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FDA Approves Eovist

2008-07-10T15:32:00.001-07:00

Bayer HealthCare Pharmaceuticals Inc., a leader in diagnostic imaging, announced today that the U.S. Food and Drug Administration (FDA) has approved Eovist (Gadoxetate Disodium) Injection, a gadolinium-based contrast agent, for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease. The approval makes Eovist the first organ-specific MRI contrast agent approved in the United States in more than a decade.

"The approval of Eovist in the United States marks a significant achievement in advancing the accurate diagnosis of liver disease," said Douglas Stefanelli, Vice President and General Manager, Diagnostic Imaging, Bayer HealthCare Pharmaceuticals. "This milestone demonstrates Bayer HealthCare Pharmaceuticals' commitment to providing innovative imaging products that can help improve the lives of patients."

Eovist is a paramagnetic MRI contrast agent that combines features of both an extracellular contrast agent and a hepatocyte-specific agent. Eovist is administered via an intravenous, bolus injection and has a dual route of excretion with approximately 50 percent eliminated through the liver and 50 percent eliminated through the kidney. Detection and characterization of malignant and benign focal liver lesions with Eovist may help enhance diagnostic accuracy and increase diagnostic confidence.

"Eovist-enhanced images can provide more comprehensive information about focal liver lesions in a single, short imaging session than was previously available," said Jeffrey Brown, MD, Professor of Radiology, School of Medicine, St. Louis. "With the availability of Eovist, our ability to evaluate patients with benign and malignant focal hepatic lesions will be improved."

The American Cancer Society estimates that 21,370 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the United States during 2008, and the incidence of liver cancer continues to increase.(1) Earlier staging of primary tumors with metastases in the liver, such as colon cancer, may improve treatment decisions and, hence, the survival rate. This year, approximately 110,000 new cases of colon cancer will be diagnosed in the United States.(2)

Stefanelli continued, "With Eovist and Nexavar, Bayer HealthCare Pharmaceuticals is uniquely positioned to help healthcare professionals detect and treat liver cancer." Nexavar (sorafenib), an oral anticancer medicine called a kinase inhibitor, is approved for use in patients with unresectable hepatocellular carcinoma (HCC).

Eovist is marketed by Bayer HealthCare affiliates outside the United States as Primovist and in Japan as EOB Primovist. It was first approved in 2004 in Europe, and with this FDA approval, is now approved in more than 40 countries.

Clinical Trials Summary

Eight-hundred sixteen (816) patients with suspected or known focal liver lesions were enrolled in two of four non-randomized, intrapatient-controlled studies that evaluated predominantly the detection (Studies one and two) or morphological characterization (Studies three and four) of liver lesions. Studies one and two ("detection" studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and the results from intra-operative ultrasound of the liver. The studies assessed the sensitivity of pre-contrast MRI and Eovist-contrasted MRI for the detection of liver lesions when each set of images was compared to the reference.

Studies three and four ("characterization" studies) enrolled patients with known or suspected focal liver lesions, including patients who were not scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and other prospectively defined criteria. The studies assessed the correctness of liver lesion characterization by pre-contrast MRI and Eovist-contrasted MRI when each set of images was compared to the reference. Lesions were characterized as one of the following choices: hepatocellular carcinoma, cholangiocarcinoma, metastasis, focal lymphoma, adenoma, focal nodular hyperplasia, hemangioma, abscess, focal liver fibrosis, regenerative nodule, focal fat, hydatid cyst, liver cyst, "not assessable," normal, no lesion or "other."

In all four studies, patients underwent a baseline, pre-contrast MRI followed by the administration of Eovist at a dose of 0.025 mmol/kg body weight, with MRI performed immediately (the "dynamic" phase) and at 10 to 20 minutes following Eovist administration (the "hepatocyte" phase). Patients also underwent computerized tomography with contrast examinations of the liver. Pre-contrast MRI and Eovist-contrasted MR images were evaluated in a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. Computed tomography (CT) images were also evaluated by the radiologists in a separate reading session.

Eovist was generally well-tolerated during the trials. The safety database was based on Eovist exposure in 1,755 adult subjects who received a dose that ranged from 0.003 to 0.5 mmol/kg body weight; the majority (N=1,365) received the recommended dose of 0.025 mmol/kg body weight.

Overall, 4.3% of subjects reported one or more drug-related adverse reactions during a follow-up period that, for most subjects, extended more than 24 hours after Eovist administration. These adverse reactions were predominantly of mild to moderate severity. Serious adverse events were reported among six patients and were attributed to underlying conditions or non-MRI procedures. All serious events occurred more than 10 hours following Eovist administration. The most common adverse reactions at the recommended dose were feeling hot, nausea, headache, injection site reaction (pain, burning, coldness, extravasation), dysgeusia (taste abnormality), flushing, parosmia (smell abnormality), dizziness and vomiting.

