Food & Drug Administration

FDA Label Changes Underline Risks With Ezogabine

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The US Food and Drug Administration (FDA) has announced approval of changes to labeling for the antiseizure medication ezogabine (Potiga, Valeant Pharmaceuticals International) to underline previously reported risks for retinal abnormalities, potential vision loss, and skin discoloration, all of which may become permanent.

“The revised label includes a new boxed warning, the most serious type of warning FDA gives,” because of this risk for retinal abnormalities, a statement from FDA notes. “We advise that Potiga use be limited to patients who have not responded adequately to several alternative therapies to decrease the frequency of seizures, or epilepsy, and for whom the benefits of treatment outweigh the risks.”

The risks were previously described in a Drug Safety Communication in April 2013, and reported by Medscape Medical News at that time.

The agency is further recommending that patients undergo eye examinations by an ophthalmic professional prior to starting ezogabine, and every 6 months during treatment. “These exams should include visual acuity and dilated fundus photography, with additional vision testing as necessary,” the FDA statement notes. “Patients whose vision cannot be monitored should generally not take Potiga.”

It is not clear which patients are at risk for these retinal changes, how long it may take for them to be detected, the rate of progression, or their reversibility after treatment withdrawal, the advisory adds.

“If retinal pigmentary abnormalities or vision changes are detected, Potiga should be stopped unless no other suitable seizure treatment options are available and the benefits of treatment outweigh the potential risk of vision loss,” the statement said. “In addition, health care professionals should stop Potiga treatment in patients who do not show substantial clinical benefit after adequate dose titration.”

Patients are advised, though, not to stop taking the drug before consulting their healthcare provider.

The new label also includes warnings about the risk for discoloration of the skin, nail, mucous membrane, and white of the eye that were also outlined in the previous statement in April. If patients develop such discoloration, an alternate treatment should be considered, the new label advises.

All of these recommendations have been added to the label’s Warnings and Precautions section and the patient Medication Guide, which should be included with each prescription that is filled.

“FDA is working on modifying the current Risk Evaluation and Mitigation Strategy (REMS) for Potiga to address the risk of retinal pigmentary abnormalities, potential vision loss, and skin discoloration,” the statement concludes.

Noninjectable Insulin Developers Make Progress

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Diabetes sufferers may soon be able to avoid the needle.

Noninjectable Insulin Developers Make ProgressLessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. [AndrzejTokarski/Fotolia]

Whether famous like Tom Hanks or not, millions of people with diabetes for generations have had to take insulin by injection, just as a 14-year-old diabetic named Leonard Thompson did when he became the first patient successfully treated with the peptide hormone in 1922.

Nearly a century later, drug developers remain unable to market a noninjectable therapeutic. But of late, lessons from past failures are being applied by drug developers pursuing clinical development of new oral and inhalable insulin products. The companies see a growing market: An estimated 552 million people are expected to develop diabetes by 2030, up from 371 million in 2012, according to the International Diabetes Federation.

No Needles Required

MannKind earlier this month resubmitted to FDA its new drug application for Afrezza® (insulin human [rDNA origin]) Inhalation Powder for adults with type 1 or type 2 diabetes)—two years after the agency required two additional clinical studies comparing its current inhaler to its first-generation MedTone inhaler.

In August, MannKind released promising results from two Phase III trials. One study in type 1 patients compared Afrezza to insulin aspart; the other measured inhalable insulin in type 2 patients with inadequate diabetes control following metformin treatment, with or without a second or third oral medication. The type 2 study showed a drop in mean A1c levels of 0.82% in patients using Afrezza, compared to a 0.42% decrease in the comparator group. The type 1 study met its primary endpoint of noninferiority to insulin aspart.

Afrezza combines an inhalation powder with an inhaler called Dreamboat™ designed for use by diabetics at the start of meals. The powder dissolves immediately when inhaled to the deep lung and delivers insulin quickly to the bloodstream. According to MannKind, peak insulin levels occur within 12 to 15 minutes of administration, compared with 45 to 90 minutes for injected rapid acting insulin analogs, and 90–150 minutes for injected regular human insulin.

