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P T. 2011;36(6): 320-324, 331

New Drugs/Drug News/New Medical Devices June 2011

NEW DRUGS

Zytiga for Prostate Cancer

Abiraterone acetate tablets (Zytiga, Centocor Ortho Biotech, Inc.) have been approved, in combination with prednisone, to treat men with late-stage, castration-resistant prostate cancer who have received chemotherapy with docetaxel (Taxotere, Sanofi-aventis).

The drug decreases the production of testosterone, which may stimulate cancer cells to keep growing. Abiraterone was approved ahead of schedule.

In a study of 1,195 patients, men receiving abiraterone plus prednisone had a median overall survival of 14.8 months, compared with 10.9 months for the men receiving placebo plus prednisone.

Abiraterone is discussed in the Pharmaceutical Approval Update column in this issue of P&T on page 372.

Source: FDA, April 28, 2011

Tradjenta for Type-2 Diabetes

Linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) has been approved, in conjunction with diet and exercise, to enhance blood glucose control in adults with type 2 diabetes.

Linagliptin increases the level of hormones that stimulate the release of insulin after a meal by blocking dipeptidyl peptidase-4 (DPP-4). In eight double-blind, placebo-controlled studies involving about 3,800 patients, blood glucose control was improved with pharmacotherapy compared with placebo.

The drug has been studied as a stand-alone therapy and in combination with other type-2 diabetes medications, such as metformin (Glucophage, Bristol-Myers Squibb), glimepiride (Amaryl, Sanofi-aventis), and pioglitazone (Takeda/Eli Lilly). Linagliptin has not been studied in combination with insulin.

Linagliptin is not indicated for patients with type-1 diabetes or diabetic ketoacidosis. For more information, please see this month’s Pharmaceutical Approval Update column, page 372.

Source: FDA, May 2, 2011

Edurant for HIV-1 Infection

The FDA has approved once-daily rilpivirine oral tablets (Edurant, Tibotec), in combination with other antiretroviral drugs, for the treatment of HIV-1 infection in treatment-naive adults.

A non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine blocks viral replication. Used as part of highly active antiretroviral therapy (HAART), it is designed to suppress the amount of virus in the blood. The drug is not intended as a cure for HIV infection.

The FDA’s approval was based on 48-week data from two phase 3 clinical trials of 1,368 adults and from a 96-week trial (with an extension to 192 weeks).

NNRTIs are discussed in detail in the article by Schafer et al. on page 346.

Source: FDA, May 20, 2011

Two Protease Inhibitors for HCV

Victrelis

Boceprevir (Victrelis, Merck), in combination with peginterferon alfa (Pegasys, Roche) and ribavirin (Copegus, Roche; Rebetol, Merck), is now approved for adults with chronic hepatitis C virus (HCV) infection. The drug is intended for patients with some remaining liver function and who either have not received pharmacotherapy for HCV or who have not responded to treatment.

Boceprevir was evaluated in two phase 3 clinical trials of 1,500 adults. Protease inhibitors work by binding to the virus and preventing it from multiplying. The drug is taken three times a day with food.

Adverse effects associated with boceprevir, when taken with pegylated interferon and ribavirin, may include fatigue, anemia, nausea, headache, and taste distortion.

Source: FDA, May 13, 2011

Incivek

Telaprevir (Incivek, Vertex) has also been approved for the treatment of chronic HCV in patients who have either not been treated or who have not responded to other drugs. It is to be used with peginterferon alfa and ribavirin.

The FDA’s approval was based on data from three phase 3 trials of 2,250 adults.

Sources: FDA, Bloomberg, May 23, 2011

NEW INDICATIONS

Two Pancreatic Cancer Drugs

Afinitor

Everolimus (Afinitor, Novartis) has been approved to treat inoperable or metastatic, progressive neuro endocrine pancreatic tumors. In a trial enrolling 410 patients, treated patients experienced progression-free survival for a median of 11 months, compared with 4.6 months for the placebo patients.

Everolimus is also approved to treat advanced renal cell carcinoma and subependymal giant cell astrocytoma associated with tuberous sclerosis. Another form of everolimus (Zortress, Novartis), is used to prevent organ rejection after kidney transplantation.

