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P T. 2011;36(9): 555–558, 562–563

New Drugs/Drug News/New Medical Devices September 2011

NEW DRUGS

Complera for HIV Infection

Complera (Gilead) has been approved for once-daily, first-line therapy of treatment-naive adults with HIV infection. Complera combines Gilead’s Truvada—which consists of the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (Emtriva) and tenofovir (Viread)—with Johnson & Johnson’s non-NRTI rilpivirine (Edurant), which was approved in May. Adverse effects have included lactic acidosis and liver damage, events that have been linked to most NRTIs when given in combination therapy. The cost is $1,705 per month.

Sources: Reuters, August 10, 2011; WebMD Health News, August 11, 2011

Adcetris for Two Lymphomas

Brentuximab vedotin (Adcetris, Seattle Genetics) is now approved to treat Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma (ALCL). This antibody–drug combination enables the antibody to direct the drug to a target on lymphoma cells known as CD30.

Adcetris is indicated for patients with Hodgkin’s lymphoma whose disease has progressed after an autologous stem-cell transplant or after two previous chemotherapy treatments for those who cannot receive a transplant. It is also used in ALCL patients with disease progression after one chemotherapy treatment.

Systemic ALCL is a rare form of non-Hodgkin’s lymphoma. Adcetris is the first new FDA-approved treatment for Hodgkin’s lymphoma since 1977, and it is the first drug specifically indicated for ALCL. It was approved under the FDA’s accelerated approval program.

Source: FDA, August 19, 2011

Orphan Drug Approvals

Anascorp for Scorpion Stings

The FDA has approved Anascorp to treat stings by the Centruroides scorpion in the U.S. Anascorp is licensed to Rare Disease Therapeutics Inc., distributed by Accredo Health Group. Inc., and manufactured by Instituto Bioclon, S.A. de C.V., in Mexico.

The injection is made from the plasma of horses immunized with scorpion venom. Steps are taken in the manufacturing process to decrease the potential for allergic reactions and to reduce the risk of transmission of viruses that might be present in the plasma. Left untreated, scorpion stings can be fatal, especially in infants and children.

Source: FDA, August 4, 2011

PLX Cells for Buerger’s Disease

Pluristem’s PLX cells have been granted orphan drug status for the treatment of thromboangiitis obliterans (Buerger’s disease). Inflammation and clotting of the vessels results in reduced blood flow to the extremities. Pain and ulcers or necrosis in these areas may occur, which may lead to amputation. Approximately 50,000 people are affected in the U.S. and Europe.

Source: Pluristem, August 25, 2011

TM-400 in Hematological Cancer

TM-400 (TikoMed) is designed to increase the number of blood cells available for hematopoietic stem-cell transplantation (HSCT) and is used to mobilize stem cells before this procedure. In HSCT, stem cells are harvested from the bloodstream of the donor and transfused to the patient.

Source: TikoMed, July 26, 2011

MM-398 for Pancreatic Cancer

Merrimack’s MM-398 has been designated as an orphan drug for patients with pancreatic cancer. MM-398 is a novel, stable nanotherapeutic encapsulation of irinotecan (Camptosar, Pfizer). The company is developing the drug with PharmaEngine, Inc., under the designation PEP02.

Source: Merrimack, August 1, 2011

Zelboraf and a Melanoma Test

Vemurafenib (Zelboraf, Genentech/Roche) has been approved to treat metastatic or inoperable melanoma; it is indicated specifically for tumors expressing a gene mutation called BRAF V600E. A companion diagnostic assessment, the cobas 4800 BRAF V600 Mutation Test, is also being approved to determine whether the mutation is present in melanoma cells.

Both the drug and the test were approved ahead of schedule because of their success in achieving impressive survival rates. The median survival of patients receiving Zelboraf had not been reached (77% were still living), compared with a median survival period of 8 months (64% were still living) for Bayer’s dacarbazine (DTIC-Dome).

In March, ipilimumab (Yervoy, Bristol-Myers Squibb) was also approved for the treatment of melanoma.

A medication guide will be provided for patients. New therapies for melanoma are also presented in this month’s Meeting Highlights feature on page 601.