Joseph Kocinsky, MannKind’s svp, pharmaceutical technology development, told GEN Afrezza’s Technosphere® pulmonary drug delivery platform offers competitive advantages. In addition to ultra-fast delivery, insulin administered via Technosphere formulation avoids the hepatic first-pass metabolism that reduces drug bioavailability.

“The Technosphere technology is applicable to a wide variety of drugs (small molecules, peptides, proteins, monoclonal antibodies) and a wide variety of clinical indications like diabetes, pain, osteoporosis, and respiratory disease,” Kocinsky said.

Perhaps Afrezza’s best advantage is the same one offered by the oral insulin products—it doesn’t require a needle. Injection remains no small hurdle to insulin use among people with diabetes, despite improvements over the past generation such as shorter and sharper disposable needles, notes Robert E. Ratner, M.D., FACP, FACE, chief scientific and medical officer for the American Diabetes Association.

Dr. Ratner’s previously work as an investigator included studying Novo Nordisk’s insulin degludec, a long-acting injectable insulin analog. He said injection has one important advantage: Doses can be titrated and adjusted.

“When you’re giving oral or inhaled insulin, that level of precision in terms of dosing is probably going to be considerably harder,” Dr. Ratner told GEN. “We don’t yet know all of the details about the pharmacokinetics of these [noninjectable] agents—how quickly they’ll get absorbed, what percentage will get absorbed, are we going to be able to change the doses to meet the biologic needs of the individual? Those all remain unknowns. Those are the hurdles the companies need to overcome before we have a viable product.”

Road to Success Paved with Failure

Drug developers have long struggled to develop noninjectable diabetes treatments. In 2007, Pfizer stopped marketing Exubera® after 13 months following disappointing sales, took $2.8 billion in pre-tax charges, and returned product rights to partner Nektar Therapeutics.

One key factor in Exubera’s failure was its delivery system: Its inhaler was about a foot long, more conspicuous and clumsier than even the needle. Afrezza can be inhaled through a smaller inhaler requiring no maintenance because it is discarded and replaced every 15 days. Also unlike Exubera, Afrezza is dosed in traditional insulin units that are linear; two three-unit cartridges equal a six-unit cartridge.

Within months of Exubera’s exit, both Novo Nordisk and Eli Lilly ended programs to develop new inhalable insulin products that had advanced to Phase III trials, insisting they had not acted from safety concerns. Lilly brought insulin to market in 1923, and 60 years later launched the first insulin analogs.

Today, Novo Nordisk and another drug developer, Oramed, are well into clinical studies of oral insulin products, with years to go: “We won’t be looking at oral insulin for the next five to six years at the very least.”

Future Possibilities

Also working on noninjectable insulin is Biocon, which last year landed Bristol-Myers Squibb (BMS) as its partner to partially fund Phase II trials of its IN-105 outside India for two years. After that, BMS has the option to assume full responsibility for IN-105, including all development and commercialization activities outside India—in return for BMS paying Biocon a license fee, milestone payments, and royalties on IN-105 sales outside India.

Oramed in July enrolled its first patient in a Phase IIa trial assessing the safety of ORMD-0801, an orally ingestible insulin capsule on patients with type 2 diabetes. A total 30 patients will be enrolled.

“Results of the trial are anticipated by the end of the calendar year,” Aviva Sherman, an Oramed spokeswoman, told GEN.

ORMD-0801 is also under study in a clinical trial in Israel in August that began recruiting patients with type 1 diabetes, for which -0801 is envisioned as a complement to injections, allowing fewer daily injections.

In September, Oramed submitted a pre-IND package to FDA for its ORMD-0901 (oral exenatide), a GLP-1 analog for type 2 diabetes. “By acting on multiple fronts, i.e., stimulation of insulin release and suppression of glucagon release, as well as other actions, GLP-1 addresses diabetes-related glycemia issues on a broader level than does exogenously administered insulin,” Sherman said.