Source: FDA, May 5, 2011

Sutent

The FDA has approved Pfizer’s sunitinib (Sutent) to treat advanced or inoperable pancreatic neuroendocrine tumors (pNET). Patients with pNET have few therapeutic options; everolimus (Afinitor) and sunitinib are the first new treatments for the condition in 30 years. The approval was based on a phase 3 trial of 171 patients. pNET is slow-growing and rare, but its incidence is rising.

Sunitinib is also approved to treat renal cell carcinoma and gastrointestinal (GI) stromal tumors that are refractory to imatinib (Gleevec, Novartis) therapy.

Source: MedPage Today, May 20, 2011

DRUG NEWS

Heart Patients Have Trouble With Complex Regimens

Patients with chronic heart disease often take numerous medications many times per day, a practice that can result in nonadherence to prescribed regimens. Also undermining adherence is the high number of pharmacy visits patients must make to pick up their prescriptions.

In a study conducted to evaluate adherence, patients received prescriptions for angiotensin-converting enzyme (ACE) inhibitors or renin–angiotensin-receptor blockers (ARBs) between June 1, 2006, and May 30, 2007. The researchers measured the number of daily doses; the number of drugs, prescribers, pharmacies, and pharmacyvisits; and the number of visits per fill during the three months from the first prescription. After this period, adherence was evaluated over the subsequent year.

During the three-month period, the statin cohort filled an average of 11.4 prescriptions for 6.3 different drugs, received prescriptions written by two prescribers, and made five visits to the pharmacy. Results for patients using ACE inhibitors and ARBs were similar.

The authors concluded that medication use and prescription filling can be quite complicated, and they emphasize the need for strategies to reduce this complexity in order to improve medication adherence.

Source: Arch Intern Med 2011;171(9): 814–822 (May 9)

Newer Epilepsy Drugs Result in Fewer Birth Defects

In a large study from Denmark, second-generation antiseizure drugs taken during the first trimester of pregnancy were not associated with an increased risk of major birth defects. However, there was one major limitation: the study did not include many women who took topiramate (Topamax, Ortho-McNeil).

In March, the FDA had warned that topiramate early in pregnancy was associated with an increased 16-fold risk for cleft lip and cleft palate in newborns. Most women in the new study took lamotrigine (Lamictal, GlaxoSmithKline), and the risk of birth defects was just slightly higher than that for women who took no antiseizure drugs.

The Danish study included data on 837,795 live births between January 1996 and September 2008, including 1,532 women who received a second-generation antiseizure drug during their first trimester. Just over 1,000 women took lamotrigine, about 400 took oxcarbazepine (Trileptal, Novartis), about 100 patients took topiramate, and close to 60 each took gabapentin (Neurontin, Pfizer) or levetiracetam (Keppra, UCB Pharma). Some women received more than one drug.

Major birth defects occurred in 3.2% of infants exposed to one of the drugs early in development, compared with 2.4% of infants who were not exposed to any of the drugs. A total of 4.6% of women taking topiramate and 3.7% to 4% of women taking lamotrigine had offspring with major birth defects.

Many pregnant women take anti-seizure drugs for epilepsy, migraine, or bipolar disorder. The risk of birth defects with the second-generation drugs appears to be much lower than that for older antiseizure drugs such as valproic acid (Depakote, Abbott). However, the findings were considered only somewhat reassuring; no recommendations could be made on the effects of topiramate.

Sources: JAMA 2011:305(19):1996–2002 (May 18); WebMD Health News, May 17, 2011

Surgery or Drug Therapy For Cardiac Patients?

Fewer than half of Americans with stable heart disease receive recommended drug therapies before they are encouraged to undergo an invasive heart procedure, such as stent implantation. Yet costly surgery may offer few benefits over drug therapy and may increase the risk of side effects.

Although percutaneous coronar y intervention (PCI) has been thought to reduce the risk of heart attacks and death, it often works no better than drugs for people who haven’t yet had a heart attack. PCI, in fact, can result in stroke, emergency bypass surgery, or even death in up to 1% of patients.

