AMIODARONE-SIMVASTATIN INTERACTION

Interaction between amiodarone (marketed as CORDARONE and PACERONE) and simvastatin (marketed as ZOCOR and generics) or simvastatin-combination products (marketed as VYTORIN and SIMCOR)
Amiodarone potentiates the risk for simvastatin-associated rhabdomyolysis
FDA continues to receive reports of rhabdomyolysis in patients given amiodarone in combination with higher doses of simvastatin. Amiodarone is an antiarrhythmic drug indicated to treat certain types of recurrent ventricular arrhythmias. Simvastatin is a 3-hydroxy-methylglutaryl-coenzyme A reductase inhibitor (statin) used to lower cholesterol levels. As with all statins, the risk of rhabdomyolysis is dose-related and increased by high plasma levels of statin. Patients who take amiodarone with simvastatin doses greater than 20 mg daily have an increased risk of rhabdomyolysis. The precise mechanism for this drug interaction is unknown, but stems, in part, from amiodarone's inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme, the same enzyme that metabolizes simvastatin (see Illustration 1). This interaction may result in an increase in the levels of simvastatin in the plasma, potentiating the risk of rhabdomyolysis. Labeling for all of the amiodarone (Cordarone and the generic drug Pacerone)1 and simvastatin-containing products [Zocor2, ezetimibe/simvastatin (Vytorin3) and niacin/simvastatin (Simcor4)] describe this potential risk.
Rhabdomyolysis, a severe form of myopathy, involves injury to and breakdown of skeletal muscles, which in some cases leads to renal failure and death.5 There are multiple etiologies for rhabdomyolysis, including, but not limited to, exposure to certain drugs, including statins.6,7 Healthcare professionals should be aware of the increased risk of rhabdomyolysis when amiodarone is taken concomitantly with doses of simvastatin that exceed 20 mg daily. Prescribers should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone (the maximum recommended simvastatin dose is 80 mg daily).
Illustration 1
Amiodarone-Simvastatin Interaction - Postulated Mechanism
Illustration 1. This illustration depicts a postulated mechanism for the amiodarone-simvastatin interaction, including the subsequent impact of this interaction on skeletal muscle and the kidney. In the first column, amiodarone inhibits the enzyme CYP3A4, limiting simvastatin metabolism (depicted by dashed arrow). By limiting the metabolism of simvastatin, there is an increase in levels of circulating simvastatin in the blood. In the second column, high circulating simvastatin levels may result in myotoxicity in the skeletal muscles (rhabdomyolysis). The rapid breakdown of muscle protein produces excessive levels of myoglobin in the blood. In the third column, myoglobin, now at high circulating levels, reaches the kidneys where it can obstruct renal tubules and lead to acute renal failure. *Amiodarone's direct inhibition of CYP3A4 has been characterized as weak, suggesting that other factors may also contribute to how these two drugs interact.
Both the simvastatin and amiodarone labels were changed in 2002 to reflect the increase in risk for myopathy when amiodarone is taken concurrently with simvastatin.1-4 The simvastatin label (Warnings, Precautions and Dosage and Administration sections) specifically indicates that the dose of simvastatin should not exceed 20 mg daily in patients concomitantly receiving amiodarone, and that the combined use of simvastatin and amiodarone at simvastatin doses higher than 20 mg daily should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The amiodarone label (Precaution section) notes that there is an increased risk for myopathy/rhabdomyolysis when amiodarone is taken in combination with HMG-CoA reductase inhibitors that are CYP 3A4 substrates, such as simvastatin.
Since this labeling change was made, FDA has received 52 additional U.S. reports of rhabdomyolysis associated with the concurrent use of amiodarone and simvastatin. This article summarizes FDA's analysis of these 52 cases from FDA's Adverse Event Reporting System (AERS) database dating from January 1, 2003 to January 1, 2008.
Reported Cases of Rhabdomyolysis
The 52 cases of rhabdomyolysis reported to AERS involved patients ranging in age from 50 to 88 years (median age was 73). Thirty-seven patients (71%) were male and 10 were female (19%). The sex was not reported for the remaining five patients (10%). In half of the reported rhabdomyolysis cases (26/52), amiodarone was being taken in combination with 80 mg simvastatin. Thirteen patients (25%) were taking amiodarone in combination with 40 mg simvastatin, while four patients (8%) were taking amiodarone with 20 mg simvastatin. One patient (2%) developed rhabdomyolysis when taking amiodarone with 5 mg simvastatin. Eight patients (15%) were taking an unknown dose of simvastatin in combination with amiodarone.