Oramed said its oral insulin mimics insulin’s natural location and gradients in the body by traveling through the gastrointestinal tract encapsulated, then releasing the insulin in the small intestine, from which it is ferried to the liver via the portal vein. The first-pass metabolism significantly reduces the risk of hypoglycemia, the most common side effect of injected insulins.

Novo Nordisk’s candidate OI362GT or NN1954, an oral basal insulin analog intended as a tablet treatment, generated successful results from a single-dose Phase I trial earlier this year. Peter Kurtzhals, svp in diabetes research at Novo Nordisk, told GEN NN1954 is delivered through enteric coated tablets targeting the duodenum, facilitated by the rise in pH that occurs when a substance passes from the acidic milieu in the stomach into the intestine.

“The delivery in duodenum is not more porous, but contents of the gall fluid secreted here may play a role in facilitating absorption of some substances from this part of the gut,” Kurtzhals said.

NN1954 absorption is enabled via partner Merrion Pharmaceuticals’ GIPET® technology. GIPET uses specifically designed oral formulations of patented absorption enhancers designed to activate micelle formation, facilitating transport of drug and increasing absorption.

The drug and enhancer are not bound to each other chemically, but are both ingredients of the tablet, with no interaction between active pharmaceutical ingredient and absorption enhancer. Co-release of the drug and absorption enhancer occurs following dissolution of the coating and a general disintegration of the tablet.

“The oral insulin project is currently in Phase I clinical development. Contingent on successful outcome of these trials, Phase II will be initiated within 1–2 years,” Kurtzhals said.

By the time Novo Nordisk and Oramed complete their required additional trials, followed by formal regulatory reviews, MannKind may have already delivered the first noninjectable insulin to grateful diabetics. Or not. FDA can be expected to show particular caution with noninjectable insulin candidates, given the problems inhalables have had in recent years. To win approvals, companies will have to show not only the usual safety and efficacy, but that their products are better than past noninjectable candidates—drugs young Leonard Thompson could only dream about when he took insulin by needle and made history nearly a century ago.

FDA Directs ADHD Drug Manufacturers to Notify Patients about Cardiovascular Adverse Events and Psychiatric Adverse Events.

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“An FDA review of reports of serious cardiovascular adverse events in patients taking usual doses of ADHD products revealed reports of sudden death in patients with underlying serious heart problems or defects, and reports of stroke and heart attack in adults with certain risk factors.”

“Another FDA review of ADHD medicines revealed an increased risk  for drug-related psychiatric adverse events, such as hearing voices, becoming suspicious for no reason, or becoming manic, even in patients who did not have previous psychiatric problems. ”

The medicines that are the focus of the revised labeling and new Patient Medication Guides include the following 15 products:

  • · Adderall (mixed salts of a single entity amphetamine product) Tablets
  • · Adderall XR (mixed salts of a single entity amphetamine product) Extended-Release Capsules
  • · Concerta (methylphenidate hydrochloride) Extended-Release Tablets
  • · Daytrana (methylphenidate) Transdermal System
  • · Desoxyn (methamphetamine HCl) Tablets
  • · Dexedrine (dextroamphetamine sulfate) Spansule Capsules and Tablets
  • · Focalin (dexmethylphenidate hydrochloride) Tablets
  • · Focalin XR (dexmethylphenidate hydrochloride) Extended-Release Capsules
  • · Metadate CD (methylphenidate hydrochloride) Extended-Release Capsules
  • · Methylin (methylphenidate hydrochloride) Oral Solution
  • · Methylin (methylphenidate hydrochloride) Chewable Tablets
  • · Ritalin (methylphenidate hydrochloride) Tablets
  • · Ritalin SR (methylphenidate hydrochloride) Sustained-Release Tablets
  • · Ritalin LA (methylphenidate hydrochloride) Extended-Release Capsules
  • · Strattera (atomoxetine HCl) Capsules

The Cardiovascular Safety of Diabetes Drugs — Insights from the Rosiglitazone Experience.