In a new study, researchers used data from more than 1,000 U.S. hospitals to see how often drugs were prescribed for patients before they underwent PCI. The study included more than 467,000 people with chest pain caused by stable coronary artery disease. Overall, 44% of patients were taking statins, aspirin, and blood pressure drugs before they underwent PCI. After the procedure, the number taking medications grew to almost two-thirds. From the start of the study in 2005 until 2009—two years after the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was published—those rates rose by only a few percentage points.

More than one million Americans undergo PCI every year, often costing more than $10,000 above the cost of drugs. PCI sometimes works better than medications, but many patients do well on drugs alone.

COURAGE lead author Dr. William Boden said that doctors could give a trial of medication a chance to work before proceeding straight to urgent PCI. He added, however, that the current health care system might not be set up to favor that approach, because in a fee-for-service model, physicians are paid for doing procedures.

Sources: JAMA online; Reuters Health, May 10, 2011

Will New Oral Drugs Be Better Than Injections for MS?

Several new drugs for multiple sclerosis (MS) may make it easier to control the flare-ups of the disease and slow its progression. Designed to be taken orally, the newer drugs could encourage more patients to take medication as needed. Currently, most MS drugs are given by injection.

The new drugs are expected to be expensive. Fingolimod (Gilenya, Novartis), the only oral MS drug on the market so far, costs about $48,000 per year. Injectables usually cost about $40,000 per year.

Physicians are being cautious about prescribing the oral drugs because their side effects have not been fully evaluated. Fingolimod, for instance, can raise the risk of infection and can lead to hepatotoxicity and macular edema.

If the new drugs in the pipeline do receive FDA approval, they could be on the market in late 2012. Merck’s cladribine (Litak) was rejected by U.S. and European regulators earlier this year because of problems related to an increased cancer rate.

Natalizumab (Tysabri, Biogen), an injectable, was approved in 2004 but was temporarily pulled from the market after it was linked to a rare brain infection. Its use is now limited mainly to patients with refractory disease.

It has been a challenge to get patients to use injectables. The easier-to-use oral agents should increase adherence, although doctors might not always recommend a new oral drug if an injectable product is working.

A survey on pharmacotherapy trends for MS is presented in this month’s P&T Snapshot, page 374.

Source: The Wall Street Journal, May 17, 2011

More Data on Bone Drugs And Thigh Fractures

Bisphosphonates, widely prescribed to prevent and treat osteoporosis, appear to be linked to an unusual type of thigh fracture, according to a large European study. Generally, however, the overall risk was considered very small.

Over the past few years, orthopedic surgeons have noted an increase in fractures in which the thighbone snapped in two. Last October, the FDA added a warning to the labeling to reflect the possible risk of atypical fractures in patients taking these drugs (P&T, 2010;35[11]: 606). In the current study, researchers analyzed data from 1.5 million women in Sweden who were 55 years of age or older in 2008. They obtained x-rays of 1,234 of the 1,271 women with fractures and found 59 who had experienced the more unusual kind of fracture.

Women with atypical fractures were also compared with 263 controls who had fractures in a similar location, and 78% of those with atypical fractures had been taking bisphosphonates, compared with 10% of controls. Nonetheless, atypical fractures were considered rare, and the benefits of using the drugs were thought to outweigh the risks.

Per Aspenberg, MD, PhD, a co-author of the study, said the findings indicated that the risk of fracture was diminished by 70% after patients stopped the drugs for a year. The American Society of Bone and Mineral Research plans to set up a national registry of patients with these unusual fractures in order to learn more about the effects of bisphosphonates.

The bisphosphonate class includes alendronate (Fosamax, Merck), risedronate (Actonel, Atelvia, Warner Chilcott) zoledronic acid (Zometa injection, Novartis), and ibandronate (Boniva, Roche/GlaxoSmithKline). Etidronate (Didronel, Norwich/Procter & Gamble) and pamidronate (Aredia, Novartis) are used to treat other bone problems.