Regarding other concomitant medications, 37 patients (71%) were taking medications in addition to amiodarone and simvastatin. These drugs included diuretics (20), beta-blockers (18), angiotensin-converting enzyme inhibitors (16) and insulin (11). Among the concurrent medications taken by these patients, all except for niacin and levofloxacin are either substrates for and/or inhibitors of CYP3A4. These medications included gemfibrozil (9), angiotensin II receptor blockers (3), clarithromycin or levofloxacin (2), protease inhibitors (2), niacin (2), fenofibrate (1), atorvastatin (1), and risperidone (1). The labels of several of these products reflect the risk of rhabdomyolysis when they are used as monotherapy or when administered concurrently with simvastatin.
The mean time interval between the initiation of amiodarone therapy in conjunction with simvastatin (or simvastatin therapy in conjunction with amiodarone) and the onset of rhabdomyolysis was five months (median-2 months). Specifically, 42% of the cases (22) indicated that symptoms of rhabdomyolysis emerged within 2 months of the initiation of concurrent amiodarone-simvastatin therapy. Forty percent of the cases (21) did not report the time interval between the onset of rhabdomyolysis and the initiation of amiodarone-simvastatin therapy.
Ninety-two percent of rhabdomyolysis cases (48) required hospitalization. Twenty-eight percent of the reported cases (15) were considered life-threatening. Ten percent of patients (5) who developed rhabdomyolysis were noted to have become disabled. One death was reported (2%).
Three representative case reports of amiodarone-simvastatin associated rhabdomyolysis are described in Box 1. These cases were selected based on their representation of the demographics and circumstances usually reported with amiodarone/simvastatin-associated rhabdomyolysis. In addition to being reported to AERS, Case 3 has also been published in the scientific literature.8
Box 1
Case 1
A 74-year-old male was hospitalized with ventricular tachycardia. While hospitalized, the patient underwent coronary artery bypass graft surgery and was subsequently started on ezetimibe/simvastatin (10/40 mg daily). At the time of discharge, the patient was also prescribed amiodarone 200 mg (to be taken twice daily), aspirin, ramipril, and metoprolol. Three weeks following his discharge from the hospital, the patient complained of extreme muscle weakness. His creatinine level was "highly elevated". A diagnosis of rhabdomyolysis was made. Ezetimibe/simvastastin was discontinued and the patient recovered.
Case 2A 50-year-old male was hospitalized for coronary artery bypass graft surgery. During his hospitalization, the patient developed atrial fibrillation and was started on amiodarone 400 mg (taken three times daily). The next day, the patient was also started on ezetimibe/simvastatin 10/80 mg daily. Six days following the initiation of simvastatin, the patient experienced progressive leg weakness with a creatine kinase (CK) of 117,400 units/L (for males, normal reference range: 60 to 400 units/L) and a serum creatinine (SCr) of 3.5 mg/dL (normal reference range: <1.5 mg/dL).9 The patient was transferred to the intensive care unit and ezetimibe/simvastatin was discontinued. Three days after the discontinuation of simvastatin, the patient's CK and SCr levels had decreased to 26,700 units/L and 2 mg/dL, respectively.
Case 3
In 2004, a 72-year-old white male was hospitalized complaining of aches and weakness in his thighs. He also noted that his urine was dark for the week prior to his admission. He had a history of diabetes mellitus, hyperlipidemia, hypertension, azotemia, and coronary artery disease. In the summer of 2004, the patient had bypass surgery. Immediately following his bypass surgery, the patient was started on 200 mg amiodarone (taken once daily). One month later, simvastatin (80 mg/day) was prescribed. Other concomitant medications included metformin, enalapril, glimepiride, hydrochlorothiazide and aspirin.
Laboratory testing at the time of the most recent hospital admission indicated a CK level of 19,620 units/L (for males, reference range: 60 to 400 units/L)9 and a SCr of 2.6 mg/dL (normal reference range: <1.5 mg/dL).9 Rhabdomyolysis was suspected and simvastatin was immediately discontinued. Amiodarone was also discontinued four days after discontinuation of simvastatin. Within one day of stopping simvastatin, CK and SCr levels began to fall. Thirteen days after admission to the hospital, CK was 323 units/L and SCr was 1.7 mg/dL.
The concomitant use of amiodarone with simvastatin reduces the dose threshold for simvastatin-associated rhabdomyolysis. The cessation of symptoms (and lowering of laboratory values indicative of rhabdomyolysis) after discontinuation of one or both of these drugs indicates that muscle breakdown can be halted and reversed if identified early. Healthcare professionals should be aware that amiodarone may potentiate the risk for simvastatin-associated rhabdomyolysis. Simvastatin doses greater than 20 mg day daily should be avoided in patients taking or initiating amiodarone therapy. Prescribers should consider use of another statin for patients on amiodarone or initiating amiodarone therapy who require simvastatin doses greater than 20 mg daily to meet their lipid goals

