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Saturday, April 23, 2011

FDA Updates PML Risk Info for Natalizumab


By John Gever, Senior Editor, MedPage Today
Published: April 22, 2011


As expected, the FDA has approved new label language for the multiple sclerosis drug natalizumab (Tysabri) with additional detail on the risks of progressive multifocal leukoencephalopathy (PML).

The label will now specify that prior immunosuppressant therapy and treatment duration above two years are major risk factors for PML, a life-threatening brain inflammation, the FDA announced Friday.

Post-marketing data collected through January 2011 under the so-called TOUCH registry program established by the drug's manufacturer, Biogen Idec, indicated that 102 patients have developed PML while under treatment with natalizumab, the FDA said.

A disproportionate number were in their third year of natalizumab treatment and had previously received such drugs as mitoxantrone or azathioprine, which are broad-spectrum immunosuppressants.
The label will include a table showing that the risk of PML is 0.3 per 1,000 patients receiving the drug for less than two years, 1.5 per 1,000 during the third year of treatment, and 0.9 per 1,000 during the fourth year.

However, the new label will not have similar quantitative estimates of the risk associated with previous immunosuppressant therapy.

Physicians are now instructed to ask patients about such treatment before starting patients on natalizumab.

The revision was expected in the wake of data reported recently by Biogen Idec noting that a history of immunosuppressants and treatment duration beyond two years dramatically hikes the risk of PML.

Still absent from the prescribing information, though, is any reference to testing for antibodies to the JC virus, which is the actual cause of PML.

At the recent American Academy of Neurology's annual meeting, Biogen Idec researchers reported that seronegativity for the virus essentially cancelled out the other risk factors.

But there is no FDA-approved serological assay presently. The FDA is believed to be waiting for results of clinical trials now being conducted by Biogen Idec before making a formal recommendation for such testing.

SOURCE - Medpage Today
















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Friday, April 22, 2011

Vitamin D Supplementation: An Update



SOURCE: Medscape Today
Christine Gonzalez, PharmD, CHHC - Authors and Disclosures
Posted: 11/11/2010; US Pharmacist © 2010 Jobson Publishing

Introduction

An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency.[1–3] This is mostly attributable to people getting less sun exposure because of climate, lifestyle, and concerns about skin cancer. The 1997 Dietary Reference Intake (DRI) values for vitamin D, initially established to prevent rickets and osteomalacia, are considered too low by many experts.[4] DRI values are 200 IU for infants, children, adults up to age 50 years, and pregnant and lactating women; 400 IU for adults aged 50 to 70 years; and 600 IU for adults older than 70 years. Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease. Emerging research supports the possible role of vitamin D in protecting against cancer, heart disease, fractures and falls, autoimmune diseases, influenza, type 2 diabetes, and depression. Many health care providers have increased their recommendations for vitamin D supplementation to at least 1,000 IU.[5] As a result, more patients are asking their pharmacists about supplementing with vitamin D.

Pharmacology

Vitamin D is a fat-soluble vitamin that acts as a steroid hormone. The body makes vitamin D from cholesterol through a process triggered by the action of the sun's ultraviolet B rays on the skin (FIGURE 1). Factors such as skin color, age, amount and time of sun exposure, and geographic location affect how much vitamin D the body makes. Vitamin D influences the bones, intestines, immune and cardiovascular systems, pancreas, muscles, brain, and the control of cell cycles.[6] Its primary functions are to maintain normal blood concentrations of calcium and phosphorus and to support bone health.
Click to zoomFigure 1.
Vitamin D synthesis.
UVB: ultraviolet B.
Source: Reference 32.
Vitamin D undergoes two hydroxylations in the body for activation. There are several metabolic products or modified versions of vitamin D (TABLE 1). Calcitriol (1,25-dihydroxyvitamin D3), the active form of vitamin D, has a half-life of about 15 hours, while calcidiol (25-hydroxyvitamin D3) has a half-life of about 15 days.[6] Vitamin D binds to receptors located throughout the body.


Deficiency, Blood Concentrations, and Toxicity

Risk factors for vitamin D deficiency include living in northern latitudes (in the U.S., above the line from San Francisco to Philadelphia), failing to get at least 15 minutes of direct sun exposure daily, being African American or dark-skinned, being elderly, or being overweight or obese.[5] Rickets and osteomalacia are the well-known diseases of severe vitamin D deficiency. Musculoskeletal pain and periodontal disease may also indicate a significant vitamin D deficiency.[7] Subtle symptoms of milder deficiency include loss of appetite, diarrhea, insomnia, vision problems, and a burning sensation in the mouth and throat.[7] Drawing a blood calcidiol concentration is the standard test for vitamin D status, since calcidiol has a longer half-life.[8]
A normal range of vitamin D is 30 to 74 ng/mL, but this can vary among laboratories.[8] Most experts agree that a concentration between 35 and 40 ng/mL is reasonable for preventive health. Some suggest that the optimal concentration for protecting against cancer and heart disease is between 50 and 70 ng/mL and up to 100 ng/mL. Side effects or toxicity can occur when blood concentrations reach 88 ng/mL or greater.[9] Symptoms include nausea, vomiting, constipation, headache, sleepiness, and weakness.[6] Too much vitamin D can raise blood calcium concentrations, and acute toxicity causes hypercalcemia and hypercalciuria.[6,9]
 

Continue reading the next (5) sections of this story by clicking here.  
Remaining topics:  Disease Prevention,  Dosing,

You may need to register with Medscape to read the remaining materials.