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The management of type 2 diabetes has been challenged by uncertainty about possible cardiovascular effects related to treatment intensity and choice of drug. Although the Food and Drug Administration (FDA) considers a decrease in glycated hemoglobin an approvable end point, very intensive glycemic control is associated with increased cardiovascular and all-cause mortality.1 The safety of specific drugs for type 2 diabetes — particularly the thiazolidinediones — has also been questioned. After rosiglitazone had been approved in the United States in 1999 and in Europe in 2000, a highly publicized meta-analysis in 2007 reported a 43% increase in myocardial infarction (P=0.03) and a 64% increase in death from cardiovascular causes (P=0.06).2 This report and subsequent FDA advisory committee reviews led to a boxed warning of myocardial ischemia in 2007 and highly restricted access to rosiglitazone in 2010. In 2010, the FDA placed a full clinical hold on the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial (ClinicalTrials.gov number, NCT00879970), a large cardiovascular-outcome trial designed to evaluate the benefit of rosiglitazone and pioglitazone as compared with placebo (superiority hypothesis) and the safety of rosiglitazone as compared with pioglitazone (noninferiority hypothesis). In part owing to the rosiglitazone experience, the FDA issued an updated Guidance for Industry in 2008 requiring that preapproval and postapproval studies for all new antidiabetic drugs rule out excess cardiovascular risk, defined as an upper bound of the two-sided 95% confidence interval for major adverse cardiovascular events (MACE) of less than 1.80 and less than 1.30, respectively.3 Regardless of the presence or absence of preclinical or clinical signals of cardiovascular risk, the guidance has been applied broadly to all new diabetes drugs, creating substantial challenges in the drug development and approval process.

On June 5 and 6, 2013, the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (on which we serve) and the Drug Safety and Risk Management Advisory Committee to further evaluate the cardiovascular safety of rosiglitazone. When rosiglitazone was approved in Europe, the European Medicines Agency raised concern about the cardiovascular risks of the thiazolidinedione class, including fluid retention, heart failure, and increased levels of low-density lipoprotein cholesterol. This concern led to a postmarketing requirement that cardiovascular-outcome trials be conducted for both pioglitazone and rosiglitazone, and these were reviewed at subsequent FDA meetings. Although the results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study (NCT00379769) did not suggest an increased risk of MACE,4issues with trial design and data integrity led the FDA to require the sponsor to perform an independent readjudication of the data. This extensive exercise, performed by the Duke Clinical Research Institute, had a minimal effect on the overall point estimates and confidence intervals for MACE, which remained at less than 1.30. The result was consistent with the FDA guidance and provided reassurance that rosiglitazone was not associated with excess cardiovascular risk.

Two groups of authors (Scirica et al. and White et al.) now report in the Journal the results of large, placebo-controlled, cardiovascular-outcome trials, these involving saxagliptin and alogliptin, members of the incretin drug class. Neither of these drugs had shown increased cardiovascular risk in its development program. Both trials were designed to first rule out excess cardiovascular risk by means of noninferiority testing; if that was shown, superiority testing followed, on the assumption that better glycemic control might yield cardiovascular benefit. Both trials clearly met the FDA 2008 guidance for cardiovascular safety, but neither showed a reduction in cardiovascular events. Saxagliptin was associated with an unexpected increased risk of hospitalization for heart failure and a high frequency of hypoglycemia. Neither trial showed any increased risk of pancreatic adverse events, including cancer.

Before rosiglitazone, the cardiovascular safety of diabetes drugs had not been well studied. The initial concern with rosiglitazone arose from observational and case–control epidemiologic studies that generated a legitimate signal of possible cardiovascular harm, but every study had substantial methodologic shortcomings, including multiplicity, which meant that a statistically positive finding might be a false positive result.5 Meta-analyses were also performed with preapproval studies that had been designed to show a positive glycemic effect as the primary end point. These studies enrolled patients at low cardiovascular risk, were short in duration, used both placebo and active controls, and did not prospectively adjudicate cardiovascular safety events. In such situations, comparison of a new drug with an active agent is challenged by the uncertain cardiovascular risk of the active comparator. In contrast, a placebo-controlled design may lead to imbalances in background therapy (as was the case with saxagliptin) that could influence the cardiovascular outcomes. Meta-analyses of these premarketing trials from phase 3 development programs were therefore relatively insensitive in assessing cardiovascular risk, making dedicated postmarketing cardiovascular-outcome trials such as the RECORD study necessary to substantiate any risk signals. But the design of the RECORD study had substantial limitations that precluded a complete assessment of the cardiovascular safety of rosiglitazone.