About Eovist

Eovist is the first gadolinium-based, liver-specific MRI contrast agent approved in the United States. Eovist enhances the T1-weighted signal. Compared to other extracellular fluid gadolinium-chelate contrast agents, Eovist exhibits a low-level binding to plasma proteins. The resulting higher relaxivity accounts for the lower dose. The recommended dose of Eovist is 0.1 mL/kg body weight (0.025 mmol/kg body weight). Based on its structural properties, Eovist is partially taken up by liver cells, thus enhancing healthy liver tissue (parenchymal enhancement). Lesions with no or minimal hepatocyte function (e.g., cysts, metastases, the majority of hepatocellular carcinomas) will remain unenhanced and will therefore be more readily detected and localized. Eovist provides useful diagnostic information at the time immediately after contrast administration (dynamic imaging) and, thus, also supports lesion characterization (i.e., distinction of malignant and benign types of liver lesions). Eovist is marketed by Bayer HealthCare affiliates outside the United States as Primovist and in Japan as EOB Primovist, and is approved in more than 40 countries, including the United States.

Warning: Nephrogenic Systemic Fibrosis

Gadolinium-based contrast agents increase the risk of Nephrogenic Systemic Fibrosis in patients with:

-- acute or chronic severe renal insufficiency (glomerular filtration) rate <30 mL/min/1.73 m2), or

-- acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

In these patients, avoid the use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.

As with other contrast media, the possibility of serious or life- threatening anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and/or cutaneous manifestations should always be considered. The most common adverse reactions observed in clinical trials at the recommended dose included feeling hot, nausea and headache.

Differentiated Mechanism of Nexavar

Nexavar targets both the tumor cell and tumor vasculature. In preclinical studies, Nexavar has been shown to target members of two classes of kinases known to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

Nexavar is currently approved in more than 40 countries for the treatment of liver cancer and in more than 70 countries for the treatment of patients with advanced kidney cancer. Nexavar is also being evaluated as a single agent or combination treatment in a wide range of cancers, including metastatic melanoma, lung cancer, breast cancer and as an adjuvant therapy for kidney cancer.

Important Safety Considerations For Patients Taking Nexavar

Based on the currently approved U.S. package insert for the treatment of patients with unresectable hepatocellular carcinoma, hypertension may occur early in the course of therapy and blood pressure should be monitored weekly during the first six weeks of therapy and treated as needed. Bleeding with a fatal outcome from any site was reported in 2.4% for Nexavar and 4% in placebo. The incidence of treatment-emergent cardiac ischemia/infarction was 2.7% for Nexavar vs. 1.3% for placebo. Most common adverse events reported with Nexavar in patients with unresectable HCC were diarrhea, fatigue, abdominal pain, weight loss, anorexia, nausea and hand-foot skin reaction. Grade 3/4 adverse events were 45% for Nexavar vs. 32% for placebo. Women of child-bearing potential should be advised to avoid becoming pregnant and advised against breast-feeding. In cases of any severe or persistent side effects, temporary treatment interruption, dose modification or permanent discontinuation should be considered.

About Bayer HealthCare Pharmaceuticals Inc.

Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Diabetes Care, and Pharmaceuticals divisions. Bayer HealthCare Pharmaceuticals comprises the following business units: Women's Healthcare, Diagnostic Imaging, General Medicine, which includes Cardiology and Primary Care and Specialty Medicine, which includes Hematology, Oncology and Multiple Sclerosis. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.
Source: drugs.com

Templeton Asset Management Rejects Sun Pharmaceutical's Tender Offer for Taro Pharmaceutical

2008-07-10T15:27:00.001-07:00

Templeton Asset Management Ltd. ("Templeton Emerging Markets Team") today rejected Sun Pharmaceutical's ("Sun") tender offer for Taro Pharmaceutical ("Taro") shares. Mark Mobius, executive chairman of Templeton Asset Management, said, "The offer is not acceptable to us as we strongly believe that it undervalues Taro Pharmaceutical."

Mobius pointed out that in the view of the Templeton Emerging Markets Team, Sun's offer does not reflect current value, since the terms of the offer were communicated and determined over 12 months ago. "In the meantime, Taro reported a strong operational turnaround and a sharp improvement of its earnings, as well as its balance sheet situation, which now continue to show momentum well into 2008." He pointed out that in Taro's statement of June 19, 2008, the company said that there had been a "dramatic financial turnaround" with net income of approximately USD 21.1 million in 2007. Taro had also underlined the high value of its new product pipeline. Mobius also said that in reaching this conclusion the Templeton Emerging Markets Team reviewed the recent fairness opinion of Merrill Lynch (May 28, 2008) which described the offer as "financially inadequate, from a financial point of view."

Mobius commented, "As we have expressed on multiple occasions, we believe USD7.75 substantially undervalues the shares."

