This activity is part of an ongoing CME/CE initiative to provide information on labeling changes reported by the FDA. Activities of this nature will be posted on Medscape on a weekly basis.

July 9, 2008 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of drug interactions that can increase the risk for serotonin syndrome in patients receiving tramadol HCl, drug interactions between atazanavir sulfate and various agents in the statin drug class, drug interactions with fentanyl, and adverse events associated with improper use of fentanyl patches.

Tramadol HCl (Ultram ER) Drug Interactions Increase Risk for Serotonin Syndrome

On February 20, the FDA approved safety labeling revisions for tramadol HCl extended-release tablets (Ultram ER; Biovail Laboratories, Inc) to warn of the risk for potentially life-threatening serotonin syndrome associated with all tramadol products.

The risk for serotonin syndrome may be increased with concomitant use of serotonergic drugs, such as selective serotonin reuptake inhibitors (eg, escitalopram), serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs, including the reversible nonselective MAOI linezolid), and triptans; drugs that impair serotonin metabolism (including MAOIs); and those that reduce tramadol metabolic clearance, such as cytochrome P 450 isoenzyme 2D6 inhibitors (eg, quinidine, fluoxetine, paroxetine, and amitryptyline) and cytochrome P 450 isoenzyme 3A4 inhibitors (eg, ketoconazole and erythromycin).

Because these drug interactions may lead to the development of serotonin syndrome at recommended tramadol doses, coadministration of drugs that affect the serotonergic neurotransmitter system should be approached with caution. If combination therapy is clinically warranted, the patient should be carefully monitored, particularly during initiation of therapy and dose increases.

Symptoms of serotonin syndrome may include mental status changes (eg, agitation, hallucinations, and coma), autonomic instability (eg, tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (eg, hyperreflexia and incoordination), and gastrointestinal tract symptoms (eg, nausea, vomiting, and diarrhea).

Tramadol is a centrally acting synthetic analgesic. In its extended-release formulation, tramadol is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period.

Atazanavir Sulfate (Reyataz) Drug Interactions Increase Statin Myopathy Risk

On February 20, the FDA approved safety labeling revisions for atazanavir sulfate capsules (Reyataz; Bristol-Myers Squibb Company) to provide specific recommendations with respect to drug interactions with statins, also known as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors.

The FDA previously warned that coadministered protease inhibitors, such as atazanavir, increase plasma levels of HMG-CoA reductase inhibitors and therefore the exposure-related risk for myopathy or rhabdomyolysis.

Coadministration of atazanavir with lovastatin or simvastatin is therefore not recommended. Instead, the lowest possible dose of atorvastatin or rosuvastatin should be used with careful monitoring, and consideration should be given to use of other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin.

Atazanavir is a protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. HMG-CoA inhibitors are a class of hypolipidemic drugs used to lower cholesterol levels in patients with or at risk for cardiovascular disease.

Fentanyl Patches (Duragesic) Black Box Warns of Drug Interactions and Other Adverse Events

On February 7, the FDA approved safety labeling revisions for fentanyl transdermal patches (Duragesic, Alza Corp) that support the inclusion of boxed warnings regarding the risk for certain drug interactions and of adverse events related to improper use of this product.

Because fentanyl is metabolized primarily via the cytochrome P450 isoenzyme 3A4 (CYP 3A4), concomitant use of strong CYP 3A4 inhibitors (eg, ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) or moderate CYP 3A4 inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) can increase fentanyl plasma concentrations. This can increase or prolong adverse drug effects and may lead to potentially fatal respiratory depression.

Patients receiving concomitant treatment with fentanyl and moderate or strong CYP 3A4 inhibitors should be monitored carefully for an extended period. Dose increases should be approached with caution, and patients should avoid grapefruit or grapefruit juice because of the negative effects on CYP 3A4 activity.

Fentanyl patches are only indicated for the management of persistent, moderate to severe chronic pain in opioid-tolerant patients aged 2 years and older who require a total opioid dose at least equivalent to a 25-µg/hour patch. Because of the risk for potentially fatal respiratory depression, the FDA emphasizes that patches should not be used for the management of postoperative, mild, or intermittent pain (ie, for use on an as-needed basis).

The FDA also stressed that patches with a broken seal and those that are cut, damaged, or changed in any way should not be used because direct exposure to fentanyl gel can cause respiratory depression and potentially fatal overdose.

Patients and caregivers should also be advised to avoid exposure of the patch application site to direct external heat sources because of the potential for temperature-dependent increases in fentanyl release that may result in overdose and death.

Heat sources include heating pads, electric blankets, heat lamps, saunas, hot tubs, and heated water beds; sunbathing and hot baths should likewise be avoided. Patients in whom fever or increased core body temperature from strenuous exertion develops should be monitored for opioid adverse events, and fentanyl dosage should be adjusted accordingly.

Ultram Prescribing Information

Reyataz Prescribing Information

Duragesic Prescribing Information

Pearls for Practice

• Tramadol HCl, including the extended-release formulation, is associated with a risk for potentially life-threatening serotonin syndrome that is increased with concomitant use of serotonergic drugs, drugs that impair serotonin metabolism, and agents that reduce tramadol metabolic clearance. These drug interactions can lead to the development of serotonin syndrome at recommended tramadol doses.
• Protease inhibitors, such as atazanavir sulfate, increase statin plasma levels and the risk for myopathy or rhabdomyolysis. Coadministration of atazanavir with lovastatin or simvastatin is not recommended; atorvastatin or rosuvastatin should be used at the lowest possible dose and substitution of pravastatin or fluvastatin considered.
• Concomitant use of fentanyl, including fentanyl patches, with cytochrome P 450 isoenzyme 3A4 inhibitors can increase the risk for adverse events, including respiratory depression. Patients should be advised not to use cut or damaged patches and avoid patch exposure to external heat sources. Caution is advised in patients with increased core body temperature.

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