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New Drugs/Drug News/New Medical Devices May 2012


Generic Approvals

Vancocin for Infection

Three companies have been granted approval to sell generic versions of Viro-Pharma’s Vancocin (vancomycin), an antibiotic. Indicated for the treatment of Clostridium difficile–associated diarrhea (see Drug Forecast, page 278), vancomycin is also used to treat patients with enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains. The generic capsules are available in strengths of 125 mg and 250 mg.

Watson Pharmaceuticals and Akorn confirmed that they received marketing approval for their versions of Vancocin. However, ViroPharma claimed that the FDA denied a petition related to determining bioequivalence for Vancocin and plans to seek an injunction to block the FDA’s approval of three generic versions. ViroPharma disputed how the FDA interpreted standards related to the approval of bioequivalent treatments. The Federal Trade Commission is investigating whether the company used unfair trade methods related to Vancocin. ViroPharma claims it has not engaged in unfair trading practices and plans to cooperate with the investigation.

Sources: The Wall Street Journal, Associated Press; April 10, 2012;

Sular for Hypertension

Prasco Laboratories has been granted approval to sell and distribute the authorized generic version of Sular (nisoldipine) extended-release tablets for hypertension. The drug will be sold in strengths of 8.5 mg, 17 mg, and 34 mg in the U.S. The tablets are AB-rated and equivalent and able to be substituted as permitted by state law. Sular is a registered trademark of Shionogi Inc.

Sources: Prasco, April 2, 2012;;


Orphan Drug Status Is Granted to Telotristat For Carcinoid Syndrome

Lexicon Pharmaceuticals has received incentives from the FDA to develop telotristat etiprate (LX1032) to treat symptoms of carcinoid syndrome, which is caused by tumors in the gastrointestinal tract. If the drug is approved, it will receive exclusivity for 7 years.

Tumors from carcinoid syndrome cause increased production of serotonin, leading to adverse effects such as severe diarrhea. Long-term effects of the syndrome can include cardiac valve disease. Oral telotristat helps to reduce serotonin levels.

Sources: FDA; Lexicon, March 21, 2012

Eye Pain and Bone Drugs

Oral bisphosphonates, which are used to prevent and treat osteoporosis, may increase the risk of inflammatory eye complications in first-time users. In a retrospective cohort study conducted at the University of British Columbia in Vancouver, patients who began to take bisphosphonates were 45% more likely to develop uveitis and were 51% more likely to develop scleritis compared with those who had never taken these drugs. Eye pain usually resolved after the drug was discontinued.

The analysis included all local residents who had visited an ophthalmologist from 2000 to 2007 (a total of 934,147). Most case reports involved the potent amino-bisphosphonates alendronate (Fosamax, Merck) and risedronate (Actonel, Warner Chilcott).

Amino-bisphosphonates play a role in releasing tumor necrosis factor, alpha-interleukin-6, and cytokines. The increase in these inflammatory mediators, especially among new patients who use bisphosphonates, may increase the risk of scleritis or uveitis. The researchers cautioned that the absolute number of cases among patients using oral bisphosphonates in the study was small.

Inflammatory ocular adverse events are not mentioned as a potential problem in most package inserts included with this drug class. The researchers urged that patients taking oral bisphosphonates be familiar with the signs and symptoms of these conditions so that they can seek immediate assessment by an ophthalmologist.

Sources: Can Med Assoc J, April 2, 2012; FDA, March 29, 2012; MedPage Today, April 3, 2012

Eye Injury and Antibiotics

In another Canadian study, a common class of antibiotics was linked to a risk of retinal detachment. Patients with this emergency condition were five times more likely to be taking a fluoroquinolone, such as ciprofloxacin (Zoxan, Proquin, Cipro) and levofloxacin (Levaquin, Cravit), compared with patients who did not have retinal detachment.

These drugs are considered toxic to connective tissue and cartilage. Researchers at the Institute of British Columbia in Vancouver used data from medical records for residents in British Columbia who had visited an ophthalmologist between 2000 and 2007 (about 1 million people, including 4,400 patients with retinal detachment). Their average age was 61 years. One patient in 30 with retinal detachment was taking a fluoroquinolone at that time, usually ciprofloxacin (Cipro), which is often used for respiratory or urinary tract infections.

Among a similar group of patients who visited an ophthalmologist but did not have retinal detachment, only one participant in 167 was taking the antibiotics. The most likely explanation of retinal detachment was that the drugs damaged fibers and connective tissue that attach the retina to the eye’s vitreous gel.

For some time, there have been concerns about the possible ocular effects of fluoroquinolones. The new study suggests only an association, and the extra risk was relatively small. Other non–drug-related risks for retinal detachment include a history of cataract surgery, nearsightedness, or eye infections.

Sources: JAMA, April 3, 2012; (online); Reuters Health

More Fake Bevacizumab (Altuzan) Enters the U.S.

A cancer drug, Altuzan (bevacizumab), has entered the U.S. and has been found to be counterfeit. Bevacizumab is approved in the U.S. as Avastin (Genentech, Roche). Injectable Altuzan (400 mg/16 mL) is approved in Turkey but not in the U.S. The fake product does not contain the active ingredient.

On February 14, 2012, the FDA had warned that some practices and clinics might have bought fake Avastin, which also contained no active ingredient. The counterfeit product entered the U.S. through foreign sources, including companies registered in the United Kingdom and La Jolla, Calif.