Mobius went on to indicate that in making its decision, the Templeton Emerging Markets Team also reviewed the analyses and recommendation of independent advisory services. He noted that both Glass Lewis and RiskMetrics Group recommended shareholders to reject the merger agreement over 12 months ago. Glass Lewis stated that "... we believe that investors are left unable to determine whether the transaction is financially fair...we cannot in good faith support a transaction that is not accompanied by current financials and/or a detailed fairness opinion." RiskMetrics Group expressed other concerns and concluded that "... we recommend shareholders to vote against the merger....it is imperative that the major shareholders be allowed an opportunity to negotiate a deal that will maximize value for all shareholders." Mobius said, "Since the terms of the tender offer are the same as those of the merger reported on by those firms, we believed that the analyses were relevant to our decision."

Mobius added, "In making our decision, we considered the recent shareholder dispute between Taro and Sun. That suit also suggests that Sun appears to have had access to some non-public information regarding the Irish operations which puts us, as ordinary shareholders, in an unequal and disadvantaged position. We are very concerned about the rather obscure nature of the dispute with regard to the Irish operating unit."

"We strongly support the Taro Board's plan to re-list Taro shares on NASDAQ and to release the fully audited financial reports for the past years to finally grant all shareholders their right of reviewing the company's results," said Mobius. "Only then can we have the information necessary to make a decision and obtain a fair price for our shares. We expect further upside revision as a result of much improved liquidity of the shares, as well as better transparency of the company."

Templeton Asset Management Ltd. is a wholly owned subsidiary of Franklin Resources, Inc. , a global investment management organization operating as Franklin Templeton Investments. Franklin Templeton Investments provides global and domestic investment management solutions managed by its Franklin, Templeton, Mutual Series, Fiduciary Trust, Darby and Bissett investment teams. The San Mateo, CA-based company has more than 60 years of investment experience and over $580 billion in assets under management as of June 30, 2008.
Source: drugs.com

Common Mechanisms May Underlie Autism's Seemingly Diverse Mutations

2008-07-10T15:03:00.000-07:00

Many of the seemingly disparate mutations recently discovered in autism may share common underlying mechanisms, say researchers supported in part by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health (NIH). The mutations may disrupt specific genes that are vital to the developing brain, and which are turned on and off by experience-triggered neuronal activity.

A research team led by Christopher Walsh, M.D., Ph.D., and Eric Morrow, M.D., Ph.D., of Harvard University, found two large sections missing on chromosomes in people with autism and traced them to likely inherited mutations in such genes regulated by neuronal activity. They report their findings in the July 11, 2008 issue of Science. The study was also supported in part by the NIH's National Center for Research Resources, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child and Human Development, and the National Institute on Neurological Disorders and Stroke.

The study breaks new ground for complex disorders like autism, taking advantage of a shortcut to genetic discovery by sampling families in which parents are cousins. The researchers found genes and mutations associated with autism in 88 families from the Middle East, Turkey and Pakistan in which cousins married and had children with the disorder.

"The emerging picture of the genetics of autism is quite surprising. There appear to be many separate mutations involved, with each family having a different genetic cause," explained NIMH Director Thomas R. Insel, M.D. "The one unifying observation from this new report is that all of the relevant mutations could disrupt the formation of vital neural connections during a critical period when experience is shaping the developing brain."

Earlier studies had suggested that the individually rare mutations are present in at least 10 percent of sporadic cases of autism, which is the most common form.

The researchers used a technique that pinpoints from a relatively small group of families genes responsible for disorders that can be amplified by parenthood among relatives, which can increase transmission of recessive diseases. Evidence had hinted at such transmission in autism, and the large amount of genetic information obtainable from such families reduced the need for a much larger sample including many families with multiple affected members.

The ratio of females to males with autism - normally one female to four males - was less lopsided in such families in which parents share a common recent ancestor, suggesting a doubling of the rate of autism, due to recessive causes on non-sex-linked chromosomes. Also, autism-linked spontaneous deletions and duplications of genetic material were relatively uncommon in these families, suggesting recessive inherited causes.

The researchers found multiple different genetic causes of autism in different individuals with little overlap between the families in which parents shared ancestry. Yet a few large inherited autism-linked deletions, likely mutations, in a minority of families stood out. The largest turned out to be in or near genes regulated, directly or indirectly, by neuronal activity.

"Autism symptoms emerge at an age when the developing brain is refining the connections between neurons in response to a child's experience," explained Walsh. "Whether or not certain important genes turn on is thus dependent on experience-triggered neural activity. Disruption of this refinement process may be a common mechanism of autism-associated mutations."

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website.

NCRR provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat, and prevent a wide range of diseases. Through the CTSA consortium and other collaborations, NCRR supports all aspects of translational and clinical research, connecting researchers with one another and with patients and communities across the nation.

NHGRI is one of 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.
Source: drugs.com