Sources: N Engl J Med 2011;364:1728–1737); The Wall Street Journal, May 5, 2011; MedPage Today, May 4, 2011

Naproxcinod: Neutral Effects On Blood Pressure

Patients who take nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis may be at an increased risk for elevated blood pressure (BP). However, findings from an integrated safety analysis of three trials involving 2,734 patients have been encouraging. Naproxcinod, an agent in development for osteoarthritis by NicOx in France, had the same effect on BP as placebo—very little—but provided pain control similar to that of naproxen (Naprosyn, Roche).

This cyclooxygenase-inhibiting nitric oxide donator (CINOD) has good gastrointestinal tolerability and is designed to release naproxen and a nitric oxide–donating moiety. For 13 weeks, patients received 375 mg and 750 mg of naproxcinod, 500 mg of naproxen (equipotent to naproxcinod 750 mg), or placebo twice daily. Systolic BP was measured in all subjects and in the subgroup taking renin–angiotensin system (RAS) inhibitors.

There were significantly fewer systolic BP changes from baseline with naproxcinod 750 mg, compared with naproxen 500 mg. In fact, naproxen tended to raise systolic BP. In patients with hypertension who were taking RAS inhibitors, the mean change in systolic BP was 4 to 5 mm Hg greater with naproxen than with naproxcinod. After 13 weeks, more patients experienced an increase in systolic BP by 10 mm Hg with naproxen than with naproxcinod (21% vs. 15%, respectively).

Small differences in systolic BP can have major physical implications. For instance, an increase of 3 to 4 mm Hg in systolic BP in older patients with hypertension and vascular disease was found to raise the risk of cardiac events within six months.

RAS inhibitors are often used in clinical practice; thus, it was noteworthy that naproxcinod was less likely to raise the systolic BP in patients who were receiving RAS inhibitors.

In 2010, an FDA panel voted not to approve naproxcinod, requesting longer-term safety and efficacy studies.

Sources: Am J Cardiol 2011;107:1338–1345 (March); Medscape, May 12, 2010

RESEARCH NEWS

Lopinavir and Cervical Cancer

Lopinavir, an antiretroviral drug used to treat HIV-1 infection, is showing promise for preventing cervical cancer caused by the human papillomavirus (HPV). Along with ritonavir (Norvir), it is a component of Kaletra (Abbott). HPV infection, the most common cause of cervical cancer, often takes many years before it results in malignancy.

Researchers from the University of Manchester and Canada discovered that lopinavir triggers a natural viral defense system in HPV-infected cells. In their study, lopinavir selectively killed HPV-infected, noncancerous cells and left healthy cells unaffected. Lopinavir also eradicated HPV-infected cells by reactivating an antiviral system that is suppressed by HPV.

Current HPV vaccines do not benefit women who already have HIV infection, and they do not protect against all types of HPV. Lopinavir would probably need to be formulated as a topical cream or a pessary to treat cervical cells effectively. For the drug to work against HPV, the virus-infected cervical cells require about 10 to 15 times the concentration used in lopinavir tablets.

Hughes et al. discuss lopinavir in the article on protease inhibitors (page 332).

Sources: EmaxHealth, May 4, 2011; R&D Magazine, May 3, 2011

Urine Test for Gastric Cancer

A type of protein excreted in urine may be able to indicate the presence of gastric cancer. Researchers at the University of Georgia discovered that the quantity of endothelial lipase (EL) differed significantly in urine samples of patients with stomach cancer and in healthy people.

Of 21 healthy people, only two subjects did not have the protein. In the 21 urine samples of patients with stomach cancer, only one sample had a relatively high level of the protein; levels in the rest were low or absent.

The researchers hope to develop a method whereby urine can change the color of a piece of paper to indicate the presence or absence of the protein. Although the test is not yet 100% accurate, it can lead at-risk patients to have a more comprehensive evaluation. If the marker protein is present in the urine, the patient most likely does not have stomach cancer.

Sources: Plos One, 2011;6:3 (March 18); Medical News Today, April 27, 2011

Early Treatment, Less HIV

Men and women with HIV infection were able to reduce the risk of transmitting the virus to their sexual partners by taking oral antiretroviral (ARV) drugs when their immune systems were still relatively healthy.