In 2010, the FDA took a cautious stance and limited exposure to rosiglitazone, given the numerous alternative therapies that were available. But this position did not acknowledge the uncertainty of cardiovascular risk associated with other diabetes drugs on the market, and the FDA decision may have had unintended consequences. The intense publicity about the ischemic cardiac risk of rosiglitazone may have diverted attention from the better-established risk of heart failure that is common to the drug class. Restricted access led patients to switch from rosiglitazone to other diabetes drugs of unproven cardiovascular safety. Patients who had a myocardial infarction while taking rosiglitazone may have concluded that the drug was the cause, adversely affecting their perceptions of their doctor, drug companies, and the FDA. And placing a hold on the TIDE trial, although arguably justifiable, prevented any further clarification of the cardiovascular risks or benefits of the thiazolidinedione drug class. The rosiglitazone experience also raises the question of how to define a regulatory standard for withdrawing drugs from the market. New drug approvals are based on “substantial evidence” of drug safety and efficacy. But there is little guidance on what constitutes substantial evidence of harm that is sufficient to justify market withdrawal or the imposition of severe market restrictions.

What have we learned from the rosiglitazone experience? Clearly, the presumed cardiovascular risks of rosiglitazone led to a major change in FDA policy regarding the approval of all new diabetes drugs. From a cardiovascular perspective, rosiglitazone, saxagliptin, and alogliptin appear to be relatively safe. It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.

Patients with type 2 diabetes and their physicians currently have numerous treatment options, and additional drugs are in development. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure. New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown. The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.

Source: NEJM

 

r�a>�,� �b� n> At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.

 

Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.

 

Source: NEJM

 

 

 

Epilepsy Drug Warnings May Slip Through Cracks.

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One-fifth of American neurologists are unaware of serious safety risks associated with epilepsydrugs and are potentially risking the health of patients who could be treated with safer medications, a new study reveals.

The 505 neurologists who took part in the survey between March and July 2012 were asked if they knew about several epilepsy drugs’ safety risks recently identified by the U.S. Food and Drug Administration.

These risks included increased danger of suicidal thoughts or behaviors linked with some newer drugs, a high risk for birth defects and mental impairment in children of mothers taking divalproex (brand nameDepakote), and the likelihood of serious hypersensitivity reactions in some Asian patients treated with carbamazepine (Tegretol).

One in five of the neurologists said they did not know about any of these risks. Neurologists who treat 200 or more epilepsy patients per year were most likely to know all the risks, according to the study, which was published online recently in the journal Epilepsy.

Although this study focused on epilepsy drugs, the findings suggest that the FDA needs to find better ways to inform doctors about newly discovered drug safety risks, said the researchers from Johns Hopkins University School of Medicine. Their results show that warnings about these risks are not getting through to doctors making important prescribing decisions.

There is no single place for neurologists to find updated drug risk information, said study leader Dr. Gregory Krauss, a professor of neurology. A few get emails from the FDA, while others get the information from neurology societies, continuing medical education courses or journal articles.

“There is poor communication from the FDA to specialists, and there’s some risk to patients because of this,” Krauss said in a Johns Hopkins news release.

“Unless it’s a major change requiring the FDA to issue a black box warning on a product, important information appears to be slipping through the cracks,” he said. “We need a more systematic and comprehensive method so that doctors receive updated safety warnings in a format that guarantees they will see and digest what they need to protect patients.”

Source: Drugs.com

When EMA and FDA decisions conflict: differences in patients or in regulation?.

