 mg/d, respectively. In the trials, patients were closely monitored and some interacting medical agents excluded.

Patients beginning simvastatin therapy and receiving increased doses should be warned of the risk for myopathy and advised to promptly report any unexplained muscle pain, tenderness, or weakness. Simvastatin should be discontinued immediately if myopathy is diagnosed or suspected.

Because simvastatin is a substrate for the cytochrome P-450 isoform 3A4 (CYP 3A4) enzyme, concomitant administration of potent CYP 3A4 inhibitors results in elevated HMG-CoA plasma activity and an increased risk for myopathy/rhabdomyolysis.

Use of simvastatin in conjunction with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 qt daily) should therefore be avoided. If treatment with itraconazole, erythromycin, clarithromycin, or telithromycin is unavoidable, use of simvastatin should be suspended during treatment.

Concurrent use of gemfibrozil and other lipid-lowering agents (including niacin at doses of 1 g/d or higher), cyclosporine, danazol, and calcium channel blockers also increase the risk for myopathy.

Concomitant use of gemfibrozil is not recommended unless the benefits outweigh the risks for combination therapy; the daily dose of simvastatin should not exceed 10 mg in patients receiving both drugs.

Caution should also be used when prescribing other fibrates or lipid-lowering doses (1 g/d or higher) of niacin with simvastatin because of the additive risk for myopathy. The benefit of further alterations in lipid levels with use of simvastatin and other fibrates or niacin should be carefully weighed against the potential risks for these combinations. Concomitant use of danazol or cyclosporine is also associated with an increased risk for myopathy, particularly at higher doses of simvastatin. The daily dose of simvastatin should not exceed 10 mg/d in patients receiving these drugs.

Calcium channel blockers have also been shown to increase the risk for simvastatin-related myopathy.

In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving 80 mg of simvastatin and amiodarone. An analysis of clinical trials in 25,248 patients has also shown that addition of verapamil significantly increases the risk for myopathy, relative to use of 20 to 80 mg of simvastatin alone (0.63% vs 0.061%).

Patients receiving amiodarone or verapamil should not receive more than 20 mg/d of simvastatin. The FDA advises that higher doses of simvastatin be avoided unless the clinical benefit is likely to outweigh the risk for myopathy.

Simvastatin is indicated for the treatment of various dyslipidemias to reduce the risk for coronary heart disease mortality and cardiovascular events.

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