A clinical trial (HPTN 052) was scheduled to end in 2015, but findings are being released early. The study began in April 2005 and enrolled 1,763 couples (97% heterosexual), all at least 18 years of age. The trial was conducted in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the U.S., and Zimbabwe. At enrollment, the HIV-infected partners (890 men, 873 women) had CD4+ T-cell levels between 350 and 550 cells/mm3 within 60 days of entering the study. Un-infected partners were HIV-negative within 14 days of entering the study. Only one case of HIV infection occurred among those couples when the HIV-infected partners began immediate ARV therapy, indicating that starting ARV drugs early led to a 96% reduction in HIV transmission to the uninfected partner.

Twenty-three patients died during the study (10 receiving immediate-treatment and 13 in the deferred-treatment group), but the difference was not significant.

The 11 drugs used included atazanavir (Reyataz, Bristol-Myers Squibb); didanosine (Videx, Bristol-Myers Squibb); efavirenz (Sustiva, Bristol-Myers Squibb); emtricitabine (Emtriva) plus tenofovir (Viread) [Truvada, Gilead]); lamivudine (Epivir, ViiV); lopinavir/ritonavir (Kaletra, Abbott); nevirapine (Viramune, Boehringer Ingelheim); ritonavir (Nor vir, Abbott); stavudine (Zerit, Bristol-Myers Squibb); tenofovir (Viread, Gilead); and zidovudine/lamivudine (Combivir, ViiV).

Two articles in the present issue of P&T review various HIV therapies (see pages 332 and 346).

Sources: NIH, The Wall Street Journal, May 12, 2011

DEVICES IN THE NEWS

Antibacterial Respirator

CCI Spectrum’s SpectraShield 9500 N95 surgical respirator eradicates 99.99% of three different kinds of bacteria when they are exposed to the outer surface of the device. The respirator is used one time only to protect against microorganisms, body fluids, and particulates. It is effective against Streptococcus pyogenes, Methicillin-resistant Staphylococcus aureus (MRSA), and Haemophilus influenzae.

The device blocks large-particle droplets, splashes, sprays, or splatter that may contain viruses and bacteria from reaching the mouth and nose. When tested, the N95 respirator was able to block at least 95% of very small particles.

Source: FDA, April 8, 2011

Test for Dengue Fever

Dengue hemorrhagic fever is a leading cause of illness and death in the tropics and subtropics. The dengue virus is transmitted to humans by the bite of an infected Aedes mosquito.

The DENV Detect IgM Capture enzyme-linked immunosorbent assay (ELISA), manufactured by Inbios, Inc., detects antibodies to the virus in blood samples from patients with signs and symptoms of dengue. There are no FDA-licensed vaccines to prevent dengue, and no specific medications have been approved to treat the infection.

FDA, April 8, 2011

Test for C. difficile Infection

The Cepheid Xpert C. difficile/Epi assay is designed to detect the toxin B gene associated with Clostridium difficile infection, a cause of diarrhea that can lead to colitis, serious intestinal conditions, and death in severe cases.

The test determines whether C. difficile bacteria are present in the stool and whether the organism is the epidemic 027/ NAP1/BI strain. The detection of this strain is for epidemiological purposes only, and the device should not be used to determine or monitor treatment.

Source: FDA, April 8, 2011

Carotid Stent Now Covers More Patients

More patients can now be treated with Abbott’s RX Acculink carotid stent. In 2004, the FDA approved the stent for patients with clogged carotid arteries who were at high risk of complications if they underwent a carotid endarterectomy. The new indication includes people with clogged carotid arteries who are at at risk for a stroke, not only patients who are not candidates for surgery.

The approval was based on a 10-year study of 2,502 patients in the U.S. and Canada. The stent was considered safe; however, an outside expert panel emphasized the need for more follow-up data about the stent’s use in conjunction with an embolic protection device to capture plaque and other debris that can break away during the procedure, with the potential to cause a stroke.

Source: FDA, May 6, 2011

NEW MEDICAL DEVICES

Marvin M. Goldenberg, PhD, RPh, MS

Name: FemVue Saline-Air Device

Manufacturer: Femasys, Inc., Suwanee, Ga.