Source: FDA, August 17, 2011

NEW FORMULATION

Self-Injectable Orencia For Rheumatoid Arthritis

A subcutaneous (SQ) formulation of the fusion-protein drug abatacept (Orencia, Bristol-Myers Squibb) is approved for adults with moderate-to-severe rheumatoid arthritis (RA). Abatacept can be taken alone or with disease-modifying antirheumatic drugs. It is not to be taken with tumor necrosis factor (TNF) antagonists or anakinra (Kineret, Biovitrum).

Abatacept is the only biologic for treating RA that is approved in an intravenous (IV) infusion form as well as in a self-injectable SQ form. This injectable form is given once weekly after a single IV loading dose, which can be omitted if patients cannot receive the infusion.

The approval was based on data from four studies, including the Abatacept Comparison of Sub(Qu)cutaneous vs. Intravenous in Inadequate Responders to Methotrexate (ACQUIRE) trial.

Source: Genet Eng Biotech, August 1, 20011

DRUG NEWS

Preventive Services for Women

As a result of the Patient Protection and Affordable Care Act (PPACA), women will now be able to receive preventive health services at no additional cost. New health insurance plans must cover well-woman visits; contraception and counseling services; breast-feeding support; screening for gestational diabetes, human papillomavirus (HPV) DNA for women 30 years of age and older, sexually transmitted infections, and HIV infection; and domestic violence counseling without charging a copayment, co-insurance, or a deductible. Before the health care reform bill was passed, many Americans used preventive services at about half the recommended rate because of the cost.

The PPACA rules required all new private health plans to cover mammograms, colonoscopies, blood pressure checks, and childhood immunizations without additional charges. Preventive services were also made free of charge for Medicare beneficiaries.

New health plans must include these services without cost sharing for insurance policies with plan years beginning on or after August 1, 2012. The plans will retain the flexibility to control costs. For example, plans can continue to charge cost sharing for branded drugs if a generic version is available and is as safe and effective as the branded product. Religious institutions will be able to opt out of insuring contraception services.

Sources: HHS, August 1, 2011, www.hhs.gov; www.hrsa.gov

Evital Contraceptive May Be Unsafe

The FDA is warning consumers not to use the emergency birth control tablets labeled as Evital. These products may be counterfeit versions of the morning-after pill and might not be safe or effective in preventing pregnancy.

Evital has not been approved for use in the U.S.; however, it may be distributed in some Hispanic communities in the U.S. The label of the potentially counterfeit version says, “Evital Anticonceptivo de emergencia, 1.5 mg, 1 tablet,” by “Fluter Domull.” Consumers should contact their health care professional if they have taken the 1.5-mg tablet and have experienced any health problems.

Sources: FDA, July 28, 2011, www.fda.gov/MedWatch/report.htm

Younger African-Americans Do Not Fare Well on Dialysis

As many as 30 studies have reported that African-Americans undergoing kidney dialysis survive longer than Caucasians. A new study from Johns Hopkins University, however, indicates that there appears to be a higher risk of dying for African-Americans younger than 50 years of age while receiving dialysis, compared with their Caucasian counterparts, thus contradicting previous research.

In a study of 1.3 million patients with end-stage kidney disease, African-Americans 18 to 30 years of age were twice as likely to die as Caucasians in the same age group, and African-Americans 31 to 40 years of age had 1.5 times the risk of death. The researchers, surprised at the results, suggested that the survival advantage for African-Americans undergoing dialysis applied only to adults older than 50 years of age. They also suggested transplantation for younger patients.

Sources: JAMA, 2011;306(6):620–626; Science Daily, August 9, 2011

Antipsychotic Agents Appear Ineffective for PTSD in Veterans

Antipsychotic medications prescribed for symptoms of severe post-traumatic stress disorder (PTSD) in veterans have been no more effective than placebo and have led to some serious side effects, including weight gain and fatigue. These surprising findings may soon change the way veterans are treated. From 10% to 20% of combat veterans experience chronic symptoms of PTSD, and about 20% of those who are treated receive antipsychotic drugs.

