Pharmacology Watch: Evidence-based updates in clinical pharmacology

Medications for Risk Reduction of Breast Cancer in Women

In this issue: USPSTF issues new guidelines for risk reduction of breast cancer; safety of Chantix in patients with depression; polypills for cardiovascular disease; and FDA actions.

Risk reduction of breast cancer

The U.S. Preventive Services Task Force (USPSTF) has published new guidance regarding medications for risk reduction of primary breast cancer in women. The group reviewed evidence on the effectiveness, adverse effects, and subgroup variations of medications to reduce breast cancer, specifically the selective estrogen receptor modulators tamoxifen and raloxifene (Evista). The USPSTF recommends that clinicians engage in shared, informed decision making with women who are at increased risk for breast cancer about medications to reduce the risk. Women who are at increased risk for breast cancer and have a low risk for adverse medication effects should be offered one of the risk-reducing medications (B recommendation). However, the group recommends against the routine use of these medications in women who are not at increased risk of breast cancer. High-risk women are defined as those with a 5-year risk of ≥ 3% based on the National Cancer Institute’s Breast Cancer Risk Assessment Tool (www.cancer.gov/bcrisktool/). Tamoxifen and raloxifene are shown to reduce the risk of estrogen receptor-positive breast cancer, but not estrogen receptor-negative cancer, which is more difficult to treat. Tamoxifen is associated with a moderate benefit for breast cancer but a slightly higher risk of endometrial cancer. Raloxifene is associated with a slightly smaller benefit for breast cancer but no risk for endometrial cancer. Both drugs may reduce the risk of nonvertebral fractures with greater benefit for raloxifene. Both drugs also increase the risk of venous thromboembolism with the risk being age-dependent (Ann Intern Med published online September 24, 2013). n

Chantix safe in patients with depression

Varenicline (Chantix) was approved in 2006 to treat smoking addiction. Since its approval, the drug has been plagued by reports of worsening depression and increases in suicidality, prompting the FDA to issue an alert in 2008 noting "serious neuropsychiatric symptoms" associated with the drug. But a new study suggests that varenicline may be safe and effective in smokers with a history of depression. In a study sponsored by Pfizer, 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events were randomized to varenicline 1 mg twice daily or placebo for 12 weeks with 40 weeks of nontreatment follow-up. The primary outcome was carbon monoxide-confirmed continuous absence rate (CAR) for weeks 9-12. Other outcomes included ratings of mood, anxiety, and suicidal ideation or behavior. About two-thirds of patients in both groups completed the study. Patients treated with varenicline had double the quit rate at weeks 9-12 (CAR 35.9% vs 15.6%; odds ratio, 3.35; 95% confidence interval [CI], 2.16-5.21; P < 0.001). The quit rates were also approximately double from weeks 9-24 and from weeks 9-52, with the CAR at week 52 for the varenicline group at 20.3% vs 10.4% for placebo. There were no clinically relevant differences between groups in suicidal ideation or behavior, or overall worsening depression or anxiety. About 27% of the treatment group experienced nausea as the most frequent adverse event. The authors conclude that varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety (Ann Intern Med 2013;159:390-400). n

Polypills for cardiovascular disease

Is a "polypill" the answer to adherence in patients with cardiovascular disease (CVD)? Long-term medication adherence is notoriously poor in these patients. Even in high-income countries, adherence rates are only 50% in patients with coronary disease and 35% in those with those a history of stroke. Polypills combine several cardiovascular medications in one, including aspirin, a statin, and one or more blood pressure medications. A recent study was designed to see if these fixed-dose combination (FDC) pills would improve compliance, LDL cholesterol, and blood pressure levels compared to usual care. Two polypills were evaluated in the study. The first pill contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and atenolol 50 mg. The second pill substituted hydrochlorothiazide 12.5 mg for atenolol. About 1000 patients received one of the FDCs with about 1000 controls continuing on usual care. After an average follow-up of 15 months, adherence was higher with the FDC vs usual care (86% vs 65%, P < 0.001), but there were only modest reductions in systolic blood pressure with FDC of about 2.6 mmHg and also modest reductions in LDL cholesterol of 4.2 mg/dL vs usual care. Subgroups of patients who showed poor adherence at baseline had higher levels of improvement in blood pressure and LDL cholesterol. There was no significant difference in cardiovascular events (5% FDC vs 3.5% usual care; relative risk, 1.45; 95% CI, 0.94-2.24; P = 0.09). The authors conclude that among patients at high risk of CVD, use of a FDC "polypill" improved medication adherence with small improvements in systolic blood pressure and LDL cholesterol (JAMA 2013;310:918-929). n

FDA actions

Treatment of chronic pain has changed dramatically in the last 3 years, shifting from concern about undertreating patients with chronic pain to concern about the safety of overuse of extended-release and long-acting opioid analgesics. With overdoses of prescription opioids skyrocketing and far outnumbering overdoses from illegal drugs, the FDA has decided to take action. The agency is requiring labeling changes and new postmarketing study requirements for these drugs, including oxycodone (Oxycontin), controlled-release and extended-release morphine (MS Contin and Avinza), and fentanyl patches (Duragesic). The labeling changes are being required to "combat the crisis of misuse, abuse, addiction, overdose, and death from these drugs that have harmed too many patients and devastated too many families and communities." The updated indications for the extended-release and long-acting opioids state that these drugs are indicated "for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate." The goal of the postmarketing studies is to further assess the known serious risks of these drugs, including misuse, abuse, hyperalgesia, addiction, overdose, and death.

The FDA is also requiring additional labeling changes to fentanyl patches due to 32 accidental pediatric exposures, including 12 deaths in the last 16 years. The labeling requirements include printing the drug’s name and strength in the clearly visible, long-lasting ink on the patch, in a color that is clearly visible to the patient and caregivers. The FDA also recommends that for disposal the patch be folded in half, sticky sides together, and flushed down the toilet immediately. These labeling changes apply to both generic fentanyl patches and brand-name Duragesic patches.

The FDA has approved the first generic version of the anticancer drug capecitabine (Xeloda), an oral chemotherapy agent used to treat metastatic colorectal cancer and metastatic breast cancer. The new generic is manufactured by Teva Pharmaceuticals while the branded product is manufactured by Roche. Two years ago, Roche settled a patent infringement case against Mylan over the same drug. It is unclear whether Mylan will now also launch its own generic. n