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Are Americans more resistant to the risks and more likely to benefit from certain drugs than Europeans or, on the contrary, is the European Medicines Agency (EMA) more resistant than the US Food and Drug Administration (FDA) to the drug industry’s desire to get approval for drugs with unique risks but without compensating benefits?

This question arises because the FDA has recently approved two diet drugs, heralded by the agency as “the first drugs for long-term weight management that FDA has approved in 13 years”1 but rejected by the EMA. In both cases FDA advisory committees earlier rejected approval but later supported the FDA’s and the companies’ desire for approval. Similarly, the FDA has also failed to ban the diabetes drug rosiglitazone (Avandia), banned three years ago by the EMA.2

In June 2012 the FDA approved lorcaserin (marketed in the United States as Belviq). The weight loss drugs dexfenfluramine and fenfluramine were banned in 1997 because of many post-approval cases of heart valve damage, attributed to adverse effects on the 2B serotonin heart receptor.3 Lorcaserin has minimal 2B serotonin receptor activity, but the FDA approved the drug despite a 16% increase in heart valve damage in randomized trials, not statistically significant but with an upper confidence interval of 67%.4 The reduction in weight loss, beyond that of placebo, was 3% to 3.7%.5 The chairman of the FDA advisory committee reviewing the drug stated, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.” The cardiologist Sanjay Kaul, a committee member who voted against approval, said, “Given the totality of evidence, the potential benefits of lorcaserin do not, in my opinion, outweigh the potential risks when used long term in a population of overweight and obese individuals.”6

Despite its approval of the drug, the FDA required the company to do post-marketing randomized trials to better evaluate cardiovascular risk, including heart valve damage.7

Before the EMA had formally rejected the application for lorcaserin, but after withdrawal of the marketing application by the drug’s sponsor, Arena, the EMA stated that “at the time of the withdrawal the CHMP [the EMA’s Committee for Medicinal Products for Human Use] . . . was of the provisional opinion that Belviq could not have been approved for weight control in obese and overweight patients” because “the benefits of Belviq did not outweigh its risks.” The committee’s safety concerns included “the potential risk of psychiatric disorders (such as depression) and valvulopathy.”8

Shortly after it approved lorcaserin, the FDA approved a combination of phentermine and topiramate (now marketed as Qsymia in the US) despite concerns about its cardiovascular risk. In studies the proportion of patients with pulse increases exceeding 10 beats per minute, a risk factor for cardiovascular disease,9 was significantly higher in the high dose Qsymia group than in the placebo group.10 In patients in the mid-dose Qsymia group, the incidence of arrhythmia related adverse events was 4.2%, compared with 1.8% in the placebo group.11 Metabolic acidosis—significantly higher in patients taking Qsymia—can be a risk factor for cardiac arrhythmias.12 Metabolic acidosis resulted in increased nephrolithiasis: 22 cases in the Qsymia groups, five in the placebo group.13 Cognitive related adverse events, including memory impairment and reduced concentration or attention, occurred in 1.7% of placebo patients and 5.6% of mid-dose Qsymia patients.14

An FDA analysis of serious adverse cardiovascular outcomes in randomized clinical trials of Qsymia found six events in 743 patients taking Qsymia but none in 227 placebo patients. These events included myocardial infarction or acute coronary syndrome in four patients.15 However, patients in the mid-dose Qsymia groups in the randomized trials lost 6.7% more weight than patients in the placebo groups.16

When Qsymia was approved in July 2012, the FDA hailed it as another treatment option but decided that a study was needed to clarify the risks of major adverse cardiac events such as heart attack and stroke—but only after it was on the market. The FDA also required training of prescribers and certification of pharmacies and a patient leaflet giving important safety information.17

The EMA rejected Qsymia for the second time in February 2013, noting that “the main studies showed clinically relevant weight loss following treatment with Qsiva [the European name for Qsymia]” but that it had “concerns about the medicine’s long-term effects on the heart and blood vessels” and “about the long-term psychiatric effects (depression and anxiety were reported in the studies) and cognitive effects (such as problems with memory and attention).”18 It concluded that “the benefits of Qsiva did not outweigh its risks and recommended that it be refused marketing authorisation.”18

Thus, two more diet drugs, following in the footsteps of the now banned phenylpropanolamine, dexfenfluramine, sibutramine and others, were found by the EMA to be too dangerous to be used for weight loss but are considered by the FDA to be “safe enough” for Americans.

