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Американцы не спешат разрешать дронедарон.


New FDA Watch List Has Drug Making Fifth Straight Appearance
Robert Lowes

July 18, 2011 — The US Food and Drug Administration (FDA) has published its latest quarterly list of drugs to monitor after having identified potential signs of serious risks or new safety information, and dronedarone (Multaq, Sanofi-Aventis), appears on it for the fifth straight time.

The new watch list covers the first 3 months of 2011. During this span, the FDA detected potential signs of renal impairment and failure for dronedarone, approved in July 2009 to reduce the risk for cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. The 4 watch lists covering 2010 reported different potential signals of risk, 3 of which preceded related label changes for the drug this year.

The FDA compiles these quarterly lists based on data collected through its Adverse Event Reporting System (AERS). The FDA cautions that a drug's appearance on the list does not mean that the agency has determined that the drug actually poses the health risk reported through AERS. However, it will study these drugs to determine whether there is a causal link. If a link is established, the agency then would consider regulatory action, such as revising the drug's label, requiring a risk evaluation and mitigation strategy, or gathering more data to better characterize the risk.

In the meantime, physicians should not stop prescribing these drugs, nor should patients stop taking them, according to the FDA.

Past Potential Signals Include CHF, Warfarin Interaction, Liver Failure

In the case of dronedarone, reports of several potential signals of risk reported for 2010 were followed by regulatory action.

The AERS watch list for the first quarter of 2010 cited potential signals of congestive heart failure for the drug. On February 22, 2011, the FDA revised the warnings and precautions section of dronedarone's label regarding patients with new or worsening heart failure during treatment to state that postmarketing cases of such problems have been reported. The label had originally stated that there were limited data for patients with atrial fibrillation/atrial flutter who develop worsening heart failure during dronedarone therapy, but nevertheless advised clinicians to consider suspending or discontinuing the drug if heart failure commences or worsens.
In the second quarter, AERS identified potential signals of torsade de pointes, a rare kind of ventricular tachycardia.
The list for the third quarter of 2010 listed a potential signal for an interaction with warfarin that increases its anticoagulant effect. On March 21, 2011, the drug interactions section of dronedarone's label was changed to mention postmarketing cases of higher internal normalized ratio (INR) clotting times with or without bleeding events in patients taking warfarin. Physicians were advised to monitor INR in such individuals. The label had originally stated that in clinical trials, "there was no observed excess risk for bleeding compared to placebo" when dronedarone was coadministered with oral anticoagulants to patients with atrial fibrillation/atrial flutter, and that INR should be monitored according to the warfarin label.
Potential signals of liver failure for dronedarone appeared in the watch list for the last 3 months of 2010. On February 11, 2011, the FDA changed the warnings and precautions section of the label to mention postmarketing cases of hepatocellular liver injury and acute liver failure, and the need to promptly discontinue dronedarone if such an injury is suspected. Other parts of the label were revised accordingly.
There were 2 other label changes for dronedarone in 2011 that do not appear to be directly related to potential risk signals detected in 2010. On January 31, 2011, the FDA revised the drug interaction section to state that exposure to dabigatran is higher when it is administered with dronedarone as opposed to alone. In addition, on June 21, 2011, the FDA revised the adverse reaction section to state that postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have surfaced.

Data Still Support "Favorable Benefit Risk Profile," Company Says

The release of the latest AERS watch list comes at a time when dronedarone is undergoing regulatory scrutiny in Europe. As reported last week by Heartwire, the European Medicines Agency will review the cardiovascular risks of dronedarone after the recent decision by Sanofi-Aventis to suspend the phase 3 Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial, which was designed to test the drug in patients with permanent atrial fibrillation, because of an increase in cardiovascular events in those randomly assigned to receive dronedarone.

During phase 3 testing and early postapproval, dronedarone had been viewed by many as potentially less effective, but safer, than amiodarone for treating atrial fibrillation. Medscape Medical News asked Sanofi-Aventis about dronedarone's safety profile in light of its regular appearances on the AERS watch list and the label changes since its approval, and received this response:

"Approximately 400,000 patients have been treated with dronedarone worldwide and post marketing surveillance continues to support the favorable benefit risk profile of Multaq in its approved indication in non-permanent atrial fibrillation."

Asked whether 5 repeat appearances on the AERS watch list is out of the ordinary, an FDA spokesperson responded, saying, "FDA acknowledges that the appearance of Multaq on 5 consecutive 921 reports may appear to be uncommon.... These FDA activities are examples of our continuous safety monitoring for marketed products, and should not be used as a surrogate marker for a product's overall safety profile. The FDA closely looks at new safety signals and conducts further evaluations when new signals arise."