AVANDIA LABEL CHANGES BY FDA IN JULY08

AVANDIA LABEL CHANGES BY FDA IN JULY08WARNINGS AND PRECAUTIONS
Cardiac Failure Myocardial Ischemia Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of Avandia Congestive Heart Failure and Myocardial Ischemia During Coadministration of Avandia With Insulin Weight Gain ADVERSE REACTIONS
Clinical Trial Experience Adult In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with Avandia... Short-Term Trials of Avandia as Monotherapy and in Combination With Other Hypoglycemic Agents (see Table 4) Long-Term Trial of Avandia as Monotherapy: A 4- to 6-year study (ADOPT) compared the use of Avandia (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication... (new) In ADOPT, fractures were reported in a greater number of women treated with Avandia... (new) Table 5 (new) Laboratory Abnormalities Serum Transaminase Levels Postmarketing Experience ...There are postmarketing reports with Avandia of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome... WARNINGS AND PRECAUTIONS
Cardiac Failure
...Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed following treatment with Avandia compared to placebo during the 52-week study. (See Table 1.)
Myocardial Ischemia: Myocardial Ischemic Events in Large Long-Term Prospective Randomized Controlled Trials of Avandia
...For these 3 trials, analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, cardiovascular death, or stroke), referred to hereafter as MACE...
Congestive Heart Failure and Myocardial Ischemia During Coadministration of Avandia With Insulin
...The total number of patients with emergent congestive heart failure was 21 (2.4%) and 7 (1.1%) in the Avandia plus insulin and insulin groups, respectively...
Weight Gain (see text after Table 3)
In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies (14.1)], the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for Avandia, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.

New Drugs

With the annual market for diabetes drugs expected to reach at least $25 billion worldwide by 2011, up from $15 billion today, drug makers have been investing heavily in new approaches to treating diabetes. And data presented at the American Diabetes Association's annual scientific conference last week suggested they are having at least some success.

One of the four treatments, Byetta, given by injection, is already on the market. Another, Exubera, an inhalable form of insulin, has been approved and will reach pharmacies next month. The other two, Galvus and Januvia, both taken as pills, are awaiting approval from the Food and Drug Administration, by early next year.

Byetta, introduced in June 2005, has stirred especially high hopes. The drug causes significant weight loss in many patients — in contrast to most existing diabetes treatments, which cause weight gain that can potentially worsen the disease. In addition, some data in animal studies hints that Byetta may help the pancreas regrow the cells that produce insulin, a crucial process in slowing the course of diabetes. Analysts are optimistic about the commercial prospects of all four of the drugs, forecasting that they will become blockbusters, with more than $1 billion in worldwide sales each. The new drugs will probably cost $1,500 to $2,000 a year per patient, more than existing treatments, analysts say. Injectable insulin typically costs about $1,200 a year per patient. Current diabetes drugs work by lowering blood sugar, either by sensitizing the body to insulin or by encouraging the pancreas to make more insulin. But over time, the conventional therapies tend to lose their effectiveness, and most patients must eventually inject themselves with insulin. That is why the new drugs, with their new approaches, are generating such interest.