Source: Medical News Today, April 4, 2012

Adulterated Ultrasound Gel

U.S. Marshals have seized Other-Sonic Generic Ultrasound Transmission Gel (Pharmaceutical Innovations Inc.) in Newark, N.J. Samples of the product were found to contain dangerous bacteria. The seizure included all lots of the gel made between June 2011 and December 2011. Until the gel was seized, it had been held under embargo by the state’s Department of Health and Senior Services at the FDA’s request.

The gel improves the transmission of ultrasound waves during an examination.

Samples were found to be contaminated with Pseudomonas aeruginosa and Klebsiella oxytoca. The gel was also misbranded and would have been dangerous to vulnerable patients if used in the manner suggested in the labeling.

The FDA received a report that 16 surgical patients had been infected with P. aeruginosa after undergoing ultrasonography of the esophagotracheal area with Other-Sonic Generic Ultrasound Transmission Gel during heart valve replacement. The affected gel products include 250-mL and 5-L containers.

Source: FDA, April 18, 2012

Label Changes

Oral Contraceptives

New drug labels are now required for Yaz, Yasmin, Beyaz, and Safyral (all made by Bayer) and for some generic versions because of a possible three-fold increased risk of blood clots. The pills all contain drospirenone, a progestin, although some studies found no additional risk of blood clots with drospirenone-containing products.

The label changes also apply to Gianvi, Loryna, Ocella, Syeda, Zarah, and two generic formulations. Each tablet contains 3 mg of drospirenone and either 0.02 or 0.03 mg of ethinyl estradiol. Beyaz and Safyral also contain 0.451 mg of levomefolate calcium.

The FDA did not declare a definite association between the drug and venous clotting. The risk of clotting still appears to be lower than the risk of thrombosis during pregnancy and in the immediate postpartum period; the risk of clots is also lower among women who take birth control pills than those women who do not take them; and it is lower for all types of oral contraceptives than it is during pregnancy and the postpartum period.

Fifteen of the 26 FDA panel members claimed that the benefits of drospirenone-containing contraceptives outweighed their risks, but the committee voted overwhelmingly for more information on the products’ labels.

Sources: The Wall Street Journal and MedPage Today, April 10, 2012

Propecia and Proscar

More potential sexual adverse events associated with finasteride (Propecia and Proscar, Merck) have been added to the product’s labeling. Both brand-name and generic finasteride formulations are affected. Propecia (1 mg) is used to treat hair loss, and Proscar (5 mg) is used to treat benign prostatic hyperplasia. The FDA is requiring manufacturers to add the following information about finasteride-associated adverse events:

  • 1 mg: Disorders of ejaculation, libido, and orgasm persisted after discontinuation of the drug.
  • 5 mg: Decreased libido continued after the drug was discontinued.
  • 1 mg and 5 mg: Male infertility or poor semen quality returned to normal or improved after discontinuation.

In 2011, the FDA required erectile dysfunction to be added to the list of potential sexual adverse events observed in some patients taking finasteride.

Source: MedPage Today, April 12, 2012

Aliskiren Warning

The FDA has warned against combining aliskiren hemifumarate (Tekturna, Novartis), a blood pressure medication, with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) for patients with diabetes or renal impairment.

Aliskiren is the first FDA-approved direct renin inhibitor (DRI). DRIs block the enzyme renin, which is necessary for constriction of blood vessels. Aliskiren causes relaxation of the vessels, thereby lowering blood pressure.

The warning, which will be accompanied by a label change, is based on results from the ALTITUDE study, which found an increased risk of adverse events in high-risk patients taking the DRI as an add-on agent to other antihypertensive drugs. Diabetic patients who take a mixture of these drugs are at risk of renal impairment, hypotension, and hyperkalemia, according to the FDA. Patients with moderate-to-severe renal impairment (i.e., a glomerular filtration rate below 60 mL/minute) should also avoid the potentially lethal combinations.

Besides Tekturna, the following drugs contain aliskiren:

  • Amturnide: aliskiren/amlodipine/hydrochlorothiazide (HCTZ)
  • Tekturna HCT: aliskiren/HCTZ
  • Tekamlo: aliskiren/amlodipine
  • Valturna: aliskiren/valsartan. Valturna will no longer be sold after July 2012.

Source: MedPage Today, April 20, 2012

New Guidelines For Rheumatoid Arthritis

The 2008 American College of Rheumatology (ACR) guidelines for rheumatoid arthritis (RA) have been updated for 2012. The guidelines’ authors emphasize the importance of more aggressive treatment in early disease to promote better outcomes. The goal of early treatment is to achieve remission or, at least, low disease activity. The guidelines address biologics, high-risk patients, screening for tuberculosis, complications of RA, hepatitis, skin cancer, and vaccinations.

Source: Arthritis Care Res, May 2012; MedPage Today, April 2, 2012

Ten Types of Breast Cancer Discovered in Landmark Study

Breast cancer stems from 10 genetic subtypes, not four as previously thought, according to a new study. The findings by researchers in the United Kingdom (U.K.) and Canada should eventually enable doctors to better predict survival times in women with the disease and tailor the most appropriate treatment to their type of tumor. Tests to diagnose the new subtypes will probably be developed and in routine use in 3 to 5 years.

The largest global gene study of breast cancer was conducted by the Cambridge Research Institute in the U.K. and by the Breast Cancer Agency in Vancouver, Canada. Scientists examined 2,000 frozen tumor samples from patients at five hospitals. Scientists analyzed genetic material in the cancer cells for mutations and other changes and grouped them into 10 subtypes with common features that correlated with long-term survival times.