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Я вас всех люблю, но порядок должен быть!

Продолжение с подробностями. Оказалось, принимавшие дронедарон умирали в два раза чаще чем принимавшие плацебо. Причем чем умирали от того, чем хвались - от инсульта! И госпитализаций по поводу ХСН было больше.


Dronedarone 'Dear Doctor' Letter Sums up Recent Alerts
Reed Miller

August 17, 2011 (Bridgewater, New Jersey) — Doctors have now received a formal alert of the problems that led Sanofi-Aventis to terminate the Permanent-Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), which was testing the antiarrhythmic drug dronedarone (Multaq) in patients with permanent atrial fibrillation and at least one other cardiovascular disease risk factor [1].

The company has sent a letter to healthcare providers explaining that the PALLAS phase 3b clinical trial was terminated because patients on dronedarone in the trial were dying at more than twice the rate of that of patients taking placebo. As reported by heartwire , the rates of stroke and hospitalization for heart failure were also more than twice as high in the dronedarone patients as the placebo patients.

In the trial, permanent AF was defined as the presence of AF/atrial flutter for at least six months prior to randomization and the decision to allow AF to continue without further efforts to restore sinus rhythm. The primary end points were major cardiovascular events, cardiovascular hospitalization, or death from any cause.

Dronedarone is already approved for the treatment of paroxysmal or persistent AF or atrial flutter, but "Multaq should not be prescribed for patients with permanent AF," Sanofi-Aventis warns in the letter. "Healthcare professionals are advised to monitor patients regularly (at least every six months) in order to ensure that they remain within the approved indication and do not progress to permanent atrial fibrillation or new or worsening heart failure."

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Я вас всех люблю, но порядок должен быть!

FDA досрочно прекращает исследование PALLAS



FDA досрочно прекращает исследование PALLAS в связи с повышением риска смерти и неблагоприятных сердечно-сосудистых событий у пациентов.

После изучения промежуточных результатов FDA ранее запланированного срока прекратило исследование PALLAS (The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy). Это связано с повышением риска смерти, мозгового инсульта и случаев госпитализации по поводу хронической сердечной недостаточности (ХСН) у пациентов с постоянной формой фибрилляции предсердий (ФП) получавших дронедарон в сравнении с плацебо.

Двойное слепое, плацебо-контролируемое исследование PALLAS, стартовавшее в июле 2010 года должно было дать дополнительную информацию о клинических преимуществах дронедарона (Мультак) в суточной дозе 400 мг в сравнении со стандартной терапией у пациентов с постоянной формой ФП и дополнительными факторами риска (ФР).

В исследовании приняли участие пациенты старше 65 лет с постоянной формой ФП ределяемой как состояние без эпизодов синусового ритма не менее 6 месяцев) и имевших по меньшей мере 1 дополнительный ФР. К таковым относились пациенты с мозговым инсультом или транзиторной ишемической атакой в анамнезе, ишемической болезнью сердца, симптомной сердечной недостаточностью, лица с заболеваниями периферических артерий, а также больные старше 75 лет. Конечными точками исследования, в котором 1572 пациента получали дронедарон в дополнение к стандартной терапии ФП, а 1577 пациентов – плацебо явились:

«большое кардиоваскулярное событие» - мозговой инсульт, системная артериальная эмболия, инфаркт миокарда, «сердечнососудистая» смерть;
внеплановая «кардиоваскулярная» госпитализация или смерть от любой причины.
Исследование прекращено досрочно в связи с повышением в группе вмешательства суммарного показателя кардиоваскулярных событий (32 пациента в группе дронедарона и 14 в группе плацебо, ОР 2.3, р 0.009), общей смертности и внеплановых госпитализаций (118 и 81 пациент соответственно, ОР 1.5, р 0.006), мозгового инсульта (17 и пациентов, ОР 2.4, р 0.047), а также тенденции к увеличению общей смертности (16 и 7 пациентов, ОР 2.3, р 0.065).

С учетом ранее проведенного исследования ANDROMEDA, в котором назначение дронедарона пациентам с нестабильным течением ХСН, а также пациентам с ХСН III-IV ФК по NYHA также продемонстрировало увеличение неблагоприятных исходов, FDA рекомендует прекратить прием дронедарона всем пациентам с постоянной или пароксизмальной формами ФП даже без предварительного согласования с лечащим врачом, а врачам воздержаться от назначения дронедарона пациентам с постоянной формой ФП.

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Я вас всех люблю, но порядок должен быть!