The new study focused on risperidone (Risperdal, Janssen), although the results may extend to the entire class, including quetiapine (Seroquel, Astra-Zeneca), ziprasidone (Geodon, Pfizer), and aripiprazole (Abilify, Bristol-Myers Squibb/Otsuka).

Many soldiers and Marines with PTSD do not respond to antidepressants, the only drugs currently indicated for the disorder. In a study by researchers at the Department of Veterans Affairs, 123 veterans with PTSD received a regimen that added risperidone to their antidepressant treatment. After 6 months of treatment, those receiving risperidone were doing no better than 124 veterans who were given placebo. About 5% of the veterans in both groups recovered; 10% to 20% reported at least some improvement.

Overall, treatment with risperidone did not seem to benefit these patients. The modest improvement could have come from simply engaging the patients in treatment and not from the drug itself.

Many veterans are sensitive about the stigma of mental illness and may be skeptical about the value of therapy. Only about 50% of veterans who are thought to need treatment seek it out. Psychotherapy, which can include relaxation techniques, may be useful in helping patients challenge fixed ideas that create anxiety.

Source: JAMA, August 3, 2011

Cranberries or Antibiotics For Urinary Tract Infections?

New research from Amsterdam indicates that antibiotics may be more effective than cranberries for urinary tract infections (UTIs) even though the drugs lead to a greater risk of antibiotic resistance. Cranberries are less effective in preventing UTIs, but they deter the growth of resistant microorganisms.

About 50% of women experience a UTI during their lifetimes, and 30% develop recurrent UTIs. Escherichia coli is one of the most common causes of UTIs.

In the study, 221 women who had at least three recurrent UTIs in the previous year received either a 12-month course of trimethoprim–sulfamethoxazole (e.g., Bactrim, Bethaprim, Cotrim, or Septra), 480 mg, taken once daily with two placebo tablets or one 500-mg capsule of cranberry extract, taken twice daily with one placebo tablet. Women taking the capsules were more likely to develop at least one symptomatic UTI compared with women receiving an antibiotic. On average, women in the cranberry group developed a new UTI after 4 months, whereas infection recurred within 8 months with the antibiotic.

Rates of antibiotic resistance tripled among women receiving trimethoprim–sulfamethoxazole but returned to baseline values 3 months after treatment ended. After 1 month of therapy, resistant bacteria developed in 85% of women taking the antibiotic and in fewer than 30% of women taking the cranberry extract.

Cranberry juice and cranberry extract contain fructose and type A proanthocyanidins, which help prevent E. coli from sticking to the bladder walls. The extract might not be as bioavailable as the antibiotic used in this study, and this could have skewed the findings in favor of the antibiotic. Some studies have suggested that 72 mg/day of proanthocyanidins is needed to keep urinary bacteria in check; the dosage in the Dutch study was only 9 mg per cranberry tablet.

Sources: Arch Intern Med, July 25, 2011; © 2011 Health Day

Alert: Birth Defects and High-Dose Diflucan

Chronic, high doses (400 to 800 mg/day) of fluconazole (Diflucan, Pfizer) may cause rare birth defects in infants whose mothers used the antifungal agent during the first trimester of pregnancy. This risk does not appear to be associated with a single 150-mg dose, which is used to treat vaginal yeast infections.

Because of reports of birth defects in infants whose mothers were given high-dose fluconazole for serious fungal infections during most or all of the first trimester, the pregnancy category in the fluconazole labeling, other than for vaginal candidiasis, has been changed from C to D. A single dose of 150 mg is still classified as Pregnancy Category C (i.e., the drug’s potential benefits are considered acceptable despite the risks).

After maternal use of high doses of fluconazole, infants were born with short, broad heads; abnormal facial features; abnormal skullcaps; oral clefts, bowing of the thigh bones; thin ribs; long bones; congenital heart disease; and muscle weakness.