The current practice of diagnosis involves testing tumor samples for the presence of genetic markers for two hormone receptors: the estrogen receptor (ER) and human epidermal growth factor receptor- 2 (HER- 2). The outcome determines which of the four types a patient has. The most common form is ER-positive/HER-2–negative breast cancer, which affects 70% of women with the disease. Another 15% have HER-2 positive tumors, which can be treated by trastuzumab (Herceptin, Genentech/Roche). However, trastuzumab carries a risk of heart damage.

The new subtypes of breast cancer include seven that were defined as ER-positive and HER-2 negative. Survival times for each of the seven subtypes range from 80% after 15 years from diagnosis to less than 40% after 15 years. This is considered a wide variation.

The study results may lead to more development of drugs that target tyrosine kinases, phosphatases, and chromatin modifiers. For instance, lapatinib (Tykerb, GlaxoSmithKline) is a kinase inhibitor that is already approved for treating HER-2–positive breast cancer.

The study also identified several new genes that contribute to the disease.

Researchers compared breast cancer to a map of the “world.” The tests currently used in hospitals are broad and divide the disease into the equivalent of “continents.” The latest findings may allow oncologists to find “countries.”

In terms of treatments, the news is slightly disappointing. There is a targeted therapy for only one of the 10 breast cancers groups (trastuzumab). The hope is that by identifying the 10 types, researchers will be able to design drugs for each group, but they still need to prove that the 10 classifications will provide benefit to patients before the therapies can be used.

Sources: Nature; Bloomberg News, BBC News, April 18, 2012

Drugs Under Surveillance

The Institute for Safe Medication Practice (ISMP) has “signaled” four drugs for adverse events via its surveillance program, QuarterWatch™. During 2011, the FDA received 40,222 reports of serious adverse events, including 6,617 deaths linked to the use of these agents.

Fingolimod (Gilenya, Novartis) is used to treat multiple sclerosis (MS). The drug was initially tested in doses of 2.5 mg and 5.0 mg as an immunosuppressant to prevent renal transplant rejection, but development was halted because of toxicity and high mortality rates.

The FDA required additional safety precautions when Novartis wanted to test the drug in lower doses for MS. During the trials, testing of a 1.25-mg dose was also halted because of two deaths and a vascular event; yet even with this poor safety record, approval was fast-tracked for the 0.5-mg dose to be used in MS.

In premarketing trials, infections, macular edema, ocular injuries, impaired lung function, liver damage, a sudden drop in the heart rate after the first dose, and birth defects were reported. Doses higher than 0.5 mg have proved too toxic for human use. The FDA is requiring a study of a 0.25-mg dose, to be completed by 2015. The ISMP wants the FDA and Novartis to consider restricting the use of fingolimod and to enhance monitoring.

Infliximab (Remicade, Janssen Ortho Biotech) inhibits tumor necrosis factor (TNF) and is approved for the treatment of rheumatoid arthritis, Crohn’s disease, and plaque psoriasis. In 2011, infliximab was found to be associated with brain infections, cancer, liver toxicity, a lupus-like syndrome, and MS-like nerve-cell damage. Four other anti-TNF products are available, but infliximab has accounted for a disproportionate number of reports of serious adverse events overall since its approval 14 years ago.

Many warnings have been added to the prescribing information for all anti-TNF products in this drug class (infections, heart failure risk, cancer, and liver damage). Physicians should be aware that these drugs have mostly second-line indications and should be used only when safer alternatives are ineffective.

Dabigatran (Pradaxa, Boehringer Ingelheim), an anticoagulant, is designed to reduce the risk of stroke. Hemorrhage was reported in elderly patients.

Metoclopramide (Reglan, Schwarz), which is used to treat reflux and other gastrointestinal disorders, may cause irreversible neurological brain damage in the form of tardive dyskinesia. Even strong boxed warnings have been insufficient to reduce injury. Safer alternatives to metoclopramide are available, and regulatory action is needed to restrict the use of this drug.

Source: ISMP, April 5, 2012;

Joint Injections Do Not Raise Bleeding Risk

It isn’t necessary to reduce the level of anticoagulation before joint injections and aspiration, say researchers at Regions Hospital in St. Paul and at the University of Minnesota. The injections, which were administered for diagnostic and therapeutic indications, were safe for patients receiving warfarin without producing an increased risk of bleeding.

The retrospective study compared 640 procedures involving arthrocentesis and joint injection in 514 patients receiving anticoagulants; 456 procedures were performed in patients with an International Normalized Ratio (INR) of 2.0 or greater, and 184 procedures were performed when the INR was below 2.0. Most injections involved the knees and shoulders. Antiplatelet therapy was routinely continued in all patients throughout the periprocedural period.

The researchers noted a minimal risk of periprocedural bleeding and no increased risk of overall complications. Only one patient, with an INR of 2.3, had clinically significant bleeding. In fact, 103 procedures were performed in patients with an INR of 3 or greater, with no complications. The highest INR was 7.81.

Four patients had early or late complications. One injection given in patients with an INR of 2 or above resulted in infection. Three patients returned for another medical visit because of pain, and one of these patients had clinically significant bleeding.

There were no statistically significant differences in early or late complications between patients with an INR of 2 and higher and those whose anticoagulation medication was adjusted to an INR of less than 2.

The researchers said that this was the first study comparing two strategies of anticoagulation management in patients who were receiving chronic warfarin therapy during joint aspiration and injection.

