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P T. 2011;36(12): 784-786, 793-797, 842

New Drugs/Drug News/New Medical Devices December 2011


Generic Kadian for Pain

Watson Pharmaceuticals, Inc., has announced the FDA’s approval of its Abbreviated New Drug Application (ANDA) for morphine sulfate extended-release capsules USP, the generic equivalent of Kadian (Actavis). This drug is indicated for patients with moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Source: Watson, November 10, 2011

Hemacord, the First Cord Blood Product

The FDA has approved Hemacord, the first licensed hematopoietic progenitor cells–cord (HPC–C) cell therapy. Manufactured by the New York Blood Center, this product is used in hematopoietic stem-cell transplantation (HSCT) in patients with disorders affecting blood formation. Cord blood transplants have been used to treat some blood cancers and some inherited metabolic and immune system disorders.

Hemacord contains hematopoietic progenitor cells (HPCs) from human cord blood, one of three sources of HPCs used in transplants; the other two are bone marrow and peripheral blood. After the cells are infused into patients, they migrate to the bone marrow, where they divide and mature. When the mature cells move into the bloodstream, they can help to restore the number of blood cells and promote immune function.

A boxed warning mentions the risks of graft-versus-host disease, engraftment syndrome, graft failure, and infusion reactions.

Source: FDA, November 10, 2011

Two Orphan Drug Approvals

Jakafi for Bone-Marrow Disease

Twice-daily ruxolitinib tablets (Jakafi, Incyte) have been approved to treat patients with myelofibrosis, a rare bone-marrow disease. This is the first drug indicated for this purpose.

In patients with myelofibrosis, the bone marrow is replaced by scar tissue, resulting in an enlarged spleen, anemia, and decreased numbers of white blood cells and platelets. Symptoms may include fatigue, abdominal discomfort, pain under the ribs, satiety, muscle and bone pain, itching, and night sweats.

Ruxolitinib inhibits enzymes called JAK 1 and 2 (Janus-associated kinase), which are involved in regulating the blood and immune system. Myelofibrosis is associated with the deregulation of JAK 1 and 2.

Ruxolitinib was evaluated in two clinical trials involving 528 patients. Serious side effects included thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness, and nausea.

This medication was approved under an expedited program.

Source: FDA, November 16, 2011

Erwinaze for Leukemia

The FDA has approved asparaginase Erwinia chrysanthemi (Erwinaze, EUSA Pharma) to treat patients with acute lymphoblastic leukemia (ALL) who have experienced hypersensitivity to asparaginase (Elspar) and pegaspargase (Oncaspar) chemotherapy drugs, which are both derived from Escherichia coli.

Erwinaze is injected directly into muscle three times a week. It works by breaking down asparagine, an amino acid in the blood that promotes cell growth. Leukemia cells cannot produce this protein building block. Normal human cells can make enough asparagine for their own needs through biosynthesis and are not affected by treatment with Erwinaze.

In a clinical trial of 58 patients, adverse effects included anaphylaxis, pancreatitis, elevated levels of liver enzymes, blood clots, hemorrhages, nausea, vomiting, and hyperglycemia.

Source: FDA, November 18, 2011

Eylea for Wet Age-Related Macular Degeneration

Aflibercept (Eylea, Regeneron) has been approved to treat patients with wet (neovascular) age-related macular degeneration (AMD). The wet form of AMD includes the growth of abnormal blood vessels.

Eylea is injected into the eye either every 4 weeks or every 8 weeks by an ophthalmologist.

Eylea was found to be as effective as ranibizumab (Lucentis, Genentech/Roche) in two clinical trials involving 2,412 adults. Side effects included eye pain, injection-site bleeding, vitreous floaters, cataracts, and an increase in eye pressure.

In addition to ranibizumab, other approved therapies for wet AMD include verteporfin (Visudyne, QLT/Novartis) and pegaptanib (Macugen, EyeTech, Inc.).


Xarelto Tablets for Stroke And Embolism Reduction

Rivaroxaban (Xarelto, Janssen) is now approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Rivaroxaban is the only oral anticoagulant approved in the U.S. that can be taken once daily without the need for routine blood monitoring.

The once-daily dosage is 20 mg or 15 mg in patients with moderate-to-severe renal impairment. The tablet is taken with the evening meal.

Rivaroxaban was originally approved in July 2011 to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hipreplacement surgery.

Source: Janssen, November 4, 2011

Erbitux for Late-Stage Head and Neck Cancer

Cetuximab (Erbitux, Eli Lilly/Bristol-Myers Squibb) has been approved for use with chemotherapy to treat metastatic head and neck cancer.

In a study conducted outside the U.S., the drug/chemotherapy combination extended life by 10.1 months, compared with 7.4 months for those receiving chemotherapy alone. A non-U.S. approved version of the drug was used.

Cetuximab was first approved in 2004 to treat epidermal growth factor receptor (EGFR)–positive, late-stage colon cancer after failure of chemotherapy. Since 2006, the drug has also been approved for patients with non-metastatic head and neck cancer in combination with radiation therapy (first-line) or as a single agent (following standard treatment).

Source: FDA, November 7, 2011


Octagam Returns to Market

The FDA has approved the return of immune globulin intravenous (human) 5% liquid (Octagam, Octapharma USA) to the market to treat disorders of the immune system. The sterile preparation is derived from human plasma.

In August 2010, Octapharma voluntarily withdrew selected lots of Octagam in the U.S. because of an increase in thromboembolic events. The withdrawal was then expanded to cover all lots. The return of the product was permitted based on improvements in the manufacturing process along with new quality-control measures.

The thromboembolic events were determined to be associated with activated Factor XI. Octapharma now uses a commercial absorbent early in the manufacturing process that minimizes the presence of Factor XI.

Source: Octapharma USA, November 4, 2011

Avastin Indication For Breast Cancer Revoked

The FDA revoked its approval of the breast cancer indication for Genentech’s bevacizumab (Avastin) after concluding that the drug was not beneficial for that use. Bevacizumab is still approved as a therapy for colon, lung, and kidney cancers and glioblastoma multiforme.

FDA Commissioner Margaret A. Hamburg, MD, said that it was a difficult decision, and she recognized the great need for more effective treatments. But she emphasized that patients must have confidence that the drugs they take are both “safe and effective for their intended use.” She cited a lack of evidence that bevacizumab prolonged life or improved quality of life. She added that women who take the drug for metastatic breast cancer are risking potentially life-threatening side effects without proof that the drug delays tumor growth. Risks associated with the drug have included severe hypertension, hemorrhage, heart problems, and perforations in respiratory and digestive organs.

The 69-page opinion involves the use of bevacizumab in combination with paclitaxel (Taxol, Bristol-Myers Squibb) for patients who have not been treated with chemotherapy for HER2-negative breast cancer. This indication must now be removed from the product labeling for bevacizumab.

Bevacizumab was approved for treating metastatic breast cancer in February 2008 under the FDA’s accelerated approval program. That approval was based on promising results from one study suggesting that the drug could increase survival time. Genentech then completed two more trials that showed only a small decrease in tumor growth and no evidence of improved or prolonged life when compared with standard chemotherapy alone. These results were considered insufficient to outweigh the risks of taking the drug.

A 2-day hearing in June 2011 included recommendations from the FDA’s Oncologic Drugs Advisory Committee (ODAC), which voted 6–0 in favor of withdrawing the approval of the breast cancer indication. Dr. Hamburg recommended that Genentech consider additional studies to identify subgroups of patients with breast cancer who might benefit from bevacizumab.

Source: FDA, November 18, 2011

Newer Contraceptives And Risk of Blood Clots

The FDA has warned of an increased risk of blood clots associated with Bayer’s Yaz contraceptive. Women who took Yaz, which contains estrogen and drospirenone, were 74% more likely to experience clots than women taking low-estrogen products. Bayer claims that the risk is no greater than that of other oral contraceptives.

Drospirenone is similar to the natural female hormone progesterone. A new study reviewed the medical histories of more than 800,000 females ranging from 10 to 55 years of age who were taking contraceptives containing the hormone or combinations over time, including Bayer’s Yaz and Beyaz and Berlex’s Angeliq. The FDA’s findings come after recent studies suggest that newer birth control pills, including those containing drospirenone, have twice the risk of potentially deadly blood clots compared with older contraceptives.

Sources: BMJ, October 25, 2011; Associated Press, Bloomberg News, October 27, 2011

Is It Better to Take Blood Pressure Drugs at Night?

Patients who take a single antihypertensive drug once daily may be able to achieve better blood pressure (BP) control if they take the dose at bedtime. In a review from China, researchers evaluated the results of 21 randomized controlled trials of at least three weeks’ duration that involved almost 2,000 patients with primary hypertension.

It is known that BP fluctuates in a daily cycle or circadian rhythm. For many people who sleep at night and are active during the day, BP surges early in the morning. The morning surge in BP may increase the risk of adverse myocardial events, such as heart attacks or strokes, in the first few hours after awakening.

The researchers speculated that if patients take their medication in the morning, levels would be lowest just when patients need it the most because it takes hours for the drug to produce its full effects. Recent evidence suggests that taking the drug in the morning would allow the full effects to take hold during mid-day, with lesser effects at night and in the early morning. Therefore, a bedtime dose may produce the greatest effects during nighttime and early morning. However, no systematic reviews of the evidence have been conducted to confirm these findings.

Although nighttime dosing improved BP control, none of the studies indicated whether the regimen reduced the rate of strokes or heart attacks. It is unclear whether doses at night decrease the risk of early-morning cardiovascular events.

Sources: Cochrane Library; Health Behavior News Service, October 5, 2011

American Heart Association Meeting News, November 2011

Xarelto Reduces Treatment Risks

The newly approved anticlotting drug rivaroxaban (Xarelto, Janssen) lowered the risk of death, heart attacks, and strokes when added to standard medical treatment in patients hospitalized with acute coronary syndrome. However, as with other anti-clotting drugs, patients taking rivaroxaban were more likely to experience a major bleeding event than those who were not taking the drug.

Sources: N Engl J Med, November 13, 2011 (online); WebMD, November 14, 2011

Vorapaxar Disappoints in Major Trial

Vorapaxar (Merck), an experimental clot-inhibiting drug, failed to reduce the odds of experiencing adverse outcomes after treatment for unstable angina or a heart attack caused by a partial artery blockage. Patients receiving this drug also had an increased risk of bleeding. Vorapaxar is the first in a new class of antiplatelet drugs, the PAR-1 antagonists.

Source: N Engl J Med, November 13, 2011 (online)

Intracoronary ReoPro After a Heart Attack

The platelet inhibitor abciximab (Reo-Pro, Lilly USA) was no more effective in improving health outcomes in patients who had experienced a severe heart attack when it was delivered directly into the blocked coronary artery than when it was given by the intravenous (IV) route. However, fewer patients receiving the intracoronary dose went on to experience heart failure within 90 days, compared with those receiving the IV dose.

High-Dose Statins Reverse Heart Disease

High doses of rosuvastatin (Crestor, AstraZeneca) and atorvastatin (Lipitor, Pfizer) reversed the progression of coronary artery disease by reducing some of the plaque in clogged arteries supplying the heart. More than two-thirds of the patients showed plaque regression. Total plaque was reduced by 71% in patients who received rosuvastatin and by 65% in patients receiving atorvastatin.

Source: N Engl J Med, November 15, 2011 (online)

New Anticoagulant (Eliquis) No Better Than Standard Therapy

A 30-day, low-dose regimen of the blood thinner apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) was no more effective than 1 to 2 weeks of standard therapy for preventing venous thromboembolism (VTE). No significant differences were noted in the rates of death, heart attacks, or strokes between patients given apixaban for 30 days and those given enoxaparin (Lovenox, sanofi-aventis) for 6 to 14 days during treatment and follow-up periods. Bleeding rates were higher with apixaban.

Source: N Engl J Med, November 13, 2011 (online)

New Omega-3 Fatty Acid Reduces Atherogenesis

In the recently completed phase 3 MARINE study, patients with very high triglyceride levels (500 mg/dL or more) who were treated with 4 g/day of AMR 101 (Amarin Corp.) experienced a significant reduction in lipoprotein particle concentrations of total low-density lipoprotein (LDL) and small LDL. Compared with placebo, AMR 101 significantly reduced the median total LDL particle count by 16.3% (P = 0.0006), which is an important factor in atherogenesis. AMR 101 is a prescription-grade omega-3 fatty acid.

Source: Amarin Corp., November 15, 2011

Niacin Doesn’t Improve Stable Heart Disease

When LDL-cholesterol is well controlled with statins, adding high doses of extended-release niacin to increase low levels of high-density lipoprotein (HDL)-cholesterol did not further lower the risk of heart attack or stroke. Taking niacin boosted levels of HDL-cholesterol and lowered triglycerides, as expected, but those changes did not translate into fewer heart attacks or strokes. Because of the lack of benefit, the AIM–HIGH trial was stopped 18 months early.

Source: N Engl J Med, November 15, 2011 (online)

Two Anticlotting Regimens Are Similar

A combination of the antiplatelet drug abciximab (ReoPro, Lilly USA) and the blood thinner heparin (e.g., Heparin Sodium Injection, Hospira) was no more effective than another anticlotting drug, bivalirudin (Angiomax, The Medicines Company), in preventing death, subsequent heart attacks, or the need for further revascularization in patients undergoing an artery-opening procedure for non–ST-elevation heart attacks. Compared with bivalirudin, the dual treatment significantly raised the risk of major bleeding.

Source: N Engl J Med, November 13, 2011 (online)

Antibody Injection Lowers LDL

In the first preliminary tests in humans, an injectable drug decreased LDL-cholesterol levels in healthy volunteers. AMG 145 (Amgen), a monoclonal antibody, disables a protein that interferes with the liver’s ability to remove LDL-cholesterol from the blood. If it proves safe and effective, the new approach could help people who are unable to control their cholesterol levels with current medications.

Source: First Word, November 14, 2011

Free Drugs Reduce Heart Attacks—Slightly

Compared with patients who had prescription co-pays, heart attack patients whose insurance company picked up the entire tab for their heart medications had fewer subsequent heart attacks and heart failure. However, no reduction was observed in the rate of revascularization to reopen clogged arteries. Patients who received the free medications were more likely to follow their prescribed regimen. The free drugs saved patients money and did not increase overall health care costs. Skeptics, however, argue that the elimination of drug copayments has only a mild effect on adherence.

Sources: N Engl Med J, November 14, 2011 (online); Health Prize Technologies

Placental Cells Repair Heart Injury

In an animal study funded by the National Institutes of Health (NIH), stem cells from the placenta migrated to injured tissue in the mother’s heart during pregnancy and created new cardiac cells. Placentas could become a novel resource for reparative therapies, according to the investigators. Using placental stem cells doesn’t violate many religious beliefs, unlike the use of embryonic stem cells. Placentas are routinely discarded in labor and delivery rooms.

Source: Circ Res, November 14, 2011 (online)

Bone-Marrow Cells Are Safe But Not Effective Six Months After MI

Bone-marrow derived cells did not improve heart function after six months, according to the Transplantation In Myocardial Infarction Evaluation (Late TIME) study, which was funded by the NIH. Although treatment and survival following a heart attack have improved over the years, the risk of heart failure following a heart attack has not decreased. Stem-cell therapy is promising for repairing the damage done by a heart attack, and it is hoped that studies like Late TIME will help physicians understand how to perform and monitor these procedures.

In earlier studies, the cells were delivered within a few days of the heart attack; in Late TIME, the cells were infused 2 to 3 weeks after the MI. Patients are not always able to get immediate treatment because of poor health after a heart attack or because the hospital does not have a stem-cell therapy program.

Sources: NIH, November 14, 2011; JAMA (online)

… But They Provide Better Recovery After Five Years

Coronary infusion of bone marrow-derived mononuclear cells into the heart days after a heart attack is safe and results in better recoveries 5 years later, according to the Intracoronary Progenitor Cells in Acute Myocardial Infarction (REPAIR–AMI) trial. Within 5 years of follow-up, fewer recurrent heart attacks occurred in those receiving the infusion compared with the placebo group (5% vs. 7%, respectively). Magnetic resonance imaging showed better heart muscle functioning in the bone-marrow cell group at the end of the study, compared with those who did not receive the therapy.

Breakthrough Therapy: Cardiac Stems Cells for Heart Failure

A small-scale trial that used the human heart’s own stem cells has shown promise in the battle against heart failure and ischemic heart disease. Researchers harvested stem cells from the patients’ hearts during bypass surgery. All of the patients had a left ventricular ejection fraction (LVEF) of 40% or lower. (A value of 50% or higher is considered normal.)

The stem cells were purified, allowed to increase in number, and re-infused into the regions of the patients’ hearts that had been scarred by the infarction. Four months after the re-infusion, LVEF values increased from 30.3% to 38.5%. One year after the surgery, some patients showed even more dramatic improvement. The area of scarred tissue also decreased in size.

Sources: The Times of India, November 15, 2011; Lancet, November 14, 2011

Heart-Assist Devices Benefit Pediatric Patients Waiting for Transplants

Children and adolescents with heart failure who received a ventricular-assist device while waiting for a transplant had 6-month outcomes similar to those of adults with the devices, according to data from a federally supported registry.

Six months after implantation of the device, 55% of pediatric patients received the transplant, 37% were alive on support, and 8% had died. Although adolescents in the study received standard ventricular-assist devices, pediatric-specific devices are likely to earn the FDA’s approval soon.

Beta Blockers Prevent Complications From Breast Cancer Therapy

Beta blockers may help prevent potential heart-related complications from a drug used to treat breast cancer. Investigators evaluated 197 patients with breast cancer who were taking trastuzumab (Herceptin, Genentech/Roche) who had no history of heart failure.

Thirty of those patients took preventive doses of beta blockers for hypertension and other heart conditions before taking the breast cancer medication.

No one in the beta-blocker group experienced heart failure during the clinical study, compared with 14 patients (8.3%) who did not take the beta blockers.

Angioplasty Patients Do Just as Well In Hospitals Without Expertise

Patients who had non-emergency artery-opening angioplasty or stent implantation at hospitals without on-site heart surgery capabilities fared no worse than patients in hospitals with heart surgeons on staff. The death rate in both groups was less than 1%. Some states restrict hospitals from performing these procedures without on-site surgical expertise except in an emergency.

Catheter Ablation Is Better Than Drugs for AF

Catheter ablation, which uses high-frequency radio waves to destroy electrical triggers in the heart, worked as well or better than drugs to reduce periodic episodes of erratic heartbeats in patients with atrial fibrillation (AF). Episodes of erratic heartbeats in the heart’s upper chambers, called paroxysmal AF, were less frequent in patients who underwent the ablation procedure. Fifteen percent of the ablation-treated patients experienced AF compared with 29% of those who were treated with drugs. The Denmark Heart Foundation funded the study.

New Surgery for AF Effective but Risky

A minimally invasive surgical procedure to treat atrial fibrillation (AF) proved more effective than catheter ablation in high-risk patients but was more likely to cause major complications, according to a European study. Complications during the surgery occurred in 23% of patients undergoing surgical ablation and in 3% of the catheter-based ablation group. The procedure, called video-assisted epicardial surgical ablation, is not approved for treating AF in the U.S.

Source: Circulation, November 14, 2011 (online)

Celivarone: No Better Than Placebo For Preventing Sudden Cardiac Death?

Celivarone (sanofi-aventis), an experimental drug for stabilizing irregular heart rhythms, was no more effective than placebo in preventing sudden cardiac death and unnecessary firings of implanted defibrillators, a recent study showed. Patients taking celivarone had fewer adverse events, but the lack of effectiveness makes further trials unlikely.

Celivarone is chemically similar to amiodarone (Cordarone, Pfizer) and another heart rhythm drug, dronedarone (Multaq, sanofi-aventis).

Source: Circulation, November 14, 2011 (online)

Multaq Increases Risk of Death In Halted Study

Dronedarone (Multaq, sanofi-aventis), a drug used to treat people with intermittent atrial fibrillation (AF), doubled the risk of death and serious cardiovascular disorders in a study of patients with permanent AF. Because of these early findings, researchers ended the study with only 30% of the 10,800 intended patients enrolled. Dronedarone is not approved for the treatment of permanent AF in the U.S.

Sources: N Engl J Med, November 14, 2011 (online)

Hypoglycemia in the Hospital

For hospitalized patients, strict glucose control reduces the risks of hyperglycemia, but is this strategy putting them at risk for hypoglycemia? Research is needed to determine the fine line between too much control and not enough.

Many studies, including a large one that ended early, have found that hypoglycemia is common during hospitalization and is strongly associated with death. However, those studies were usually conducted among critically ill older patients.

More recently, researchers from Montefiore Medical Center and Albert Einstein College of Medicine in the Bronx, N.Y., theorized that comorbidities, not the drug treatments, might be responsible for what appear to be hypoglycemia-related deaths. Researchers designed a retrospective observational study to determine whether the hypoglycemia was associated with a higher risk of death in patients who were not critically ill.

The team analyzed data from a cohort of almost 32,000 patients, 3,349 of whom (11%) had experienced at least one episode of hypoglycemia. Those who had experienced hypoglycemic events were older; had a lower body mass index; had more comorbidities (including diabetes); and received more insulin, sulfonylureas, or a thiazolidinedione rather than metformin (Glucophage, Bristol-Myers Squibb). Spontaneous hypoglycemia (which was not related to glucose-lowering treatment) and drug-associated hypoglycemia also occurred in similar numbers of patients.

In-hospital mortality rates were four times higher among patients with hypoglycemia (4.39% vs. 1.06%). The risk of death was also higher among patients with hypoglycemia whether or not they had diabetes. However, patients without diabetes but with hypoglycemia had about double the mortality rate of diabetic patients with hypoglycemia (5.88% vs. 2.97%).

The association between hypoglycemia and mortality differed markedly among subjects when hypoglycemia developed spontaneously, compared with when it developed after glucose-lowering treatment. Among patients who were not receiving insulin, those with hypoglycemia had significantly higher mortality rates, compared with those who did not develop hypoglycemia. By contrast, the risk of death was similar for patients receiving insulin or oral antidiabetic drugs, whether or not they developed hypoglycemia.

When the researchers subdivided the drugs according to class, they found that patients who developed hypoglycemia that was associated with sulfonylureas or insulin did not have an increased risk of mortality compared with normoglycemic patients taking the same drugs. The lower rate of death among patients receiving metformin, thiazolidinediones, and sulfonylureas might have reflected the fact that oral drugs are discouraged during hospitalization. After patient demographics and comorbidities were considered, the association between spontaneous hypoglycemia and mortality was eliminated.

The study results suggested that hypoglycemia in these patients might be a marker of disease burden rather than a direct cause of death. The results should reassure clinicians who manage glucose levels in hospitalized patients.

Source: Am J Med 2011;124:1028–1035

Birth Defects and Hypertension in Pregnancy

Women who take angiotensin-converting enzyme (ACE) inhibitors to treat hypertension in the first trimester of pregnancy are at no greater risk of having offspring with birth defects than women taking other types of high blood pressure (BP) drugs or women who take no BP drugs, according to a new study. The Agency for Healthcare Research and Quality (AHRQ) suggests that the underlying hypertension itself might increase the risk of birth defects, rather than the medications taken during the first trimester.

ACE inhibitors are widely prescribed to treat high BP, especially in patients with diabetes. However, these medications have been associated with birth defects when they are taken during pregnancy. The AHRQ report did not find a link between first-trimester ACE inhibitor use and birth defects. The report should lead to more informed discussions between women and their doctors about the best way to manage hypertension, especially if a woman becomes pregnant.

Because ACE inhibitors block an enzyme in the kidney, physicians advise caution during the second and third trimesters, a crucial period of fetal development. The drugs carry a boxed warning against their use during the last two trimesters. Reducing BP before pregnancy, losing weight, and lowering sodium intake may be helpful in decreasing the risk of birth defects.

Sources: BMJ, October 18, 2011; AHRQ,

Part of Pulmonary Fibrosis Trial Stopped

The National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), has stopped one arm of a three-arm, multicenter, clinical trial in patients with idiopathic pulmonary fibrosis (IPF) because of safety concerns. In the study, patients who received triple-drug therapy (prednisone, azathioprine, and N-acetylcysteine [NAC]) had worse outcomes than those who received placebo.

IPF is a progressive, incurable disease characterized by the buildup of fibrous scar tissue within the lungs that can lead to breathing difficulties, coughing, chest pain, and fatigue. Approximately 200,000 people in the U.S. have IPF. The cause of the disease remains unknown.

Compared with placebo patients, those treated with triple therapy had higher mortality rates (11% vs. 1%), more hospitalizations (29% vs. 8%), more serious adverse events (31% vs.9%), and lower rates of adherence to treatment (78% vs. 98%).

The study results applied only to patients with well-defined IPF, not to those taking a combination of drugs for other lung diseases.

PANTHER–IPF (Prednisone, Azathioprine, and N-acetylcysteine: A Study that Evaluates Response in Idiopathic Pulmonary Fibrosis) began enrollment in October 2009. The placebo and NAC arms will continue enrollment, which is expected to be completed by late 2013.

Source: NIH, October 21, 2011

Giving Valproic Acid Another Chance

Valproic acid (e.g., Depakene, Abbott) has a number of adverse effects on the blood, some of them serious, such as pancytopenia. When valproate-induced pancytopenia develops and alternative drugs don’t work, there are no guidelines as to whether it’s safe to restart valproate therapy, says a physician who cared for a patient in this situation.

The patient, a 73-year-old man with a lifelong history of bipolar illness, had done well with conventional doses of valproic acid for 10 years, with nearly complete control of his mood symptoms. He had only minor thrombocytopenia, even though he also had coronary artery disease, diabetes, hypertension, osteoporosis, and benign prostatic hypertrophy. In addition to receiving valproic acid, he had been and was then taking sertraline (Zoloft, Pfizer), epoetin alfa (e.g., Procrit, Janssen), terazosin (Hytrin, Abbott), finasteride (Proscar, Merck), omeprazole (Prilosec, AstraZeneca), aspirin, and calcium.

When pancytopenia developed, his valproic acid dosage was 500 mg twice daily with no recent adjustments. His serum level was 62.1 mcg/mL. Serum B12 and folate levels were normal, and there was no history of hematological problems. The physician discontinued the valproic acid and substituted lithium carbonate. All cell lines returned to normal within a week.

At first the patient did well, but his manic symptoms and paranoid delusions returned within 6 months. Over the next year, lamotrigine (Lamictal, Glaxo-SmithKline), gabapentin (Neurontin, Pfizer), quetiapine (Seroquel, Astra-Zeneca), risperidone (Risperdal, Ortho-McNeil-Janssen), haloperidol (Haldol, Ortho-McNeil-Janssen), and loxapine (Loxitane, Watson) were tried. The medical team then cautiously re-introduced valproic acid, with the dose titrated to achieve lower serum levels (40–50 mcg/mL).

The patient’s symptoms promptly improved and remained controlled with a combination of valproic acid and lamotrigine. Blood counts also remained stable within normal ranges.

Valproate-induced hematological abnormalities generally occur early in therapy. A late adverse event might be explained by dosage or medication adjustments, but no changes had been documented in this patient. The fact that the pancytopenia resolved quickly suggested that it was not due to an underlying problem.

Only one other drug—omeprazole—is associated with pancytopenia. The patient had been taking valproate for some time, but the rapid resolution of symptoms pointed to that drug.

Although pancytopenia can be fatal, it was encouraging that it might not represent an absolute contraindication to carefully restarting valproate therapy with close hematological monitoring.

Source: Am J Geriatr Pharmacol 2011; 9:351–353

LABAs May Increase Asthma Attacks in Children

Long-acting beta-agonists (LABAs), which are used to prevent wheezing and shortness of breath in patients with asthma, may raise the risk of asthma attacks in children and increase the need for hospitalization. However, a new FDA analysis suggests that when LABAs are used with inhaled corticosteroids, the extra risk disappears. Whether the inhaled corticosteroids eliminate all added risk is still not clear.

According to the Centers for Disease Control and Prevention (CDC), 7 million children in the U.S. have asthma (about 9%).

LABAs are also used to treat chronic obstructive pulmonary disease (COPD). The FDA report combined safety data from more than 100 studies, including about 60,000 patients with asthma. The original trials were conducted by companies that market LABAs. The drugs include Merck’s formoterol (Foradil) and GlaxoSmithKline’s salmeterol (Serevent).

Compared with patients who did not take LABAs, adults and children who did take them were 27% more likely to be hospitalized. In rare cases, they died or needed intubation because of an asthma attack. That extra risk was greatest in the youngest participants; those children between 4 and 11 years of age who were taking a LABA were 67% more likely to be hospitalized for asthma than those who did not receive the medication. A few people of all ages who were regularly taking an inhaled corticosteroid with a LABA did not have an extra risk of hospitalization.

Last year, the FDA began requiring drug companies to write on LABA labels that the drugs should not be used without a long-term asthma control agent such as an inhaled corticosteroid. Some asthma medications, including fluticasone (Advair, GlaxoSmithKline) and budesonide/formoterol (Symbicort, Astra-Zeneca), contain both a LABA and corticosteroid. The FDA recommends such combined products for pediatric patients with asthma.

Younger children may have a higher risk when taking a LABA alone. The analysis wasn’t designed to examine the cause of the extra risk; the problem might be related to smaller airways in young patients.

It will be important for researchers to determine whether the attacks are a direct result of the medications themselves.

Sources: Pediatrics, October 24, 2011 (online); Reuters, October 26, 2011


Curing Sickle Cell Disease in Mice

Funded by the National Institutes of Health (NIH), researchers at Harvard Medical School and the University of Texas corrected sickle cell disease in adult mice by activating the production of a blood component that is normally produced before, but not after, birth.

People with sickle cell disease have two copies of an altered gene that produces sickled hemoglobin instead of normal adult hemoglobin. The hemoglobin changes shape after releasing its oxygen, causing the red blood cells (RBCs) to become stiff, misshapen, and sticky, slowing blood flow to tissues. This process damages organs and causes pain.

The scientists sought to increase the production of fetal hemoglobin, which is predominant before birth but becomes silent after that, when adult hemoglobin production takes over. Elevated levels of fetal hemoglobin within RBCs reduces the tendency of sickled hemoglobin to change the shape of RBCs. Hydroxyurea increases production of fetal hemoglobin and reduces the number of pain crises; however, not all patients respond well to hydroxyurea.

In earlier studies, a protein (BCL11A) normally suppressed the production of fetal hemoglobin soon after birth. The researchers wanted to see what would happen if they blocked production of this protein. Silencing the gene turned off production of BCL11A and enabled the adult mice to continue to produce fetal hemoglobin.

Sources: Science and NIH, October 13, 2011


Delivery of Chemotherapy By Nebulizer in Lung Cancer

Administering chemotherapy via a nebulizer to patients with lung cancer might help to reduce harmful adverse effects, such as kidney damage. Scottish researchers at the Strathclyde Institute of Pharmacy and Biomedical Sciences in Glasgow say the technique would also be faster and safer than the current intravenous route and would enable health care practitioners to prescribe the drugs in smaller doses without a decrease in benefits. By delivering cisplatin in a vaporized form, oncologists hope to attack the cancerous cells and avoid damage to healthy cells.

Sources: United Press International, The Oncology Pharmacist, October 12, 2011

A Sensitive PSA Test

Quanterix Corp. has announced promising results for Accu PSA, a prostate-specific antigen (PSA) test. The digital immunoassay allows the measurement of PSA in men who have undergone radical prostatectomy for prostate cancer. After surgery, PSA levels typically become undetectable with conventional third-generation tests. With Accu PSA, the researchers were able to accurately measure PSA levels. The test appears reliable in predicting 5-year recurrence-free survival following surgery. The evidence indicates that a more sensitive PSA assay could improve a patient’s prognosis.

Sources: Clin Chem, October 13, 2011 (online); Quanterix, November 2, 2011,


Marvin M. Goldenberg, PhD, RPh, MS

Name: Excellagen Gel

Manufacturer: Cardium Therapeutics, San Diego, Calif.

Approval Date: October 10, 2011

Purpose: Excellagen gel is used in the treatment of diabetic foot ulcers and other wounds affecting the skin. The gel is applied immediately following surgical debridement.

Description: This refined, fibrillar, flowable bovine collagen topical gel, 2.6%, will initially be marketed as a sterile, syringe-based advanced wound-care product. It is approved for foot, pressure, and venous ulcers and partial-thickness, full-thickness, tunneled, surgical, traumatic, and draining wounds.

Benefit: Sterile fills of single-use syringes are available for topical application. In a clinical trial, the product reduced wound radius and accelerated healing, compared with standard-of-care therapy for diabetic neuropathic foot ulcers. The gel also helped to activate and release the wound-healing protein (platelet-derived growth factor).


Name: SenoBright Spectral Mammography

Manufacturer: GE Healthcare, Waukesha, Wisc.

Approval Date: October 14, 2011

Purpose: Contrast-enhanced images of the breast are produced during mammography to produce a clear image.

Description: X-rays of multiple energies are used to create two separate, but almost simultaneous, exposures. The resulting images illuminate areas of iodinated contrast. The two images are produced in the same orientation for each standard craniocaudal and mediolateral oblique view. The first image exposure uses standard mammography parameters, and the second image shows contrast-enhanced areas with the background tissue signal suppressed. With the combination of two types of images generated by the system (one obtained at low-energy spectrum and one at high-energy spectrum), radiologists have one clear final image in which signal from the normal tissue is removed and contrast appears distinct.

Benefit: SenoBright can be an alternative modality when additional tests are needed to diagnose a lesion. Surgeons and oncologists can review the images in only 5 to 10 minutes on the same day as the traditional screening. The Senographe DS and Senographe Essential digital mammography systems now in use can be upgraded to SenoBright.


Name: Ilumien Optimization System

Manufacturer: St. Jude Medical, Inc., St. Paul, Minn.

Approval Date: October 26, 2011

Purpose: High-resolution images of stent placement may help to improve the diagnosis and treatment of coronary artery disease.

Description: Ilumien combines optical coherence tomography (OCT) and fractional flow reserve (FFR) technologies on one platform. FFR is an index that can determine the severity of narrowing in the coronary arteries and identify the narrowings that are causing the ischemia. A wireless tool is used to measure FFR to evaluate the severity of blood flow blockages in the coronary arteries. OCT utilizes near-infrared light to create images of vessel characteristics that would not otherwise be visible with older intracoronary imaging modalities (fluoroscopy and intravascular ultrasound). OCT can be very valuable in assessing stent placement. High-resolution images show precisely how the stent is holding the artery open and whether it is positioned correctly against the arterial wall.

Benefit: Two technologies are integrated into one platform to provide precise measurements of lesion dimensions as well as vessel size and structure. Aortic pressure readings can be received wirelessly, thus providing a cable-free FFR solution. Using FFR before placing the coronary stents pinpoints the lesions that are responsible for the narrowing.