Source: FDA, August 4, 2011

Vaccine Reduces Deaths From Chickenpox

Chickenpox deaths in the U.S. have been nearly eliminated as a result of the widespread use of the varicella vaccine. According to a new study from the Centers for Disease Control and Prevention (CDC), deaths from this disease dropped by 88% overall and by 97% among children and adolescents since 1995, when the varicella vaccine program began in the U.S. Before the program was available, chickenpox was responsible for about 100 deaths and 11,000 hospitalizations each year.

In 2006, a second varicella vaccine dose given to children 4 to 6 years of age was added to national vaccination recommendations. The first dose is given to children 12 to 18 months of age.

Since 2005, the varicella vaccine has also been available as part of a combination vaccine that offers protection against measles, mumps, rubella, and varicella. Chickenpox is usually mild, but it can be life-threatening in rare cases, especially among those with weakened immune systems, such as infants and the elderly.

Sources: Pediatrics, July 26 online; WebMD, July 28, 2011; http://children.webmd.com

Heparins Work Well For Deep Vein Thrombosis

Long-term treatment with low-molecular-weight heparin (LMWH) may be more beneficial than oral anticoagulation medications in preventing post-thrombotic syndrome (PTS), say researchers in the United Kingdom and Canada. They describe a paradigm shift in current understanding: accepting that PTS can develop more rapidly after an episode of deep vein thrombosis (DVT) than had been thought. In fact, they suggest that treating patients with early signs and symptoms of DVT with long-term LMWHs might limit or prevent PTS.

The researchers identified nine studies for review. Because different authors diagnosed and reported PTS-related endpoints differently and complete data were not always included, a meta-analysis was possible only for a small number of studies. However, the authors emphasized that long-term LMWH treatment tended to be superior to oral anticoagulation for every endpoint they considered.

In a pooled analysis of two studies, LMWH, compared with oral anticoagulation, reduced the risk of venous ulcers by 87% at follow-up examinations of 3 months or longer. Four studies reported significantly more patients with recanalization and lysis of thrombi with LMWH than with oral anticoagulation during follow-up periods of 3 months to 1 year. A pooled analysis of five studies found a risk–benefit ratio of 0.66 in favor of LMWH for complete recanalization of thrombosed veins.

In the Home–LITE study, which examined at-home treatment with LMWH, patients completed a questionnaire at 3 months on eight signs and symptoms commonly used to diagnose PTS. For all eight symptoms, the trend favored LMWH. The researchers noted that it was difficult to distinguish early signs and symptoms after a DVT from acute manifestations of DVT, a recurrent DVT, or evolving PTS. The Scientific and Standardization Committee recommends that PTS be diagnosed only after 3 months to avoid any possibility of attributing acute signs and symptoms to PTS.

In light of the negative effects of PTS, it was considered surprising that preventive and therapeutic options remain limited. No sound evidence exists to recommend thrombolysis for preventing PTS, and waiting until the syndrome is established obviously isn’t good for the patient. Given the scarcity of options for treating PTS successfully, the investigators say, their findings could be of considerable clinical and economic benefit. They suggest considering long-term LMWH therapy, especially for patients with severe PTS symptoms, because greater symptom severity at 1 month usually predicts higher PTS scores over time.

The apparent superiority of long-term LMWH in preventing various PTS-related endpoints suggests that more than anticoagulant activity might be involved. LMWHs stimulate the release of tissue factor pathway inhibitor, which has anti-inflammatory and anti-angiogenic effects and may reduce inflammation and subsequent damage to the veins.

RESEARCH NEWS

Skin Cancer and PTEN

PTEN, a tumor suppressor, may be able to eliminate DNA damage derived from ultraviolet B (UVB) radiation, a risk factor for non-melanoma skin cancer. Yu-Ying He, PhD, from the University of Chicago, found that laboratory mice with reduced levels of PTEN were more likely to have UVB-induced skin cancers.

Non-melanoma skin cancer is the most common cancer in the U.S. The major risk factor for this type of skin cancer is UVB radiation from sunlight, which leads to DNA damage. PTEN, first identified in 1997, promotes cellular repair and helps reduce molecular misfiring, which leads to cancer and tumor progression. Dr. He found that lower PTEN levels were linked to slower rates of DNA repair.