Source: Am J Med 2012;125:265–269 (March)

Diclofenac Gel Found Safe For Osteoarthritis Pain

When oral nonsteroidal anti-inflammatory drugs (NSAIDs) are too risky for patients with joint pain, topical diclofenac gel might be a safe option, according to findings from the Center for Rheumatology and Bone Research in Wheaton, Md.

Researchers analyzed data from five randomized, double-blind, placebo-controlled trials involving 2,209 patients with mild-to-moderate osteoarthritis of the knee or hand. Patients applied 4 g of diclofenac sodium 1% gel or placebo to the affected knees four times per day for 12 weeks or 2 g of gel or placebo to the affected hands for 8 weeks.

Adherence was high in both groups, and most participants applied at least three of the four prescribed doses every day. Treatment was well tolerated, regardless of age and comorbidities (e.g., hypertension, diabetes, cerebrovascular disease, or cardiovascular disease).

In all subgroups, patients using the gel were slightly more likely to experience adverse events (AEs), such as application-site reactions and dermatitis and to stop treatment because of these effects.

In the subset of patients who were treated for knee problems, about 3% of those younger than 65 years of age and 4% of those older than age 65 had AEs. Treatment-related gastrointestinal AEs and serious AEs were rare. The only cardiovascular AE considered potentially related to treatment occurred in an 80-year-old woman with hypertension and type-2 diabetes. She developed deep-vein thrombosis and pulmonary embolism but was treated successfully with heparin and warfarin.

Results were similar among patients with osteoarthritis of the hand. Older patients were more likely to stop treatment because of allergic dermatitis or application-site reactions.

The data were pooled from relatively short trials of 8 or 12 weeks; therefore, longer studies are needed to determine whether tolerability can be maintained. Moreover, because patients with severe renal, hepatic, or cardiovascular disease were excluded from the analysis, closer monitoring may be warranted for those with severe comorbidities.

Source: Am J Geriatr Pharmacother 2012;10(1):47–60 (February)

Opioids, Sedatives, and Alcohol—A Dangerous Mix

As many as one-third of patients who are treated with opioids are also using sedatives and are engaging in risky drinking, despite a risk of oversedation and respiratory depression. In a study from Kaiser Permanente of Northern California in Oakland; the University of Washington in Seattle; and Harborview Medical Center in Seattle, the problem was prevalent even among patients who had no history of substance abuse.

Researchers used data from the CON-sortium to Study Opioid Risks and Trends (CONSORT) and from telephone surveys of 1,848 patients who were using long-acting or short-acting opioids for chronic non-cancer pain.

Participants were classified as concurrent users of alcohol if they reported having had two or more drinks within 2 hours before or after taking opiates in the preceding 2 weeks. Concurrent sedative use was defined as receiving sedatives for 45 or more days of the 90 days preceding the inter view. Substance abuse was defined as a diagnosis in the 3 years before the study, self-report of an alcohol or drug problem, or a score of 7 or higher (on a scale of 0 to 12) on the Alcohol Use Disorders Identification Test (AUDIT-C). Alcohol consumption increased markedly with AUDIT-C scores of 7 or higher. Risky drinking was defined by AUDIT-C scores of 3 to 6 for women and 4 to 6 for men.

Of 2,163 survey respondents, 1,883 (87%) reported using opioids every day for the previous 2 weeks; this group included 1,848 patients who could be classified according to substance abuse status. One-third of the respondents had a history of substance abuse.

About 12% of participants concurrently used alcohol, 32% were taking sedatives, and 3% were using all three substances concurrently. More than half of the participants were classified as depressed. Women were at a greater risk for combining sedatives and opioids, and men tended to use potentially dangerous combinations of alcohol and opioids.

One in eight patients had consumed two or more drinks within 2 hours of taking an opioid, regardless of substance abuse history. In fact, rates of concurrent alcohol use were similar among respondents with a history of substance abuse (13%) and those with no such history (12%). By contrast, concurrent sedative use was higher among patients with a history of substance abuse (39%) than among those without a history (29%).

Most patients reported very high levels of pain, although the majority said that opioids were helpful in managing the pain. Two-thirds of patients were taking opioids for more than one pain condition. The average daily opioid dose was 81 mg (morphine-equivalent dose). The close timing between drinking and taking the opioids suggests that some patients might view alcohol as another way of controlling pain.

Concurrent sedative use was associated with female sex, younger age, depression, higher daily opioid doses, and taking opioids for more than one pain condition. Patients taking the highest daily doses were twice as likely to use sedatives.

The prescribed sedatives were mostly those used to treat anxiety and sleep disorders, which are common with chronic pain. However, the researchers advised that the widespread practice of prescribing high-dose opioids and sedatives together deserves increased scrutiny. They also emphasized that even patients without a history of substance abuse can be at risk for misuse of alcohol and sedatives.

Source: J Pain 2012;13(3):266–275 (March)

Timing Immunoglobulins For Patients With Sepsis

Guidelines for treating patients with sepsis recommend that interventions, such as intravenous immunoglobulin (IVIg), be timely. However, it is difficult to establish what “timely” means, because the onset of sepsis and septic shock may be hard to determine.

Researchers in Trieste, Italy, say that the actual window of opportunity for interventions might be narrower than expected, especially if a patient is not in an intensive-care unit (ICU) when sepsis develops and if the signs and symptoms of sepsis are not immediately recognized.