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Cardiovascular Risks With Oral Fingolimod for Multiple Sclerosis


Allison Gandey - Authors and Disclosures

April 21, 2011 (Honolulu, Hawaii) — Results from a pooled analyses of phase 3 clinical trials of fingolimod — the first oral agent for multiple sclerosis — show the drug has transient and long-term cardiovascular effects.
Reporting here at the American Academy of Neurology (AAN) 63rd Annual Meeting, investigators showed fingolimod increases the risk for hypertension. At initiation, physicians can also expect to see transient heart rate and atrioventricular conduction slowing.
Prescribing information for the Novartis product marketed as Gilenya already advises that patients be monitored for signs and symptoms of bradycardia for 6 hours after first dose. These new results confirm this recommendation and point to other longer-term risks.
"Transient heart rate reduction and atrioventricular conduction slowing are expected pharmacodynamic effects of fingolimod therapy initiation and were usually asymptomatic," John DiMarco, MD, from the University of Virginia Medical Center in Charlottesville, said at the meeting. "Rates of hypertension-related adverse events were higher with fingolimod than placebo."
Investigators pooled safety data from the original clinical trials. FREEDOMS, also known as FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis, included US Food and Drug Administration (FDA)–mandated safety measures.
The Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) showed a benefit with fingolimod against interferon beta and against placebo, but the adverse events were significant. One patient died of disseminated primary varicella zoster and another of herpes simplex encephalitis.
The pooled analysis included 2552 people. Investigators found an increase in arterial pressure at 1 year and more hypertension-related adverse events in patients taking fingolimod.
Table. Increase in Arterial Pressure at 1 Year in FREEDOMS Patients
OutcomeFingolimod, 0.5 mgFingolimod, 1.25 mgPlacebo
Arterial pressure, mm Hg+1.1+2.6–0.5
Hypertension-related adverse events, %6.16.33.8
Antihypertensive drug use, %5.05.85.5
FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis
As anticipated, the researchers found that fingolimod was associated with a dose-dependent decrease in heart rate that reached its nadir 5 hours after dosing. Patients taking low-dose fingolimod had an average decline of 8 beats per minute. Those in the high-dose group had a decline of 11 beats per minute.
The atrioventricular conduction slowing was asymptomatic in most patients; however, 4 people received medication for bradycardia.
Dr. DiMarco said these changes tended to lessen with continued therapy and return to baseline levels by month 1. His team confirmed heart rate and electrocardiogram findings by 24-hour Holter monitoring in a subset of patients from TRANSFORMS (n = 129). Echocardiography, performed on some of these patients, revealed no relevant changes in left ventricular function (n = 33).
Fingolimod acts as a superagonist to sphingosine-1-phosphate receptors on the surface of thymocytes and lymphocytes. This reportedly reduces the overall number of circulating lymphocytes available to mount an autoimmune reaction to the myelin sheath surrounding axons in multiple sclerosis.
Adverse Events
According to the FDA, the most frequent adverse reactions reported by patients taking fingolimod in clinical trials include headache, influenza, diarrhea, back pain, elevation of liver enzyme levels, and cough.
At the ANA meeting in September, FREEDOMS investigators reported serious adverse events.
Gordon Francis, MD, head of the clinical science unit at Novartis, showed bradycardia in both low- and high-dose patients, multiple sclerosis relapse, basal cell carcinoma, chest pain, and macular edema. In the high-dose group, there were also 2 cases of epilepsy, headache, and lymphopenia.
When the FREEDOMS trial was first published in January 2010, William Carroll, MD, from Sir Charles Gairdner Hospital in Perth, Australia, wrote an accompanying editorial. "Clinicians and patients will need to evaluate the risks and benefits," he noted. "Given the recent studies documenting the development of progressive multifocal leukoencephalopathy among patients receiving natalizumab...close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects."
Dr. Carroll told Medscape Medical News at the time of publication that it is likely that neurologists will be under a lot of pressure from the "needle-phobic" patient to move to an oral drug. Still, he said, the adverse effect profiles appear to be more serious than those of currently available drugs and are simply not completely known as yet.
This study was funded by Novartis. Dr. DiMarco received compensation from the company.
American Academy of Neurology (ANA) 63rd Annual Meeting: Abstract S41.007. Presented April 14, 2010.
 
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