Source: Cancer Res; 2011;71(15);5287–5295

DEVICE NEWS

Tiotropium Mist Inhalers: How Safe Are They?

Tiotropium bromide mist inhalers may raise the risk of death in patients with chronic obstructive pulmonary disease (COPD), according to researchers in the U.S. and the United Kingdom. Data from five randomized controlled trials of 6,522 patients with COPD suggested that the tiotropium inhaler was associated with a 52% higher risk of all-cause mortality compared with placebo.

Inhaled tiotropium is available as a powder (Spiriva, Boehringer Ingelheim/Pfizer), delivered with a HandiHaler device, and in solution as a mist, delivered with the Respimat Soft Mist Inhaler (Boehringer Ingelheim). The mist inhaler is a propellant-free device that delivers a fine, slow-moving cloud. Peak plasma concentrations with the mist inhaler at doses of 5 mcg and 10 mcg were 35% and three times higher, respectively, than with tiotropium 18 mcg delivered by the HandiHaler. In the five trials analyzed, 3,585 patients used the inhaler and 2,836 received a placebo. Overall, the tiotropium mist inhaler was associated with an increased risk of mortality compared with placebo. A trend toward a dose–response effect was noted. For the current study, patients receiving the drug via the mist inhaler might have been exposed to higher concentrations.

A two-year, head-to-head comparison of the tiotropium mist inhaler and tiotropium powder is under way. Until the results are known, caution is advised when the inhaler is prescribed, particularly for patients with cardiovascular disease.

The FDA approved the tiotropium inhaler in 2004. The mist inhaler is available in 55 countries but is not yet approved in the U.S.

Source: BMJ, June 14, 2011

Recalls

CardioGen-82. Bracco Diagnostics has recalled the CardioGen-82 device, which is used for cardiac positron emission tomography (PET) scans. The CardioGen-82 consists of a generator that produces a rubidium (Rb)-82 chloride injection. Radioactive drugs are used to evaluate the heart.

On July 15, the FDA issued an alert about the potential for inadvertent, increased radiation exposure in patients undergoing cardiac PET scans with an injection from the CardioGen-82 generator. The FDA had received reports that two patients were exposed to more radiation than had been expected from the device. Although the risk of harm may be minimal, exposure to any excessive radiation is undesirable.

Manufacturing procedures were found to be inadequate to ensure reliable performance of the generator, which is essential to prevent exposure to excess radiation. The FDA recommends an alternative method for nuclear medicine cardiac scans.

Sources: FDA, July 28, 2011; heartwire, July 26, 2011

GEM Cartridges. On August 12, GEM Premier 4000 PAK Cartridges, used to analyze whole blood samples, were recalled because measured potassium levels were too low when compared with those of a reference analyzer. The Class I recall was initiated because biases exceeded the allowable error claim of ±0.5 mmol/L by as much as 2.0 mmol/L. The cartridges were made and distributed from May 2006 through July 2011. Clients have been instructed to disable the potassium test to eliminate the possibility of inaccurate reporting of results.

Sources: FDA, August 4, 2011; Medscape, August 2, 2011, www.medscape.com/viewarticle/747383

NEW MEDICAL DEVICES

Marvin M. Goldenberg, PhD, RPh, MS

Name: HydroFix Ortho Shield

Manufacturer: MiMedx Group Inc., Marietta, Ga.

Approval Date: June 22, 2011

Purpose: The shield is indicated for managing tendon injuries in patients who have not experienced a substantial loss of tendon tissue.

Description: The biocompatible polyvinyl alcohol polymer membrane helps to minimize tissue attachment to the device in case there is direct contact with the tissues.

Benefit: Soft-tissue attachments to repaired tendons can reduce the effectiveness of the repair and can result in a reduced range of motion after surgery. A permanent protective sheet minimizes soft-tissue attachments to the device, providing a protective environment for the repaired tendon to heal. The shield is conformable, suturable, and biocompatible, providing tendon protection. A smooth inner gliding surface enables the tendon to move as part of normal motion.