This safe diet drug delusion recalls the editorial by the UK endocrinologist Gareth Williams after sibutramine was removed from the European market by the EMA but was, unfortunately, still available for many more months in the US until it was banned. He wrote, “The fate of sibutramine reminds us how little antiobesity drugs have had to offer—at best, a reduction of a few per cent in the total burden of excess weight carried until death. With energy homoeostasis so deeply enmeshed in physiology, it has always seemed unlikely that a magic bullet could ever switch off food intake without hitting something vital.”19

This is not to say that the EMA is perfect but rather that its recent record on drugs such as these puts the FDA to shame. It is not the resistance of Americans to the risks of these drugs but the intermittently dangerous malleability of the FDA that is the problem in the cases discussed here.

Source: BMJ

FDA Approves Extended-Release Once-Daily Epilepsy Drug.

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An oral once-daily extended release formulation of topiramate (Trokendi XR) for the treatment of epilepsy has received final approval from the US Food and Drug Administration (FDA), according to an announcement from Supernus Pharmaceuticals Inc.

The specialty pharmaceutical company said the product should be available in pharmacies over the next few weeks. It is indicated for initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures, adjunctive therapy in patients 6 years of age and older with partial-onset or primary generalized tonic-clonic seizures, and adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome.

“We are very excited about the approval of Trokendi XR and its upcoming launch,” said Jack Khattar, chief executive officer, president and director of Supernus, in a press statement. “This is excellent news for Supernus, its shareholders, and patients with epilepsy. We remain committed to the epilepsy community and very much look forward to now having two products, Trokendi XR and Oxtellar XR, available to patients.”

The approval letter states that the FDA has completed its review of the application and that Trokendi XR is approved effective August 16 for use as recommended in the agreed-upon labeling, according to the statement that appears on the Supernus Web site.

The company noted that the product will be available in 25-mg, 50-mg, 100-mg, and 200-mg extended-release capsules.

The FDA granted a waiver for certain pediatric study requirements and a deferral for submission of postmarketing pediatric pharmacokinetic assessments that are due in 2019, followed by clinical assessments in 2025, according to the press release.

Oxtellar XR (extended-release oxcarbazepine) received FDA approval in late 2012 and was introduced in the United States earlier this year. Oxtellar XR is indicated for adjunctive therapy in the treatment of partial seizures in adults and in children aged 6 to 17 years.

Source: medscape.com

Supplements: Nutrition in a pill?

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Supplements aren’t for everyone, but older adults and others may benefit from specific supplements.

The Dietary Guidelines for Americans make it clear that your nutritional needs should be met primarily through your diet. For some people, however, supplements may be a useful way to get nutrients they might otherwise be lacking. But before you go shopping for supplements, get the facts on what they will and won’t do for you.

Supplements vs. whole foods

Supplements aren’t intended to be a food substitute because they can’t replicate all of the nutrients and benefits of whole foods, such as fruits and vegetables. So depending on your situation and your eating habits, dietary supplements may not be worth the expense.

Whole foods offer three main benefits over dietary supplements:

  • Greater nutrition. Whole foods are complex, containing a variety of the micronutrients your body needs — not just one. An orange, for example, provides vitamin C plus some beta carotene, calcium and other nutrients. A vitamin C supplement lacks these other micronutrients.
  • Essential fiber. Whole foods, such as whole grains, fruits, vegetables and legumes, provide dietary fiber. Most high-fiber foods are also packed with other essential nutrients. Fiber, as part of a healthy diet, can help prevent certain diseases, such as type 2 diabetes and heart disease, and it can also help manage constipation.
  • Protective substances. Whole foods contain other substances important for good health. Fruits and vegetables, for example, contain naturally occurring substances called phytochemicals, which may help protect you against cancer, heart disease, diabetes and high blood pressure. Many are also good sources of antioxidants — substances that slow down oxidation, a natural process that leads to cell and tissue damage.