The investigators conducted a retrospective study to determine the best timing for enriched IgM and IgA immunoglobulins (e-Ig) in 129 patients admitted to the ICU for severe sepsis or septic shock over the course of 5 years. Treatment included antibiotics and decontamination of the digestive tract. e-Ig was administered at a dose of 250 mg/kg IV on the day of the diagnosis. The infusion lasted for 10 hours and was repeated for 3 days. Ten patients received recombinant human activated protein C (rhAPC), and six patients were treated with coupled plasma filtration adsorption.

Forty-two patients (33%) died during their stay in the ICU. Survivors had received Ig therapy much earlier than non-survivors (23 vs. 63 hours, respectively). This delay was a significant predictor of the odds of dying during the ICU stay. A 24-hour delay in administering Ig nearly tripled the probability of dying in the ICU; this risk was independent of the patient’s sex, diagnosis at admission, presence of septic shock before admission, administration of rhAPC, treatment with coupled plasma filtration adsorption, and propensity scores. Among survivors, a 24-hour delay almost doubled the length of stay in the ICU.

The role of IVIg and e-Ig in patients with sepsis and sepsis-related conditions remains less clearly defined than other measures. This treatment is still not universally accepted, even though meta-analyses have demonstrated its effectiveness.

Source: J Crit Care 2012;27:167–171 (April)

Testosterone Supplements May Help Patients With Heart Failure

Testosterone supplements might be able to improve exercise capacity and metabolic factors in patients with heart failure, says researchers from Alberta, Canada. In pooled results from four small randomized, placebo-controlled trials, testosterone therapy was associated with 16% to 23% improvements in walking distance and peak oxygen consumption. Fasting glucose levels, insulin levels, and insulin sensitivity also improved.

Low testosterone levels are common in patients with heart failure and are associated with reduced exercise capacity and poor clinical outcomes. Researchers performed a meta-analysis of four randomized trials that included a total of 198 patients (84% men, mean age 67). Most of the patients (71%) had ischemic heart failure and an average left ventricular ejection fraction of 28%.

Two of the studies used intramuscular (IM) injections of testosterone, and two used a transdermal patch. Treatment lasted 12 to 52 weeks. On average, the patients receiving testosterone walked 54 meters (16.7%) longer on the 6-minute walk test and 46.7 meters (15.9%) longer on the incremental shuttle walk test. Peak oxygen consumption improved by 2.70 mL/kg per minute (22.7%).

The change in 6-minute walk test exceeded the improvements observed with other heart failure treatments, including angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and cardiac resynchronization. The apparent benefits of testosterone might be related to increased cardiac output, increased muscle mass, anti-inflammatory and immunosuppressive effects, an increase in hemoglobin, and enhanced baroreceptor sensitivity.

Although left ventricular ejection fraction was not affected, the percentage of patients who improved (as measured by the New York Heart Association classification system) was greater with testosterone (35%) than with placebo (9.8%).

The researchers said there were no major safety concerns but acknowledged the small sample sizes and short follow-up periods. The data did not suggest a link between testosterone replacement therapy and prostate cancer. Adequately powered trials are required to assess the benefits of testosterone, quality of life, clinical events, and safety in patients with heart failure. The researchers believe the results could also apply to women with heart failure.

Sources: Circ Heart Fail 2012 online; Med Page today, April 17, 2012

Cochrane Reviews

Statins Before Heart Surgery Help Prevent Complications

Taking statins before cardiac surgery can reduce the chance of postoperative atrial fibrillation (AF) and may shorten hospital stays.

German researchers analyzed data from 11 randomized controlled studies that included a total of 984 participants. Administering statins before surgery reduced the incidence of AF afterward, suggesting a beneficial effect for statintreated patients compared with non-treated patients. Patients who took statins preoperatively also tended to leave the ICU about 3.5 hours earlier and left the hospital about one-half day earlier. However, pretreatment with statins did not affect the risk of dying, stroke, heart attack, or kidney failure soon after the operation.

The researchers indicated that the results could not be applied to patients undergoing procedures other than coronary artery bypass operations, such as heart valve or aortic surgery. They emphasized the need for more data.

Source: Cochrane Database Syst Rev, Art. No.: CD008493; April 18, 2012

Heart Risks With Trastuzumab (Herceptin) in Breast Cancer

Tumor cells that produce excess quantities of human epidermal growth factor receptor-2 (HER-2) are classified as HER-2–positive; cells with normal HER-2 production are referred to as HER-2–negative. Trastuzumab (Herceptin, Genentech/Roche) blocks the receptor and stops it from triggering the excessive cell growth that causes tumors.

Adding trastuzumab to the treatment offered to women with HER-2–positive breast cancer may increase the chances for longer survival and reduce the risk of recurrence. HER-2–positive tumors are associated with a worse outlook than HER-2–negative tumors if they are untreated, but women receiving trastuzumab have a higher risk of cardiac problems.

Researchers in Italy evaluated eight trials that enrolled 11,991 women with HER-2–positive operable breast cancer. The women received trastuzumab or placebo as well as other treatments and were observed for 3 years on average.

Overall, deaths from breast cancer were reduced by one-third, but the risk of heart toxicity increased by five times for women receiving trastuzumab compared with women receiving standard therapy alone. About 26 in 1,000 women (2.6%) taking trastuzumab experienced serious heart toxicity. Toxicity was reversible if trastuzumab was stopped immediately. The researchers concluded that trastuzumab offered more benefits than risks in women at higher risk of disease recurrence and with no signs of a weak heart.

The risk–benefit ratio must be carefully evaluated in women with breast cancer who have a lower risk of recurrence (e.g., if they have a small tumor) and in women who are at increased risk for cardiac complications.