Будут запрещать? затем менять формулу лекарства, затем снова разрешать?
С метформином уже такое было

Если FDA против, то это конец препарата. Кстати сейчас проблемы у ривораксобана при МА. Победил варфарин без достоверности. Да ещё в группе варфарина МНО было в нужном значении только в 57% случаях.


FDA Will Argue Against Rivaroxaban Approval for AF Indication


September 6, 2011 (Rockville, Maryland) — The Food and Drug Administration (FDA) will recommend against approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in atrial-fibrillation patients, when the Cardiovascular and Renal Drugs Advisory Committee meets September 8, 2011.

In the FDA briefing documents for the committee, which were posted online Tuesday, the clinical review recommends that a complete response letter (CRL) be issued and that the drug's sponsor conduct additional studies before the FDA approves the latest anticoagulant on the scene for stroke prevention.

The critical FDA review states the drug should not be approved because "there is a lack of substantial evidence that rivaroxaban will have its desired effect when used as recommended in labeling." Specifically, the agency review is concerned about dosing in the warfarin arm of ROCKET-AF, the large clinical trial showing that rivaroxaban was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non–central nervous system (CNS) embolism. The FDA is concerned because the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), the time spent at the optimal international normalized ratio (INR), which was lower than in other trials with warfarin.

According to the FDA, any study testing a new anticoagulant that protects atrial-fibrillation patients from the risk of thrombotic events must show that the "new therapy . . . be as effective as an approved therapy when the approved-therapy drug is used skillfully." This is a requirement based on an FDA policy for drugs for conditions that are "life-threatening or capable of causing irreversible morbidity (eg, stroke or heart attack)."

Rivaroxaban is currently approved by the FDA for prevention of deep venous thrombosis in the setting of knee- or hip-replacement surgery.

In the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial, a study of dabigatran etexilate (Pradaxa, Boehringer Ingelheim) vs warfarin for stroke prevention in patients with atrial fibrillation, the average TTR was 64% and the median TTR 67%. Last October, the FDA voted to approve dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The drug is available in two doses, 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily.

In the review, the FDA states that patients might be at a higher risk of harm from stroke and/or bleeding than those taking warfarin at therapeutic doses. For this reason, the review recommends that rivaroxaban not be approved until Bayer/Johnson & Johnson provide more data showing that it is as safe and effective as warfarin in a subgroup of patients where the TTR is greater than 67%. That said, the review also notes that if clinicians are in need of an additional oral anticoagulant, it might make sense to approve rivaroxaban as a second- or third-line agent in atrial fibrillation.

"It might be useful in patients who are poorly controlled on warfarin or refuse to take it," according to the review. "However, given that dabigatran has been shown to be superior to warfarin when it is used reasonably well and robustly noninferior to warfarin when it is used extremely well, it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran."

Speaking with heartwire about the FDA review, Dr Anne Curtis (University of Buffalo, NY) said that when ROCKET-AF was presented last year at the American Heart Association meeting, there was a significant buzz in the electrophysiology community about the results for the first Xa inhibitor, with physicians excited to have options other than warfarin for stroke prevention in atrial-fibrillation patients. That said, the concerns about the TTR are valid criticisms of the ROCKET-AF trial, although she said the TTR was not all that far off what was observed in the warfarin-treated patients in RE-LY.

"Clearly, anybody studying these drugs is going to have to be very, very careful about the warfarin groups going forward, that they maximize the opportunities to keep people in the target ranges," said Curtis.

Asked about the clinical need for rivaroxaban and the questions raised by the FDA review, Curtis said more drugs are still needed, especially drugs with different mechanisms of action, as some patients might not be able to tolerate dabigatran. If dabigatran failed, for example, then the clinician and patient are left with no other option except warfarin.

When the ROCKET-AF study was presented, and reported by heartwire at that time, study investigators pointed out that the patients in ROCKET-AF were fairly sick, with 90% of patients hypertensive, 62% having congestive heart failure, and 55% having a prior history of stroke, transient ischemic attack, or non-CNS systemic embolism. In addition, 90% of the patients had a CHADS2 score of 3 or higher, much higher than scores of patients enrolled in comparable studies, and because of these factors, the INR might have been more difficult to manage, said investigators.

Events Occurring After Discontinuing Rivaroxaban

In addition to concerns about warfarin dosing, the FDA review questions the 20-mg once-daily dosing of rivaroxaban, saying the evidence supporting the rationale for evaluating the dose is not strong. In addition, the FDA is troubled by the rebound effect that occurs when patients stop taking rivaroxaban and the sponsor's proposed label instructions for the transition from rivaroxaban to warfarin. The review notes there were an excessive number of strokes in the rivaroxaban arm when the patients were transitioned from the blinded study drug to warfarin at the end of the study, an increased risk that was likely the result of the study design.