Sources: www.mimedx.com; www.geronguide.com; www.orthospinenews.com, Reuters, June 22, 2011

Name: Interlock–35 Fibered Interlocking Detachable Coil (IDC) Occlusion System

Manufacturer: Boston Scientific, Natick, Mass.

Approval Date: June 30, 2011

Purpose: The coil occlusion system is used to obstruct or reduce blood flow in the peripheral vessels during embolization. The procedure is designed to block blood vessels to control gastrointestinal bleeding, aneurysms, epistaxis, hemoptysis, postpartum hemorrhage, and trauma-associated bleeding. Abnormal vascular communications (e.g., arteriovenous malformations and arteriovenous fistulas) may be corrected via precise placement of embolic materials to interrupt blood flow. Potentially fatal consequences of aneurysm or pseudoaneurysm rupture may be avoided by embolization of the sac.

Description: An embolic agent is placed into a blood vessel, and the procedure is performed under x-ray guidance. A 0.035-inch detachable coil features an interlocking connection between the coil and the delivery wire. The coil can be advanced, retracted, and repositioned before final deployment in the vessel.

The system is available in 31 configurations. Coil lengths range from 4 to 40 cm, and diameters range from 3 to 20 mm. The coils are available in three distinct shapes (cube, two-dimensional helical, and diamond), enabling physicians to treat diverse vessel anatomies.

Benefit: The procedure is minimally invasive. The coil can be easily detached by pushing the detachment zone beyond the distal end of the 5 French delivery catheter. Compatibility with 5 French catheters allows the placement of larger coils, which can accomplish embolization with fewer coils, potentially reducing procedure times. The platinum coil is constructed with a dense network of synthetic fibers, providing excellent blockage of blood flow and rapid stasis. The coil provides sufficient occlusive power while allowing precise retrievable placement; this represents a major advantage over standard 0.035-inch pushable coil techniques. This new technology offers interventional radiologists more options to address clinical and anatomic challenges in treating peripheral vascular embolizations.

Sources: http://bostonscientific.com; www.qmed.com; The Wall Street Journal, June 30, 2011

Name: Vasomedical-Biox Model 2302 Combined 12-Channel ECG Holter/Ambulatory Blood Pressure Monitor and Model 1804 Ambulatory Blood Pressure Monitor

Manufacturer: Vasomedical, Inc., Westbury, N.Y.

Approval Date: June 30, 2011

Purpose: Ambulatory monitoring products are used for the long-term recording and analysis of electrocardiographic (ECG) and blood pressure data.

Description: Model 2302 complements the Model 1305 3-Channel ECG Holter Monitor and Model 2301 Combined 3-Channel ECG Holter/Ambulatory Blood Pressure Monitor. Model 1804 and the previously approved Model 1305 provide economic alternatives for applications when only blood pressure or ECG recording is needed. All monitors in the Biox series work with the CB Series Analysis Software for data scanning, analysis, and reporting.

Benefit: Ambulatory ECG and blood pressure monitoring provides important data about cardiovascular abnormalities that are not always observed during a physician visit; the data are thus valuable for early diagnosis of cardiovascular disease. Reliable patient information is crucial to early diagnosis and successful treatment. The collection and analysis of multi-parameter data, with full disclosure consisting of 12-lead ECG and simultaneous blood pressure measurements, enable physicians to identify cardiac irregularities and to assess the effect of specific treatments. The devices are easy for clinicians to use and for patients to wear.

Sources: www.vasomedical.com; The New York Times, June 29, 2011; www.businesswire.com

Device Review

Medtronic’s Infuse, a spinal surgery product, has come under scrutiny. The company has agreed to spend $2.5 million for an independent assessment of the safety and effectiveness of the device by Yale University researchers. Medtronic will provide the Yale team with patient data from all clinical trials involving Infuse, as well as all reports of adverse events sent to the FDA since the product was approved in 2002.

The company’s unprecedented move comes after studies by independent investigators raised concerns about complications with the product, which were not revealed in journal articles published for nearly a decade. The articles had been written by physicians who received tens of millions of dollars in royalties and other payments from Medtronic.

Sources: The New York Times and The Milwaukee Journal Sentinel, August 3, 2011