Source: Cochrane Database Syst Rev, Art. No. CD006243, April 18, 2012

Type of Care Affects Cancer Outcomes

In a review of studies by Cochrane researchers, survival rates for cancer patients improved in specialized cancer centers.

In the past, cancer patients were often treated by non-specialist surgeons and hospitals. In developed countries, most cancer care is now organized into networks of specialized centers, with on-site experts and dedicated nursing staff. This centralized approach, although costly, may help improve outcomes for patients.

The Cochrane review focused on data from five studies involving more than 62,000 women who were treated from the late 1990s onward. One analysis showed that women treated at a teaching center or a regional cancer center lived longer than those treated at community or general hospitals. Similarly, in a review of ovarian cancer, women who were treated at institutions with gynecologists on-site lived longer than those treated at hospitals.

There was consistent evidence that treatment by a specialist prolonged survival rates in women with gynecological cancer. The effect seemed strongest for ovarian cancer.

The researchers suggested that survival rates could be improved. Better-designed studies are needed to confirm the results.

Source: Cochrane Database Syst Rev, Art. No. CD007945, March 14, 2012

Drugs Are Better Than Non-Drug Methods for Labor Pain

Drug-based approaches fare better for relieving labor pains than non-drug approaches, say Cochrane researchers, who brought together the results of 15 previous Cochrane reviews and three non-Cochrane reviews, including data from a total of 310 trials. To distinguish between well-supported and less well-supported pain-relief approaches, they divided interventions into three categories.

The first category (“what works”) included pain relievers administered by the epidural, spinal/epidural, and inhalation routes.

There was less evidence for the second categor y (“what might work”), which included immersion in water, relaxation, acupuncture, massage, local anesthetic nerve blocks, and non-opioid drugs. However, more adverse effects were associated with the interventions for which there was the best evidence, including nausea and vomiting caused by inhaled painkillers and hypotension caused by the epidural route.

The second group of pain-relief approaches was better tolerated, and the women reported improved satisfaction with pain relief for all modalities except massage.

The third category (“insufficient evidence”) included hypnosis, biofeedback, sterile water injection, aromatherapy, transcutaneous electrical nerve stimulation (TENS), and injected or intravenous opioids.

More research is needed to evaluate the non-drug interventions in the second and third categories. Most of these interventions were safe, but the evidence was based on only one or two trials.

Source: Cochrane Database Syst Rev, Art. No. CD009234, March 14, 2012


NIH Studies

Ibrutinib and Aggressive Lymphomas

In patients with refractory lymphoma, oral ibrutinib might be able to provoke anti-cancer responses with only modest side effects. Pharmacyclics Inc. and Janssen are developing ibrutinib to target B-cell malignancies, leukemia, lymphoma, and multiple myeloma.

One type, diffuse large B-cell lymphoma (DLBCL), grows rapidly and represents 30% to 40% of newly diagnosed lymphoma cases. DLBCL originates from B cells, which are instrumental in evoking an immune response. There are at least three molecular subtypes, each derived from B cells at specific stages in their development. The activated B-cell (ABC) subtype of DLBCL accounts for 40% of cases and has the poorest clinical outcome with current therapy.

Receptors on the surface of B cells play a role in the progression of ABC lymphomas. In normal B cells, B-cell receptors help the cells recognize infections. In malignant B cells of ABC lymphomas, the receptors provide signals that promote tumor cell survival. More than one-fifth of ABC tumors have mutations that alter the activity of the B-cell receptor.

Researchers looked for ways to target B-cell receptor signaling and identified the enzyme Bruton’s tyrosine kinase (BTK) as a key element in the B-cell receptor pathway that is required to maintain the survival of ABC lymphoma cells. Based on this molecular research, the investigators used ibrutinib (PCI-32765), an oral inhibitor of the BTK enzyme. Ibrutinib was first evaluated in a pilot trial of ABC DLBCL and is being evaluated in an ongoing study of DLBCL. The single-agent tablet form of ibrutinib has so far elicited major anti-lymphoma effects with minimal side effects.

Participants received ibrutinib at a fixed dose of 560 mg/day until disease progression. Ibrutinib induced multiple responses and some complete remissions in patients with ABC lymphomas and with non-ABC DLBCL.

Sources: NIH, March 31, 2012; Medscape News, April 2, 2012, WebMD

Metformin Studies

Preventing Liver Cancer

Metformin (Glucophage, Bristol-Myers Squibb) is a widely used, well-tolerated drug prescribed for patients with diabetes. According to a new study, it might also protect against liver cancer.

A research team, led by Geoffrey D. Girnun, PhD, at the University of Maryland, chemically induced liver tumors in mice. The mice receiving metformin displayed minimal tumor activity, whereas control mice displayed tumor growth.

Metformin prevented liver cancer in part by inhibiting lipid synthesis in the liver, a process that promotes cancer. Patients with diabetes, obese individuals, patients with hepatitis, or patients with nonalcoholic fatty liver disease are at the greatest risk for liver cancer, because all of these diseases are associated with increased lipid synthesis.

Dr. Girnun plans to conduct a trial to see whether the benefits of metformin apply to humans.

Sources: Cancer Prev Res and Science Daily, March 31, 2012

Protection Against Oral Cancer

Researchers at the National Institutes of Health induced premalignant lesions in laboratory mice and studied the effect of metformin on the progression of these lesions to oral cancers. They reported strong activity against mammalian target of rapamycin complex 1 (mTORC1), which contributes to these cancers.