At the completion of ROCKET-AF, the blinded study medication was stopped and patients were transitioned to alternative anticoagulant therapy, usually warfarin. However, unlike RE-LY and other studies, patients did not undergo a short-term period of dual anticoagulant therapy--rivaroxaban and warfarin--during the lag period of INR control at the beginning of warfarin therapy. Rivaroxaban has a half-life of six to eight hours, so that a patient starting warfarin the day after rivaroxaban was stopped would not receive adequate anticoagulation for about five days, assuming it would take five days to reach an INR of 2.0.

As a result, there were significantly more strokes in the rivaroxaban study arm compared with warfarin--22 vs six events--from the end of the on-treatment period to day 30, with most events occurring early.

Bayer/Johnson & Johnson are proposing labeling instructions to assist physicians with the transition from rivaroxaban to warfarin, calling for a period of dual therapy with warfarin and rivaroxaban until the INR is under control. However, the FDA review notes that the recommendations are based on pharmacokinetic and pharmacodynamic modeling and have not been tested in studies.

"It seems prudent to require the sponsor to demonstrate in a clinical study in atrial-fibrillation patients receiving rivaroxaban therapy that the proposed transition regimen is safe and effective," the review states.

Regarding safety, particularly bleeding, the review suggests there are no safety concerns with rivaroxaban. Based on the FDA assessment of the data, "there is not a rationale with respect to major bleeding that would prevent an approval decision."

"I think rivaroxaban does what it is supposed to do, and that is prevent strokes," Curtis told heartwire. "I think the Xa inhibitors are needed, and even the FDA said they didn't see a safety concern with bleeding, but it'll be interesting to see how the panel reacts to this."

In terms of predicting how the vote will go, Curtis, who has previously chaired the circulatory system devices advisory panel, suspects the panel members will comprehend the agency's concerns but might vote for approval, given that the drug was shown to be safe and effective in the major clinical-outcomes trial.

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Я вас всех люблю, но порядок должен быть!

FDA всё-таки одобрил ривораксобан. 9 против 2, при одном воздержавшемся.

September 8, 2011 (Adelphi, Maryland) — The Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2, with one abstention, in favor of recommending the approval of rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, for the prevention of stroke in patients with atrial fibrillation.

The approval is based on data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), a study first presented at the American Heart Association 2010 Scientific Sessions and later published in the New England Journal of Medicine [1]. In ROCKET-AF, investigators showed that the new anticoagulant met its primary end point, with rivaroxaban noninferior to warfarin in terms of stroke and non–central-nervous-system (CNS) embolism.

Panel member Dr Darren McGuire (University of Texas Southwestern Medical School, Dallas) said he voted to recommend approval because he felt that ROCKET-AF was a well-designed and well-executed study, although it wasn't perfect. It was a large, international study that included a very high-risk patient population. "The results, fairly convincingly, demonstrate the primary objective of the trial," said McGuire. Dr Vasilios Papademetriou (Veterans Affairs Medical Center, Washington, DC), who also voted in favor of approving rivaroxaban, said that there is a clinical need for anticoagulants in atrial fibrillation, given how difficult warfarin is to use. The data from ROCKET-AF show overwhelmingly that rivaroxaban is as effective as warfarin for the prevention of strokes, he said.

The results, fairly convincingly, demonstrate the primary objective of the trial.
Dr Steven Nissen (Cleveland Clinic, OH), on the other hand, was one of the two panelists who voted "no" to rivaroxaban. Explaining his decision, Nissen said he thinks there might be a better way to administer the Xa inhibitor than once-daily dosing at 20 mg, given the drug's relatively short half-life. He also raised the issue of the amount of time the warfarin-treated patients spent at the optimal international normalized ratio (INR), an issue that also caught the attention of the FDA clinical reviewers. In ROCKET-AF, the warfarin-treated patients spent just 57.8% of the time in therapeutic range (TTR), which was lower than in other trials with warfarin, including the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial with dabigatran etexilate (Pradaxa, Boehringer Ingelheim).

"The TTR was well below other studies, where they were all in the mid- to high 60s [%], so we introduce a level of uncertainty as to the efficacy of the drug," said Nissen. "The question you can ask is, 'Could the TTR have been better?' My conclusion is that it could have been. There was a fatal flaw in the study design in that there were not instructions given, so if you were cynical, you could say that warfarin was designed not to be given particularly well in the trial, but I think it was an oversight and not necessarily intent. The other trials in this field used algorithms for treatment that allowed them to get the TTR into the mid-60s. That wasn't done here, and it left me with a sense of doubt."