Who needs supplements?

If you’re generally healthy and eat a wide variety of foods, including fruits, vegetables, whole grains, legumes, low-fat dairy products, lean meats and fish, you likely don’t need supplements.

However, the dietary guidelines recommend supplements — or fortified foods — in the following situations:

  • Women who may become pregnant should get 400 micrograms a day of folic acid from fortified foods or supplements, in addition to eating foods that naturally contain folate.
  • Women who are pregnant should take a prenatal vitamin that includes iron or a separate iron supplement.
  • Adults age 50 or older should eat foods fortified with vitamin B-12, such as fortified cereals, or take a multivitamin that contains B-12 or a separate B-12 supplement.

Dietary supplements also may be appropriate if you:

  • Don’t eat well or consume less than 1,600 calories a day
  • Are a vegan or a vegetarian who eats a limited variety of foods
  • Are a woman who experiences heavy bleeding during your menstrual period
  • Have a medical condition that affects how your body absorbs or uses nutrients, such as chronic diarrhea, food allergies, food intolerance or a disease of the liver, gallbladder, intestines or pancreas
  • Have had surgery on your digestive tract and are not able to digest and absorb nutrients properly

Talk to your doctor or a dietitian about which supplements and what doses might be appropriate for you. Be sure to ask about possible side effects and interactions with any medications you take.

Choosing and using supplements

If you decide to take a vitamin or mineral supplement, consider these factors:

  • Check the label. Read labels carefully. Product labels can tell you what the active ingredient or ingredients are, which nutrients are included, the serving size — for example, capsule, packet or teaspoonful — and the amount of nutrients in each serving.
  • Avoid megadoses. In general, choose a multivitamin-mineral supplement that provides about 100 percent of the Daily Value (DV) of all the vitamins and minerals, rather than one which has, for example, 500 percent of the DV for one vitamin and only 20 percent of the DV for another.
  • Check expiration dates. Dietary supplements can lose potency over time, especially in hot and humid climates. If a supplement doesn’t have an expiration date, don’t buy it. If your supplements have expired, discard them.
  • Watch what you eat. Vitamins and minerals are being added to a growing number of foods, including breakfast cereals and beverages. If you’re also taking supplements, you may be getting more than you realize of certain nutrients. Taking more than you need is expensive and can raise your risk of side effects. For example, too much iron can cause nausea and vomiting and may damage the liver and other organs.

Keep up with supplement safety alerts

The Food and Drug Administration (FDA) keeps a list of dietary supplements that are under regulatory review or that have been reported to cause adverse effects. If you’re taking a supplement, it’s a good idea to check the FDA website periodically for updates.

Source: Mayo clinic

 

 

white�pn�t� X1� font-size:9.0pt;font-family:”Arial”,”sans-serif”;color:#666666′>And, I’ll tell you right now, after this last year, leaving Waiheke Island, going to Hawaii (as detailed in Going Out On A Limb), well… I feel freer, happier, more peaceful and more my true self than I ever have in 35 years and I categorically COULD NOT have done it if I had not reached out for support.

 

So, I implore you, if you are someone who is afraid to reach out for support, please… for the love of all things… swallow your fears, your negative self-talk, your pride or whatever is keeping you stuck and please, please put your freaking hand up! The Universe will deliver what you need if you will only step up to help yourself. People will materialise to support you. Information will find its way to you when you move forward to open your arms to receive it. You will find help in the most unlikely of places if you are willing to step outside your comfort zone. Do not judge how things may have gone before… perhaps once before you reached out and you didn’t get the response and support you needed. The past is gone and it has no bearing now. Life is short, don’t waste one second of it when the support you need lies all around you, beckoning you to call upon it.