Scientists have noticed a trend toward reduced cancer rates in several organ sites when metformin was used. In this study, metformin therapy resulted in smaller and fewer carcinogen-induced oral tumoral lesions in mice and reduced the development of squamous cell carcinomas by 70% to 90%. Metformin inhibited mTORC1 function in the basal layer of oral premalignant tissues and prevented their spontaneous development into squamous cell carcinomas of the head and neck.

Sources: Cancer Res 2012;5(4):562; American Association for Cancer Research, March 31, 2012

Improving the Prognosis For Pancreatic Cancer

Patients with diabetes and pancreatic cancer who take metformin have experience improved survival compared with patients who did not use the drug. Although the cause of pancreatic cancer is unknown, patients often have a high prevalence of diabetes and impaired glucose tolerance.

In a retrospective study, researchers at the University of Texas evaluated 302 patients with diabetes and pancreatic cancer; 117 of these patients received metformin. At 1 year, 64% of the treated patients were still living, whereas 46% of the non-metformin group survived. By 2 years, 30% of the metformin group remained alive compared with 15% of the non-metformin group.

Median survival was 15.2 months with metformin and 11.1 months without it. Patients receiving metformin had a 32% lower risk of death. This protective effect was evident at all stages, except for metastatic disease.

In another study, the authors cautioned that gaps in knowledge must be addressed before metformin can be “re-purposed” for oncological indications.

Sources: Clin Cancer Res 2012;18(10); 1–3; American Association for Cancer Research, March 31, 2012

Antidepressants Help Mood In Parkinson’s Disease

Newer antidepressants boosted mood in patients with Parkinson’s disease (PD) without worsening motor function, according to the Study of Antidepressants in Parkinson’s Disease (SAD–PD).

Unlike older tricyclic antidepressants, which affect the heart and the autonomic nervous system in patients with PD, paroxetine HCl (GlaxoSmithKline), paroxetine mesylate (Pexeva, Noven), and venlafaxine extended release (Effexor XR, Wyeth/Pfizer) were well tolerated and had no effect on motor function.

An earlier study of PD, published in Neurology in 2008, had suggested that the older tricyclics might be preferred despite their adverse effects. That study had questioned the efficacy of selective serotonin reuptake inhibitors (SSRIs) after paroxetine and placebo provided similar improvements in depression. The conflicting results might have stemmed from a shorter treatment period, a higher dropout rate, and a strategy used for missing data in that study, the investigators suggested.

The effects with paroxetine and venlafaxine XR were convincing, and the study provided level I evidence for an antidepressant effect in patients without dementia with very mild PD. However, it is not clear whether the newer results apply to patients with more severe PD.

In the study, 115 patients with PD who did not have dementia received 12 weeks of treatment with paroxetine or the serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine XR at maximum daily doses of 40 mg and 225 mg, respectively, or with placebo. All three groups improved by week 12. Both active treatments were superior to placebo, but the two treatments did not differ significantly from each other.

Quality of life was not affected by either antidepressant. Although the two drugs appeared to produce similar effects, the study was not powered to make comparisons between the two and the trial was not large enough to look for responder characteristics.

Sources: Neurology 2012;78:1198–1199; Med Page Today, April 12, 2012

Bapineuzumab Shrinks Tau Tangles in Alzheimer’s Disease

Treatment with bapineuzumab, an investigational anti-amyloid beta monoclonal antibody, significantly lowered levels of phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD). However, there were no changes in CSF levels of amyloid-beta, the protein that bapineuzumab targets for removal in the brain. Patients with AD typically have lower levels of amyloid-beta but higher levels of tau proteins.

In a pooled analysis from two earlier phase 2 studies, p-tau levels declined in bapineuzumab-treated patients, compared with levels in controls. There was also a trend toward diminished total tau (t-tau) in these patients. Whether the effects will translate to clinical improvements remains to be seen.

To evaluate the effects of bapineuzumab on CSF biomarkers, researchers conducted an exploratory post hoc analysis of two phase 2 randomized, double-blind, placebo-controlled trials. Each trial was 1 year in duration and involved 46 patients with mild-to-moderate AD from the U.S., the United Kingdom, and Finland. Twenty-seven patients received bapineuzumab, and 19 were given placebo. There was a significant drop in CSF p-tau levels from baseline with the medication but no change with placebo.

Although t-tau levels in the CSF also fell significantly in treated patients, the difference between bapineuzumab and placebo indicated only a trend.

The declines in p-tau could have signified decreased formation of tau tangles in the brain; however, there were no clear-cut differences in amyloid-beta levels in the CSF. That could have resulted from clearance of cortical amyloid-beta through other pathways, or the binding of amyloid-beta to the antibody could have masked a change in CSF protein levels.

It was unclear whether the changes in tau correlated with clinical benefit. The study was limited, being based on pooled analyses of two previous trials. Elan and Wyeth first began working with bapineuzumab, and development is continuing with Pfizer.

Sources: Arch Neurol April 2, 2012 (online); MedPage Today, April 2, 2012

Painless Vaccine Patch

In the near future, annual flu shots might consist of a sticky, spiny bandage applied to the skin. In 2011, researchers at Emory University and the Georgia Institute of Technology developed a dime-sized vaccine patch, sprinkled with about 100 microscopic needles and coated with a vaccine solution. The patch, which comes in a metal or a dissolvable polymer version, was found to protect mice against influenza.