A Little Upstaged by Dabigatran

Despite this being rivaroxaban's big day, the specter of the recently approved dabigatran did loom over the committee hearing. Even Dr Norman Stockbridge, director of the FDA's Division of Cardiovascular and Renal Products, noted that dabigatran changed the anticoagulation landscape. For many panel members, it was difficult to look at rivaroxaban in isolation, considering the robust noninferiority of dabigatran compared with warfarin.

In October 2010, dabigatran was approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation, based on the strength of the RE-LY trial. In the 18 000-patient RE-LY study, dabigatran 150 mg twice daily prevented strokes and peripheral embolic events in patients with atrial fibrillation significantly better than warfarin, and the drug fared just as well as warfarin when the 110-mg twice-daily dose was used. In the ROCKET-AF intention-to-treat superiority analysis, rivaroxaban was not shown to be superior to warfarin, but it fared better when investigators analyzed only patients treated with the drug in an on-treatment superiority comparison.

Overwhelmingly, however, the panel felt rivaroxaban was not superior to warfarin, but many felt it was at least an effective alternative to warfarin, including advisory committee chair Dr A Michael Lincoff (Cleveland Clinic), Dr Philip Sager (Cardiac Safety Research Consortium, San Francisco, CA), and Dr Andrei Kindzelski (National Institutes of Health, Bethesda, MD). Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) felt the drug should be used as a third-line agent only, an option for patients who failed other anticoagulant therapies.

"What constitutes failure? Patients who aren't well anticoagulated on warfarin or don't want to be on warfarin because of diet or medications they're on, or simply because they refuse to take warfarin because they don't want to be bothered with monitoring anticoagulation," said Kaul. "These are the types of patients where I think rivaroxaban would be an effective alternative to warfarin and other anticoagulants that are approved. So, a third-line option."

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Я вас всех люблю, но порядок должен быть!

FDA также одобрил в свое время (после успешных исследований) и дронедарон. Иначе объясните мне тогда как препарат был допущен на рынок и мало того как он вошел в рекомендации всех кардиологических обществ по лечению ФП, в том числе и американских.

Что-то я не уверен что FDA разрешала дронедарон и что он есть в американских рекомендациях. Вот в Европейских есть, а там я что-то не помню. Можете дать ссылку?

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Я вас всех люблю, но порядок должен быть!

Конечно могу, Вы же нам их и поставляете (за что мы ВАМ очень и очень благодарствуем).
Смотрите лекции С-П школы кардиологов (в разделе Конференции), где то есть тема по сравнению европейских и американских рекомендаций. Там дронедарон - черным по белому, при пароксизмальных формах ФП.

Слайды с лекции проф. Овсыщер

Как-то не очень понятно. FDA его не зарегистрировал даже в июле (смотри мое сообщение выше)а в феврале он уже рекомендован. Как они там между собой разбираются? Правда применение обговорено. При ХСН 4 нельзя, в амбулаторных условиях считай нельзя начинать - 2б.

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Я вас всех люблю, но порядок должен быть!

Так же как и у нас. Везде цирк, бардак и заказухи. И америкосы тоже не святые.

Или они ориентируясь на исследования, то казнят то милуют.
А исследования у нас то с таким результатом, то с прямо-противоположным. С одними и теми же целями и условиями.

Я про это последнее исследование Паллас, в котором достоверно увеличивается смертность, и предыдущие, в которых тоже очень достоверно она уменьшается ? Сейчас найду слайды.

и с точностью все наоборот

FDA досрочно прекращает исследование PALLAS в связи с повышением риска смерти и неблагоприятных сердечно-сосудистых событий у пациентов.

После изучения промежуточных результатов FDA ранее запланированного срока прекратило исследование PALLAS (The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy). Это связано с повышением риска смерти, мозгового инсульта и случаев госпитализации по поводу хронической сердечной недостаточности (ХСН) у пациентов с постоянной формой фибрилляции предсердий (ФП) получавших дронедарон в сравнении с плацебо.

В Атене больных с ХСН 4 нельзя было вовлекать в исследование. На мой взгляд, там косяки гораздо хуже. Это точки по которым считали -комбинированные. Лично я ценю и признаю препарат только когда твердые точки- смерть в группе препарата исследования и контрольного препарата.

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Я вас всех люблю, но порядок должен быть!

Там..сям Тяп...ляп
Вот такая у нас доказательная медицина