Thiazolidinediones and Risk of Heart Failure

Pharmacology Watch

In this issue: FDA is reviewing safety of TZDs; SSRI use with tamoxifen; Metformin smells like fish; FDA Actions.

FDA reviews TZD safety

Thiazolidinediones (TZDs) have been under intense scrutiny in recent years after rosiglitazone (Avandia®) was linked to increased cardiovascular morbidity and mortality in several studies. In recent weeks, The New York Times has reported that some FDA staffers are recommending that rosiglitazone be removed from the market. According to the story in the Times, a "confidential government report" states that about 500 heart attacks and 300 cases of heart failure per month could be averted if patients were switched from rosiglitazone to pioglitazone (Actos®). Congress has even gotten involved, specifically the Senate's Committee on Finance, which in January issued a 350-page report on rosiglitazone, focusing on GlaxoSmithKline's handling of evidence of possible cardiac risks associated with use of the drug. Now the American Heart Association and the American College of Cardiology have weighed in on the issue suggesting there is insufficient evidence to support the use of pioglitazone over rosiglitazone and that both drugs increase the risk for heart failure and should not be initiated in patients with class III/IV heart failure. They further state that the drugs should not be used with an expectation of benefit with respect to ischemic heart disease events (Circulation, published on-line Feb. 23, 2010). Meanwhile, the FDA web site reports that the Agency is reviewing data on rosiglitazone and is planning a public meeting in July 2010 to present all known heart-related safety data on the drug and provide an updated assessment of the risks and benefits of rosiglitazone and the treatment of type 2 diabetes.

SSRI use with tamoxifen

The SSRI paroxetine (Paxil®) reduces the effect of tamoxifen in women with breast cancer leading to higher breast cancer mortality according to a new study in the British Medical Journal. Concern about SSRIs interfering with the metabolism of tamoxifen was raised last June at the American Society of Clinical Oncology meeting. Tamoxifen is converted from its prodrug to the active metabolite via the cytochrome P450 pathway, specifically CYP2D6. Paroxetine is an exceptionally strong inhibitor of CYP2D6, the strongest inhibitor of all the SSRIs. In the study, Canadian researchers looked at more than 2400 women from Ontario treated with tamoxifen for breast cancer along with a single SSRI. After adjustment for confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P < 0.05, for each comparison). No such risk was seen with any other antidepressant. The authors conclude that paroxetine use during tamoxifen treatments is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer (BMJ 2010;340:c693). The study is important because up to one-quarter of women diagnosed with breast cancer experience a depressive disorder, and antidepressants are commonly used during tamoxifen treatment for not only depression, but also for treatment of hot flashes and other symptoms. It is evident that paroxetine should never be prescribed to women taking tamoxifen for treatment of breast cancer and that preference should be given to antidepressants that show little or no inhibition of CYP2D6. Among the SSRIs, the strongest inhibitors of CYP2D6 besides paroxetine are fluoxetine (Prozac®), duloxetine (Cymbalta®), and to a lesser extent sertraline (Zoloft®). Among non-SSRI antidepressants, bupropion (Wellbutrin®) also is a strong CYP2D6 inhibitor. Drugs that are not inhibitors of the enzyme include citalopram (Celexa®) and venlafaxine (Effexor®).

Generic metformin smells fishy?

If your patients tell you their pills smell like fish, they may be taking generic metformin. A letter to the Annals of Internal Medicine describes two patients who stopped taking generic metformin because of a fishy taste that caused nausea. The fishy smell is a property of metformin and is well known to pharmacists. Apparently the film-coated extended-release formulations have less smell and may be better tolerated (Ann Intern Med 2010;152:267-268).

FDA actions

A new FDA warning states that long-acting beta agonists (LABAs) should never be used alone in the treatment of asthma in children or adults. The LABAs salmeterol (Serevent®) and formoterol (Foradil®) have been associated with severe worsening of symptoms when used without a controller medication such as an inhaled corticosteroid. Both products will be required to include warnings on the product label that states:

  • Use of LABAs is contraindicated without the use of an asthma controller medication;
  • LABAs should only be used long term in patients whose asthma cannot be adequately controlled on asthma controller medications;
  • LABAs should be used for the shortest duration of time required to achieve control, and should be discontinued once asthma control is achieved;
  • Pediatric and adolescent patients who require an LABA in addition to an inhaled corticosteroid should use a combination product containing both an inhaled steroid and a LABA to ensure compliance with both medications.

The FDA has approved rosuvastatin (Crestor®) for primary prevention in patients without elevated LDL-cholesterol but who have an elevated C-reactive protein (2 mg/L or higher) and at least one additional cardiovascular risk factors such as low HDL, hypertension, or family history of premature heart disease. The approval was based on the JUPITER trial, which showed a 44% reduced relative risk of cardiovascular events in patients with normal LDL cholesterol but elevated CRP.

The FDA has approved a new pneumococcal vaccine for infants and children. Wyeth Pharmaceuticals' Prevnar 13™ is a 13-valent conjugate vaccine that will replace the currently available 7-valent Prevnar®. It is approved for the prevention of invasive disease caused by 13 different serotypes of S. pneumoniae.

The FDA has approved the monoclonal antibody rituximab (Rituxan®) to treat certain patients with chronic lymphocytic leukemia (CLL). Rituximab is approved for CLL patients who are starting chemotherapy for the first time and also for those who have not responded to other CLL therapies. It is administered with fludarabine and cyclophosphamide for the treatment of CLL. Rituximab is manufactured by Genentech.

The FDA is initiating a risk-management program for erythropoiesis-stimulating agents (ESAs) for the treatment of chemotherapy-related anemia. The drugs, which include epoetin alfa (Procrit®, Epogen®) and darbepoetin alfa (Aranesp®), have been associated with accelerated tumor growth and higher mortality rates in some cancer patients. The Risk Evaluation and Medication Strategy (REMS) requires that patients receive a medication guide on safety issues associated with the drugs and requires training and certification of health care professionals who administer chemotherapy to patients with cancer and counseling of patient regarding the risks of the drugs. The REMS does not currently apply to patients being treated with an ESA for anemia due to other conditions, specifically renal failure.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: