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P T. 2013;38(1): 8-13, 16

New Drugs/Drug News/New Medical Devices January 2013

NEW DRUGS

Cometriq for Thyroid Cancer

Cabozantinib (Cometriq, Exelixis) has been approved with an orphan drug designation to treat metastatic medullary thyroid cancer (MTC). Cabozantinib blocks abnormal kinase proteins involved in the development and growth of medullary cancer cells. In a clinical study, treatment with cabozantinib increased progression-free survival and, in some patients, reduced the size of tumors.

A boxed warning mentions the risk of severe and fatal bleeding. Perforated colon occurred in some patients.

Another therapy for MTC, Astra-Zeneca’s vandetanib (Caprelsa, formerly Zactima), was approved in April 2011.

Source: FDA, November 29, 2012

Iclusig Tablets For Drug-Resistant Leukemia

Ponatinib (Iclusig, Ariad), a third-generation tyrosine kinase inhibitor, has been approved to treat two forms of leukemia that are resistant to prior tyrosine kinase inhibitor therapy—chronic myeloid leukemia (CML) and Philadelphia (Ph) chromosome–positive acute lymphoblastic leukemia (ALL) in adults. The accelerated approval was based on a single phase 2 trial.

This pan–bcr-abl inhibitor is effective against native and mutant forms of the bcr-abl protein, produced by the Ph chromosome, which gives rise to CML and Ph-positive ALL.

A boxed warning refers to a risk of blood clots and liver toxicity.

Ponatinib will be available in specialty pharmacies.

Sources: www.4-traders.com; MedPage Today, December 14, 2012

Signifor, An Orphan Drug, For Cushing’s Disease

Pasireotide diaspartate (Signifor, Novartis) injection has been approved for patients with Cushing’s disease when surgery is not an option.

Cushing’s disease is caused by the overproduction of cortisol. In a clinical trial, the drug resulted in decreased cortisol levels, as measured in urine collected over a 24-hour period. The reduction was seen as early as 1 month after starting treatment. About 20% of patients achieved normal urinary cortisol levels, although continued treatment caused or worsened diabetes in some patients.

Pasireotide is given subcutaneously twice daily. It will be dispensed with a medication guide.

Adverse reactions have included hyperglycemia, diarrhea, nausea, abdominal pain, and gallstones.

Source: FDA, December 14, 2012

Raxibacumab For Inhalational Anthrax

Raxibacumab injection (Human Genome Sciences/GlaxoSmithKline) has been approved to treat inhalational anthrax, a form of the infectious disease caused by breathing in the spores of the bacterium Bacillus anthracis. The drug is also approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.

Raxibacumab is a monoclonal antibody that neutralizes toxins produced by B. anthracis that can cause irreversible tissue injury and death. Anthrax is a potential biological terrorism threat; the spores are resistant to destruction and can be easily spread by release in the air.

The FDA granted this medication a fast-track designation, a priority review, and an orphan product designation.

Raxibacumab is the first monoclonal antibody approved under the FDA’s Animal Efficacy Rule, which allows efficacy findings from well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct trials in humans. Because inhalational anthrax is a rare and lethal disease, it is not possible to conduct adequate efficacy trials in humans.

Source: FDA, December 14, 2012

NEW INDICATIONS

Promacta for Hepatitis C

Eltrombopag (Promacta, GlaxoSmith-Kline/Ligand) has been approved to allow patients with chronic hepatitis C virus infection (HCV) to initiate and maintain interferon-based therapy. A thrombopoietin receptor agonist, eltrombopag was approved in 2008 for the treatment of thrombocytopenia.

Abnormally low platelet counts can lead to mild-to-serious bleeding. Eltrombopag increases the platelet count by increasing megakaryocyte differentiation and proliferation. Approximately 4.2 million patients (3.5%) with chronic HCV infection have low platelet counts that could make them ineligible to start or maintain their interferon-based therapy. In combination with interferon, eltrombopag led to improved chances of achieving a sustained virological response or viral cure. Eltrombopag should not be used in an attempt to normalize platelet counts; it is intended only for patients with chronic HCV infection who cannot begin interferon therapy.

A boxed warning mentions a risk of hepatotoxicity. Promacta is known as Revolade outside the U.S.

Sources: The Wall Street Journal, November 19, 2012; www.gsk.com

Zytiga Before Chemotherapy For Prostate Cancer

Abiraterone acetate (Zytiga, Janssen Biotech) can now be used to treat men with late-stage castration-resistant prostate cancer before they receive chemotherapy. The FDA approved the new indication under a priority review program. The drug was originally approved in April 2011 for men with disease progression after treatment with docetaxel (Taxotere, Sanofi).

Abiraterone decreases the production of testosterone, which can stimulate the growth of prostate tumors. In men with castration-resistant prostate cancer, the prostate cancer cells continue to grow even with low levels of testosterone.

Abiraterone acetate is the topic of the Drug Forecast column on page 23.

Source: FDA, December 10, 2012

DRUG NEWS

Off the Market

Zofran 32 mg IV

The 32-mg dose of the antinausea drug ondansetron (Zofran, GlaxoSmithKline) has been pulled from the market because of concerns about cardiac problems. Ondansetron is approved for preventing chemotherapy-induced nausea and vomiting; in lower doses, it is approved for postoperative nausea and vomiting. The 32-mg formulation is given as a single intravenous (IV) dose.

The FDA did not expect the removal of the 32-mg dose to contribute to a drug shortage of IV ondansetron; the 32-mg IV dose makes up only a small percentage of the current market. In June 2012, the FDA had warned that this dose should be avoided because of the risk of QT interval prolongation, which can lead to potentially fatal arrhythmias.

The IV regimen of 0.15 mg/kg, administered every 4 hours for three doses is still recomended to prevent chemotherapy-induced nausea and vomiting. Oral ondansetron also remains effective for this indication.

Source: MedPage Today, December 4, 2012

Generic Atorvastatin

Ranbaxy Pharmaceuticals, based in New Delhi and owned by Daiichi Sankyo, has recalled its atorvastatin product, a cholesterol-lowering medication. The recall affects 41 lots of atorvastatin, the generic version of Pfizer’s Lipitor, because of the possibility that small glass particles, less than 1 mm in size, might be present. The 10-mg, 20-mg, and 40-mg dosages, but not the 80-mg tablets, are affected. The recall was issued as a safety precaution.

Ranbaxy’s product constitutes almost half of the U.S. market for atorvastatin, including generic and brand-name products. In 2012, Ranbaxy agreed not to sell various generic drugs on the U.S. market until it addressed manufacturing and quality-control flaws at some plants. Those plants did not make the generic drug now being recalled.

Ranbaxy began selling generic Lipitor a year ago under the terms of a prior settlement of patent litigation with Pfizer, whose market exclusivity for the block-buster branded drug had expired. Pfizer had also recalled some lots of Lipitor in 2010 because of uncharacteristic odors in the product.

Sources: Bloomberg News and The Wall Street Journal, November 23, 2012; WebMD Health News, November 26, 2012

Adcetris, an Orphan Drug, For Mycosis Fungoides

Brentuximab vedotin (Adcetris, Seattle Genetics) has been granted an orphan drug designation by the FDA for the treatment of mycosis fungoides, a common type of cutaneous T-cell lymphoma. A phase 3 trial is evaluating the medication in patients with CD30-positive relapsed disease, including mycosis fungoides. Brentuximab is not approved for the treatment of cutaneous T-cell lymphoma or peripheral T-cell lymphoma not otherwise specified.

Brentuximab received an accelerated approval by the FDA in August 2011 for Hodgkin’s lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multiagent chemotherapy regimens in patients who were not candidates for transplantation and for systemic anaplastic large-cell lymphoma in patients not responding to at least one multiagent chemotherapy regimen.

A boxed warning mentions the risk of progressive multifocal leukoencephalopathy–John Cunningham virus (JVC) infection, which can result in death.

Sources: www.empr.com; www.adcetris.com

Aspirin in the News

Safe Before Polypectomy?

It might not be necessary to withhold aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) before a colonoscopy or a polypectomy, say researchers at the Veterans Affairs Medical Center in Syracuse, N.Y.

Of 1,174 patients, 502 (43%) were taking aspirin, NSAIDs, or both (group A). Those patients did not differ statistically from patients who were not taking aspirin or NSAIDs (group B) in the number or location of colonic polyps, adenoma detection rates, or polypectomy technique.

Bleeding was considered significant if the patient became hemodynamically unstable, if hemoglobin or hematocrit values fell, or if the patient required hospitalization, transfusions, or other interventions.

The overall risk of bleeding in the entire cohort was 3.1%. In group A, 10 patients experienced immediate bleeding after polypectomy and six patients experienced delayed bleeding (1 to 9 days after surgery). In group B, 14 patients had immediate postoperative bleeding and six patients had delayed bleeding. Five patients with delayed bleeding needed hospitalization, transfusions, or other procedures, but there was no long-term morbidity. One patient in each group underwent a colonoscopy for postoperative bleeding.

The total number of polyps removed was the only risk factor significantly associated with bleeding.

This was not the only study to find that aspirin and NSAIDs did not increase the risk of postoperative bleeding; the risk has also been assessed in patients who had other invasive procedures, such as transrectal prostate and transbronchial lung biopsies.

Source: Am J Med 2012;125:1222–1227

A Decreased Risk Of Liver Cancer

In an observational study, patients with chronic liver disease (CLD) who used aspirin or a non-aspirin nonsteroidal anti-inflammatory drug (NSAID) had a 36% reduced risk of developing hepatocellular carcinoma (HCC) and a 57% reduced risk of dying from CLD compared with individuals who did not use either aspirin or an NSAID. Risk factors for both HCC and CLD included obesity, smoking, and diabetes. The reduced risk of HCC prevailed whether or not participants took the drugs daily, weekly, or monthly.

Those who took aspirin regularly, whether or not they also took NSAIDs, had a 41% reduced risk of developing HCC, compared with those who did not use aspirin, as well as a 45% reduction in the risk of death from CLD. Participants who took only aspirin had an even greater reduction in risk of HCC (49%), compared with those who did not.

Regular use of other NSAIDS did not reduce the development of HCC.

Previous studies had shown that regular aspirin use might decrease the risk of colon cancer and the risk of death from cancer overall. Aspirin and other NSAIDs may reduce inflammation, which may have an antitumor effect.

The current study was limited by a lack of information on the risk factors for CLD and HCC among the participants.

Aspirin is often prescribed to people 50 years of age and older as a preventive measure against cardiovascular and cerebrovascular diseases. Most patients with CLD are advised to avoid NSAIDs because of the risk of bleeding. For aspirin to be practically useful, the potential benefits of chemoprevention need to be weighed against the potential risks.

Some recommended strategies for preventing liver disease include avoiding alcohol or consuming it moderately; being vaccinated for hepatitis A and B; avoiding hepatotoxins (e.g., NSAIDs and herbal products); being physically active; and maintaining a healthy weight.

Sources: J Natl Cancer Inst, November 28, 2012; Cancer Network, November 29, 2012

Metformin and Survival In Ovarian Cancer

In a retrospective, case–control study from the Mayo Clinic, women who had been taking metformin (Glucophage, Bristol-Myers Squibb) during treatment for type-2 diabetes had better survival rates (73%) than cancer patients not taking the drug (44%).

Metformin had previously shown anti-cancer effects in ovarian cancer, both in vitro and in vivo, and in neoplasms of the prostate gland, colon, pancreas, and brain. A more recent retrospective case–control study was conducted to evaluate ovarian cancer patients who were treated between 1995 and 2010. Of these women, 72 had been taking metformin for type-2 diabetes during cancer treatment. They were matched with 143 controls who did not have diabetes and were not taking metformin.

The researchers also assessed a subset of 61 women who had had epithelial ovarian cancer and compared them with 178 nondiabetic controls with the same cancer. Another control group of 103 patients had both diabetes and epithelial ovarian cancer and were taking insulin or other diabetes drugs instead of metformin. Overall, the mean duration of metformin intake was 2.3 years, given at doses ranging from 500 mg twice a day to 1 g twice a day.

The study was limited by its retrospective nature, a small sample size, and a lack of information on patients’ metformin intake before their cancer diagnosis. However, the authors concluded that metformin seemed to correspond to better survival in ovarian cancer patients and that the drug should be evaluated in prospective trials.

Source: Cancer, 2012 online; MedPage Today, December 3, 2012

Steroids Reduce Bone Density

In an observational study from Henry Ford Hospital in Michigan, a single epidural steroid injection led to a significant decrease in bone mineral density (BMD) of the hip among postmenopausal women. Mean BMD at the hip declined from baseline by 0.018 g/cm2 at 6 months after an injection of 80 mg triamcinolone acetonide injectable suspension (Kenalog, Apothecon). This synthetic glucocorticoid corticosteroid has anti-inflammatory action and is indicated for intra-articular and intralesional use only. It is about eight times more potent than prednisone.

Age-matched controls had a decrease of only 0.003 g/cm2, a significantly smaller loss in BMD. These findings suggested that there could be a six-fold rise in annual bone loss at the hip among women receiving the injections.

Epidural steroid injections have been in the news lately because of more than 500 cases of fungal meningitis linked to the procedure. The injections relieve pain and may help to avoid the need for surgery. However, oral and inhaled glucocorticoids have adverse effects on BMD, which is often low in older women, and can increase the risk of fractures.

The women in the study were not taking any other drugs that could have affected BMD.

With the cohort experiencing significant changes in BMD in only 6 months after a single epidural steroid injection, the researchers urged caution before prescribing steroids for patients at risk for fractures and recommended bone-protective measures such as exercise and an increased intake of calcium and vitamin D.

Limitations of the study included the small sample size, a high rate of attrition, and the lack of a control group.

Sources: Spine, December 1, 2012; MedPage Today, December 2, 2012; www.rxlist.com; Medline Plus, December 3, 2012

10 Years of Tamoxifen Better Than 5 for Preventing Breast Cancer Recurrence

In a randomized trial conducted at the University of Oxford, a decade of tamoxifen citrate (Nolvadex, AstraZeneca) therapy conferred greater benefits in women with early estrogen receptor (ER)–positive breast cancer than in those who stopped taking the drug after 5 years. The extra time with tamoxifen reduced recurrence and mortality rates.

Results from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial suggested that 10 years of therapy might cut mortality rates by half during the second decade after diagnosis. The extended treatment appeared to be beneficial in premenopausal women.

Tamoxifen, taken daily for 5 years after surgery for estrogen receptor (ER)–positive breast cancer, reduces breast cancer recurrence not only during the treatment period but also afterward. An earlier report from ATLAS had indicated no potential benefit of longer therapy.

For the recent study, researchers enrolled 12,894 women with early breast cancer who had completed 5 years of tamoxifen and randomly allocated them to continue for another 5 years or to stop therapy. Among the women with ER-positive disease, there were 1,328 recurrences of breast cancer. The risk of recurrence during years 5 through 14 was 21.4% for women continuing therapy and 25.1% for controls (a 3.7% reduction). Continuing with tamoxifen also reduced mortality rates from breast cancer.

Among all patients, there was an increased incidence of pulmonary embolus, no increased risk of stroke, an apparent protective effect against ischemic heart disease, and a higher risk of endometrial cancer. It was concluded that the risks were smaller than the benefits, especially since the trial results apply mainly to younger women, whose risk of endometrial cancer is low.

Sources: Lancet (online) and MedPage Today, December 5, 2012

Statin Benefits After a Stroke

Various studies suggest that statins might offer protection against stroke, although their effect on mortality rates and functional outcomes after stroke is less clear, especially in older patients. A study from Sweden suggests that statins might be both helpful and not so helpful.

The study involved 799 patients (mean age, 78 years) with acute ischemic stroke; 183 patients were using statins before the stroke. At the 12-month follow-up visits, 67% of patients were still participating.

Statins improved outcomes at 90 days and 12 months after stroke. Patients using statins after hospital discharge (61%) had significantly better neurological outcomes than patients who did not receive these drugs. One year after the stroke, about 74% of patients who were treated with statins had favorable scores on the modified Rankin Scale. Only 51% of the untreated group of patients reached the same level.

Statins used before a stroke did not significantly influence stroke severity, although there was a weak trend toward less stroke severity. The drugs also did not improve 30-day survival; 70 patients died of all causes (55 in the hospital).

Statin treatment did not influence the rate of recurrent stroke during the first year of follow-up, although 12 months might not have been long enough to pinpoint the true effects. In other studies, significant differences in rates of recurrent stroke began only 36 months after statin therapy was was initiated. However, statins did promote long-term survival. Patients with glycosylated hemoglobin (HbA1c) values of 6.5% or higher benefited more from statins.

As for the negative findings in regard to poor 30-day survival, the researchers said that any acute neuro-protective effect of statins might have been counteracted by the fact that the patients taking statins were sicker. Half of the patients who had used statins previously had had an ischemic stroke, and half had associated cardiac pathology; these patients were also elderly and frail. All of these factors could have reduced the effects of statins. In fact, treatment with statins could be a marker for disease rather than a protective factor.

Source: Am J Geriatr Pharmacother 2012;10:313–322

Bronchchodilator Safety After Cardiac Surgery

Atrial fibrillation (AF) is often a concern after heart surgery, because it can result from many causes. Although bronchodilators have been thought to induce tachycardia, a study from Missouri suggests that they might not, in fact, trigger postoperative AF. Moreover, levalbuterol (Xopenex, Sepracor/Sunovion) and albuterol (e.g., Proventil, Schering/Merck) have almost the same preventive effects.

Bronchodilators are prescribed to improve lung function that has been negatively affected by cardiac surgery and to improve any underlying cardiopulmonary disease that may predispose patients to complications. Albuterol includes sinister (S) albuterol and rectus (R) albuterol. S-albuterol is believed to cause inflammatory reactions and to precipitate bronchospasms. R-albuterol is 100 times more potent than S-albuterol. Levalbuterol contains pure R-albuterol; it is more expensive but more potent without the adverse effects of albuterol.

A chart review of 506 cardiac surgery patients was designed to see whether bronchodilators contributed to postoperative AF and whether one drug was more effective than the other. One group of 173 patients received bronchodilators, and 333 patients did not. Overall, 141 patients (28%) developed postoperative AF. There was no difference between the two drugs or in the incidence of AF between those who received bronchodilators and those who did not. In the treatment group, 42 patients (24%) were given albuterol, 92 (53%) received levalbuterol, and 39 (23%) received both. Nine patients (21%) receiving albuterol and 17 (19%) receiving levalbuterol developed postoperative AF.

Patients who received both drugs had a much higher risk, with postoperative AF developing in half of these patients. It was not explained why the patients received both drugs, but this practice might have stemmed from a lack of agreement among health care providers or from a change to a different bronchodilator.

The time to the development of arrhythmia in the 45 patients who experienced postoperative AF after bronchodilators was 343 minutes for albuterol and 423 minutes for levalbuterol. The fact that AF did not occur until more than 5 to 8 hours later (“well beyond their half-lives,” the researchers say) makes any plausible association between bronchodilators and postoperative AF less likely.

Source: Heart Lung 2012;41:463–468

DEVICE NEWS

Recall: Isovue Injector

The FDA has issued a class I recall of prefilled syringes of iopamidol injection used in angiography because of the presence of visible particulate matter. Nine lots of Isovue Pre-Filled Power Injector Syringes (made by Bracco Diagnostics) were recalled. The presence of particles can cause serious adverse events, including stroke, if the product is used during an arterial injection.

The affected lots were distributed in the U.S. from January 21, 2010, to May 9, 2012, with expiration dates ranging from November 30, 2012, to May 31, 2013. The FDA recommends that all unused products be quarantined. Bracco Diagnostics advises customers to contact Stericycle, the firm handling the recall.

Source: FDA, November 28, 2012; MedPage Today, November 29, 2012

NEW MEDICAL DEVICES

Marvin M. Goldenberg, PhD, RPh, MS

Name: HeartWare Ventricular Assist System

Manufacturer: HeartWare, Inc., Framingham, Mass.

Approval Date: November 20, 2012

Purpose: The device is a bridge to heart transplantation in patients with refractory end-stage left ventricular heart failure.

Description: The left ventricular assist device (LVAD) is a mechanical pump that delivers oxygenated blood to the rest of the body. The pump, with an inflow cannula, weighs approximately 5 ounces and displaces a volume of approximately 50 mL. The miniaturized device and cannula are placed within the pericardial sac, thereby avoiding the need to create a pump pocket with its attendant risks of infection.

Benefit: Surgical insertion of the LVAD is simplified. This lightweight device is compact enough that no parts need to be surgically implanted in the abdomen. The small size also allows it to be used in smaller patients. The LVAD can be used inside or outside the hospital. It was approved based on results from the ADVANCE clinical trial.

Sources: ww.fda.gov; www.medpagetoday.com

Name: Propel Mini

Manufacturer: Intersect Ent, Palo Alto, Calif.

Approval Date: November 6, 2012

Purpose: Propel Mini, a steroid-releasing implant, is a smaller version of the Propel implant, which was approved in 2011. The device is used for patients with chronic sinusitis.

Description: A physician inserts the spring-like device to prevent obstruction of the ethmoid sinus after endoscopic sinus surgery. The implant expands to prop open the sinus and gradually delivers a corticosteroid with anti-inflammatory properties, mometasone furoate (e.g., Nasonex, Schering/Merck), directly to the sinus lining. The medication then dissolves in the body. Propel Mini delivers the same dose of mometasone furoate as that provided by Propel.

Benefit: Propel Mini reduces the need for additional surgical procedures and for systemic steroids, which can have serious side effects. The device provides localized, controlled delivery directly to the sinus tissue. It is beneficial for patients undergoing less extensive surgery or for those with a smaller sinus anatomy.

Sources: www.empr.com; Otolaryngol Head Neck Surg 2012;146:1004–1011; Med Device Evidence Res 2012;5:75–80; Int Forum Allergy Rhinol 2012;2:271–279; www.intersect.com, November 6, 2012

Name: PCM Cervical Disc System

Manufacturer: NuVasive, Inc., San Diego, Calif.

Approval Date: October 26, 2012

Purpose: The device is used to replace a diseased cervical disc (from C3–C7) that is causing pain, weakness, or numbness in the arm. The system is intended for skeletally mature patients.

Description: The disc consists of two cobalt-chrome alloy endplates and an ultra-high-molecular-weight polyethylene insert that fits between the endplates. The device is placed between two adjacent neck vertebrae to replace the diseased disc.

Benefit: The implanted disk system is designed to restore the distance between the two vertebrae. Unlike a fusion procedure, surgery with the PCM Cervical Disc is designed to allow motion at the operated spinal level. There is a high potential for pain relief and improved function after the diseased disc is removed.

Precautions: The disc should not be implanted in patients with acute or chronic infections, osteoporosis or osteopenia, congenital stenosis, or an allergy or sensitivity to any of the implant materials (i.e., cobalt, chromium, molybdenum, titanium, or polyethylene).

Sources: www.fda.gov; www.nuvasive.com

Class I Recalls

Public Access Defibrillator 300/300P

In September 2012, HeartSine Technologies, Ltd., issued a class 1 recall because some of its Samaritan devices (300 and 300P public access defibrillators) were turning on and off intermittently. This type of problem can eventually deplete the battery. Some of the devices, which are indicated for patients experiencing sudden cardiac arrest, contained early versions of the battery-management software and might be misinterpreting a temporary drop in battery voltage as signaling a low battery. As a result, the device may turn itself off. A device experiencing either condition could be unable to deliver therapy during a cardiac event.

The affected devices were manufactured and distributed from August 1, 2004, to January 31, 2011. HeartSine wrote to customers on September 11, 2012, describing the problem and providing instructions for correction.

Source: FDA, November 19, 2012

A3 and A5 Anesthesia Delivery System

On August 13, 2012, Mindray DS USA, Inc., recalled its A3 and A5 Anesthesia Delivery System because of a possible gasket leak. The system is used to administer continuous or intermittent general anesthesia gases and to maintain breathing during surgery in adults and children.

The company identified the cause of the leak as a small step in the gasket surface that could interfere with the full seating of the gasket within the canister. This type of leak can disrupt or cause inadequate patient anesthesia and ventilation, resulting in temporary or permanent patient injury or death. Backup equipment should be available to maintain ventilation in case the device fails because of this problem. A gasket leak can also cause injury to operating room personnel who might be exposed to escaping anesthesia gases.

The A3 and A5 devices were made from May 2011 to March 2012 and were distributed from May 31, 2011, to July 15, 2012.

Source: FDA, November 30, 2012