In 2011, the researchers found that vaccine delivery via microneedle patches was often more protective than delivery by the subcutaneous or intramuscular route. Microneedle immunization resulted in an immediate and dramatic local increase in subdermal cytokines, which recruit important immune cells to the site of immunization. The strategy also resulted in a prolonged presence of antigens—viral targets of the immune cells. The research illustrated the mechanism of microneedle delivery of antigens via the skin.

In another study from Brigham and Women’s Hospital in Boston, a research team demonstrated that a population of immune cells in the skin mediated a stronger immune response than that mediated by T cells in the bloodstream. As investigators learn more about the early immune responses in the skin, they may be able to expand the use of the patch by testing other antigens in addition to influenza and by observing the immune response.

Immunization with the microneedle patch could simplify vaccination programs in schools and in assisted-living facilities because it eliminates the need for trained personnel to give the injection. It could also reduce the risks associated with the reuse of hypodermic needles, a practice that is common in some developing countries.

The Emory–Georgia Tech team hopes to begin a phase I trial with the patch in the next year or so.

Sources: The Scientist, April 2, 2012; MBio, January–February 2012, online.


Biodegradable Stents Safe for 10 Years

In a Japanese study, the Igaki-Tamai stent was found to be safe over a period of 10 years. Major complication rates among 50 patients were similar for metal stents. Only one patient died of cardiac causes, and four patients had a heart attack over the 10-year period.

The stents, made of poly-l-lactic acid (derived from cornstarch) dissolve into the artery wall and leave no foreign material permanently in an artery. Metal stents remain in arteries, which can become clogged again even if the stent is drug-eluting.

Initially, investigators expected the Igaki-Tamai stents to last 6 months on average, but they lasted about 3 years. These stents are not used in the U.S. Some experts think that the device could become an alternative to the drug-eluting stents, although not a replacement for them. It is unclear how long the stents will last and how many patients might need to be treated for recurrent disease.

Because the analysis was small and observational and not randomized, more research is needed.

Sources: Circulation online, Med Page Today, April 16, 2012


Marvin M. Goldenberg, PhD, RPh, MS

Name: Prometra Programmable Pump

Manufacturer: Medasys (formerly InSet Technologies), Mount Olive, N.J.

Approval Date: February 17, 2012

Purpose: The implantable pump is used to treat intractable chronic pain.

Description: Patients receive an intra-spinal administration of preservative-free morphine sulfate sterile solution (Infumorph, Baxter) at a dose of 10 or 25 mg/mL. The pump is implanted near the spine, and a microcatheter runs to the intrathecal area of the lower spine.

Benefit: Dose variations caused by fluctuating temperatures, pressures, flow rates, or reservoir fill levels are minimized. The device has few moving parts and no complex gears and rotors. Intrathecal delivery makes it possible to use very low doses, thus minimizing the risk of side effects and lowering the amount of medication needed in the reservoir. The reservoir can be refilled percutaneously with a syringe and a needle.

This is the first non-peristaltic, programmable, implantable FDA-approved device for delivering preservative-free morphine. During clinical trials, the pump showed 97% accuracy in drug delivery. Because the pump is implanted, patients have the mobility to pursue everyday activities.

Precaution: Individuals whose pain can be relieved by drugs and other remedies might not be suitable candidates for intrathecal pumps. In most instances, chronic pain is best treated with a combination-therapy approach. The concentrated Infumorph solution is not intended for single-dose intravenous, intramuscular, or subcutaneous administration, and it should not be used to replace other forms of morphine.

The first dose should be given in a health care facility where naloxone injection (e.g., Talwin, Sanofi) and resuscitative equipment are available. Patients should be observed for at least 24 hours after they receive the initial dose and for the first few days after intrathecal catheter implantation, as appropriate.


Name: Ion Paclitaxel-Eluting Platinum Chromium Coronary Stent System and Taxus Liberté Paclitaxel-Eluting Coronary Stent System

Manufacturer: Boston Scientific Corp., Natick, Mass.

Approval Date: February 23, 2012

Purpose: The Ion and Taxus coronary stent systems are used in patients experiencing an acute myocardial infarction (MI). These are the only drug-eluting stent systems in the U.S. indicated for acute MI.

Description: The Ion stent is similar to the Taxus stent but differs in its platinum chromium metal alloy structure and design, which allow more flexibility within the coronary arteries.

Platinum chromium provides strength and deliverability. Platinum is more than twice as dense as iron or cobalt and has excellent radiopacity characteristics. Because platinum is evenly distributed throughout the alloy, visibility is improved. When platinum is combined with stainless steel, the alloy’s strength enables thinner struts to be used without compromising flexibility or visibility.

Benefit: The FDA’s approval of the new indication was granted on the basis of data derived from the paclitaxel (Taxus) program and the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS–AMI) trial. The paclitaxel-eluting stents resulted in less restenosis compared with bare-metal stents, and safety was comparable at 3 years.


Device Recall

On February 3, 2012, Cardiac Science Corp., initiated a correction of a limited number of automated external defibrillators (AEDs) made between July 1 and December 30, 2011. The AEDs contained a component with the potential to fail unexpectedly because of a manufacturing defect by the supplier. Failure during a rescue attempt might cause inadequate defibrillation therapy to be delivered. and the ability to resuscitate the patient. It is possible that the unit’s self-test might not detect a failure, or an impending failure, of the component.

Affected AED models include Power-heart 9300A, 9300E, 9300P, 9390A, and 9390E; CardioVive 92532 and 9253; CardioLife 9200G and 9231; GE Responder and Responder Pro; and Nihon–Kohden.