Approval Date: May 4, 2011

Purpose: The FemVue device enables physicians to evaluate the fallopian tubes with existing ultrasound equipment.

Description: An alternating mixture of air and saline is introduced into the uterine cavity as a contrast agent for a fluoroscopic hysterosalpingogram (HSG) to assess any potential blockages within the fallopian tubes.

Benefit: FemVue is an improvement over the standard fluoroscopic HSG. Patients can be examined in the physician’s office, and a gynecologist or an infertility specialist can quickly perform a cost-effective, convenient, and a non-radiation HSG.

Sources: www.femvue.com; http://medgadget.com/archives/2011/05/femvue_airsaline_injector_for_sono_hsg_to_help_evaluate_fallopian_tubes.html

Name: cPAX Aneurysm Treatment System

Manufacturer: Neurovasx, Inc., Maple Grove, MN

Approval Date: April 1, 2011

Purpose: Approved under a Humanitarian Device Exemption, the cPAX system is used in the surgical treatment of brain aneurysms that are difficult to manage because of their size and shape.

Description: Implant material is delivered through a catheter in a blood vessel upward into the aneurysm within the brain. A stent or a small balloon-type device is used to keep the implant material trapped within the aneurysm. With the material filling up the space within the aneurysm, blood flow through the aneurysm is stopped. Any remaining spaces around the implant material become filled with the clotted blood, which reduces the potential for aneurysm rupture and helps to facilitate shrinkage of the aneurysm over time.

Benefit: Aneurysms that are larger than 10 mm are difficult to treat with the usual methods of clipping and coiling. With the cPax system of endovascular repair, instead of tiny metallic coils, a polymeric material is used to fill the space within the aneurysm. When the bulging space within the aneurysm is filled with the implant material, blood flow through the aneurysm is stopped and the remaining space around the implant material clots, reducing the risk of aneurysm rupture.

Precaution: The cPAX system is indicated for adults 22 years of age and older. It is not intended for patients with an active infection or who cannot take anticoagulation or antiplatelet drugs.

Sources: www.fda.com; www.emax-health.com/1024/cpax-aneurysm-treatment-system-approved-treatment-large-aneurysms

Name: NovoTTF-100A System

Manufacturer: Novocure, Israel

Approval Date: April 15, 2011

Purpose: The device is used to treat adults with glioblastoma multiforme (GBM) after chemotherapy and radiation therapy have failed. GBM, the most common primary brain tumor diagnosed in adults, is highly resistant to surgery, radiation, and chemotherapy. Median survival is only 15 months, and fewer than 10% of patients are alive five years after a diagnosis of this brain tumor.

Description: Four sets of electrodes are attached to a patient’s shaved head. The electrodes are placed on the surface of the patient’s scalp to deliver low-intensity electrical fields to the tumor site. An alternating electric field is created within the tumor and exerts physical forces on electrically charged cellular components. This prevents the normal mitotic process and causes cancer cells to die before they can divide.

The system is portable and can be powered with a six-pound battery pack that the patient carries in an over-the-shoulder bag, or the device can be plugged into an electrical outlet. Patients can use the device at home and can continue their daily activities.

Benefit: This is the first cancer-treating device that patients can carry around, allowing them to remain active during therapy. It is a noninvasive alternative to chemotherapy. In a clinical trial, although the device did not outperform chemotherapy as a cancer treatment, it was associated with fewer and less severe adverse effects. Patients using the device did not live any longer than patients receiving chemotherapy (median survival, 6.3 months vs. 6.4 months, respectively).

The portable device produced relatively little toxicity and none of the effects associated with chemotherapy (e.g., nausea, anemia, fatigue, or infections). However, convulsions and headaches were more common in the group using the device than in patients receiving chemotherapy.

Precaution: Patients with a skull defect, an implanted medical device, or a sensitivity to conductive hydrogels (such as those used with electrocardiograms) are not candidates for the Novocure system. The device should not be used in combination with other cancer treatments.

Sources: www.fda.com; www.novo-cure.com; www.eurekalert.org/pub_releases/2011-04/epr-fat041411.php