Galvus, from the Swiss drug company Novartis, and Januvia, from Merck, raise the levels of a naturally occurring hormone that is released in the stomach and intestines during eating. The hormone, called GLP-1, causes the pancreas to produce more insulin while simultaneously discouraging the liver from producing sugar.Both Galvus and Januvia, which are sometimes called gliptins, appear to have few side effects and work well with existing diabetes drugs, according to papers presented at the A.D.A. conference. Galvus and Januvia do not appear to be quite as potent at lowering blood sugar as metformin, the existing first-line diabetes drug. But because of their mild side effects, they will probably be given as an adjunct to metformin,. Galvus and Januvia could have annual sales as high as $2 billion each.

T he fourth new drug is Exubera, Pfizer's inhalable insulin, which the F.D.A. approved in January and Pfizer plans to begin marketing this month. Insulin, the standard treatment for late-stage diabetes since the 1920's, is the most potent method of controlling blood sugar and is used by about five million Americans every day.

Dr.Vikram.K Source: Bionews

Diabetes news

Diabetes news

DIABETES BEING A HUGE TOPIC, I HAVE STARTED THIS THREAD ON DIABETES DRUGS:

Spending on prescription medicines increased by only 2% last year for clients of the nation's largest stand-alone pharmacy benefits manager as patients used more generic drugs, according to a report from Medco Health Solutions Inc. (MHS) .

Diabetes treatments replaced cholesterol-lowering drugs as the primary contributor to higher spending on prescription medicines, according to Medco, which also predicted that expenditures on cancer drugs will surge in the next three years.

Diabetes drug accounted for nearly 21% of the increase in drug spending among Medco clients last year, according to the company's drug-trend report.

Spending on diabetes drugs rose by 12% as patients shifted to higher-cost treatments, more people received medication and brand-name drug prices increased. The use of diabetes drugs increased only moderately, Medco said, predicting, however that spending on diabetes drugs will rise 8% to 12% a year through 2010.

While use of cholesterol drugs continues to grow, spending fell 8.5% last year as lower-cost generic versions of the cholesterol medicines Pravachol, from Bristol-Myers Squibb (BMY), and Merck & Co.'s (MRK) Zocor took greater hold in the market, Medco said.

Cholesterol drugs had been the largest driver of drug-spending growth for a decade and account for 10.8% of all prescription costs, Medco said.

Costly targeted cancer and transplant therapies caused spending on those areas to grow by 15.5% last year, and Medco predicts annual spending will grow by 11% to 17%.

The company noted that more than 25 first-time generic drugs are scheduled for introduction to the market in the next three years, which should allow clients and patients to experience lower costs for affected medications.

DR.VIKRAM.K
Source: CNN Money.com-By Dinah Wisenberg Brin, Dow Jones Newswires

Draft Legislation for FDA inspections:

Draft legislation has been put forward which would require the US Food and Drug Administration (FDA) to inspect foreign manufacturing plants every four years. The Food and Drug Administration Globalisation Act of 2008 is based around four existing bills and has come to prominence as a result of the turbulent times recently faced by the FDA, including the heparin contamination case, which has been linked to 62 deaths, as well as concerns over the safety of imported ingredients such as glycerin.Until an inspection is carried out any drug, active pharmaceutical ingredient, class II or III device or device component may not be sold interstate. This covers anything manufactured, prepared, propagated, compounded or processed at the site.To enforce the monitoring of foreign plants the bill proposes the creation of a permanent foreign inspection force, with staff assigned to specific countries. This way they would gain an understanding of the companies, language and culture, leaving them better prepared to perform their duties.Some of the funding required to support the initiative will come from an annual registration fee to be paid by drug and device manufacturers, the amount of which will be determined by the Secretary.The implementation of this is proposed to take place at the start of the 2009 fiscal year. In addition drug labels and medical devices would have to state the source of the active ingredient or the nation in which the device was manufactured. Those behind the legislation feel that consumers have the right to know where their purchases come from.Speaking about the legislation Senator Dingell said: "For example, if it comes from Great Britain, you're going to assume it's pretty safe. If it comes from Canada, it's probably pretty safe. If it comes from China, you're going to say, 'Holy cats, we better watch out.'"The Pharmaceutical Research and Manufacturers of America (PhRMA) has not taken a stance on the inspections or labeling but has weighed into the debate over the FDA's funding.Ken Johnson, senior vice president PhRMA said: "The agency's responsibilities have soared, yet its resources have not kept up to meet these increasing demands." The senate had sought a 20 per cent increase to the FDA's funding but President Bush's budget only granted a 3 per cent rise to the agency.There are aspects of the draft legislation that the Bush administration had wanted to be brought into statute, including a reduction in the FDA's powers to recall products. Under this legislation the FDA would merely be able to request companies undertake a recall, whereas it can currently force a recall.The first hearing of the draft is due to take place on April 24, with others expected to follow.
Dr.Vikram.KSource: Fierce Pharma

DIA in India.

DIA has announced the recent opening of its first office in India, in Mumbai, along with the creation of a Provisional Advisory Council of India (ACI).

The "rapid growth" of India's biopharmaceutical industry, which is predicted to reach $1bn by 2010 up from $100m in 2006, was behind the DIA's decision to establish a presence in the country."The statistics are incredible… More than 15 per cent of the world's clinical trials are expected to be conducted in India by 2011", said Linda McGoldrick, DIA's worldwide executive director."The industry's meteoric rise in this emerging region creates a significant need for DIA's credible international forum that is precedent-setting. We bring together industry, academia, regulators and patient organisations to provide ongoing training for professionals on regulations, clinical practices and safety standards that will impact the approval of drugs developed in India for the global market." The DIA's Indian office is the fourth global location for the association, which also operates from Pennsylvania, US, Basel, Switzerland, and Tokyo, Japan.In conjunction with the new office, the provisional ACI has been established to assist in the early planning stages of DIA initiatives in India and advise on the region's educational needs for training programs and conferences.Chaired by Dr Nandkumar K. Chodankar, president of the API Division of Watson Pharmaceuticals, the ACI is comprised of 13 members who represent industry, academia, and government agencies.Ron Fitzmartin, president of the DIA's Board of Directors said that the agency's "comprehensive outreach" to the Indian marketplace is "a natural one" for DIA. "The interest in this region is global…So many of our existing North American, European, and Japanese members are looking at India as an important region in drug development," he said. "Our presence there means we can help our membership around the globe understand the evolving Indian pharmaceutical landscape while also providing impartial training forums and multidisciplinary perspectives for the growing number of Indian drug development professionals."As a first step, the DIA is launching its first annual Indian regulatory conference, to be held next week on April 28-29 in Mumbai, which will address the issues surrounding the quality and safety of clinical trials in the country. Over the past two years, the agency has already started running conferences on drug discovery and clinical development in India, pertaining to the global development of biopharma products.
Dr.Vikram.K
Source: Fierce Pharma

India News: Astra Zeneca Vs Ranbaxy!

India News: Astra Zeneca Vs Ranbaxy!!!

AstraZeneca, Ranbaxy settle Nexium fight
AstraZeneca investors were jumping for joy this morning when the drugmaker announced it had played Let's Make a Deal with Indian generics maker Ranbaxy. The copycat company agreed to wait till 2014 to sell its version of the heartburn med Nexium, AstraZeneca's top selling drug with $5.22 billion in revenues.

That's a huge coup for AstraZeneca, which has been fighting off the generic challenge since 2005. But it's also a good deal for Ranbaxy: the Indian drugmaker gets U.S. distribution rights to two off-patent AstraZeneca meds, Prilosec and Plendil, and will start supplying the active ingredient in Nexium to AstraZeneca beginning in 2009.

AstraZeneca still faces patent challenges on Nexium from Teva Pharmaceutical Industries and India's Dr Reddy's, but analysts said that Ranbaxy's willingness to settle may signal the strength of AstraZeneca's case. Market watchers also upped AstraZeneca's target share price.

Dr.Vikram.K
Source: Fierce Bioresearcher