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[h=1]FDA Approves Aveed Testosterone Jab, with Restrictions[/h]Miriam E. Tucker
March 07, 2014 The US Food and Drug Administration (FDA) has approved testosterone undecanoate injectable (Aveed, Endo Pharmaceuticals), for the treatment of men with hypogonadism, but with a boxed warning and very strong prescribing restrictions.
Aveed is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. It offers a novel dosing schedule, with a single 3-mL (750 mg) intramuscular injection given once at initiation of therapy, at 4 weeks, and then every 10 weeks thereafter.
The approval follows 3 previous rejections of Aveed by the FDA for safety and risk/benefit concerns and comes just a month after the FDA announced that it is investigating cardiovascular safety data for all testosterone preparations.
The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary-oil microembolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits outweigh the risks.
But one expert, Bradley D. Anawalt, MD, chief of medicine at the University of Washington Medical Center, Seattle, told Medscape Medical News that — despite the cardiovascular concerns, which he says require more investigation — he welcomes the approval. Aveed will offer men with genuinely low testosterone levels and hypogonadism a more convenient treatment option than currently available preparations and has other potential advantages, he observed.
REMS Revised; Aveed Advantages Over Other Products
The REMS requires that patients must be observed for 30 minutes following injection to rule out serious POME or anaphylaxis, that healthcare settings and providers be specially certified in order to prescribe and dispense Aveed, and that they must have on-site equipment and trained personnel to manage such emergencies.
Endo Pharmaceuticals will be required to assess the effectiveness of the REMS and report its findings to the agency on a regular basis.
"I will prescribe [Aveed]. I think that many men will prefer it because of convenience," Dr. Anawalt told Medscape Medical News, noting that the product has been used safely in Europe and elsewhere around the world for many years.
"The safety [issues] relate to cough and concern that the oil that the testosterone is suspended in was being embolized to the lung. Transient cough is a rare side effect with this product and not seen with other testosterone injectables."
Dr. Anawalt, who has no financial ties to Endo Pharmaceuticals or any other company, added that injection-site reactions with Aveed are rare but slightly more common than with other injectable testosterone products because of the larger volumes injected.
And he said that Aveed has "major advantages," including fewer injections (about every 2 to 3 months), less fluctuation in testosterone levels, and possibly less risk of erythrocytosis.
The last time FDA rejected Aveed was in May 2013, following a joint meeting in April of its Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee, in which panel members' votes were evenly split 9-9 on overall safety of the testosterone replacement and 17-1 against the adequacy of the REMS that the company had proposed at the time.
In a statement provided to Medscape Medical News, the FDA said it "had carefully considered the recommendations of the joint advisory committee and approved Aveed with a boxed warning to inform healthcare professionals about the risks of serious POME and anaphylaxis." The REMS for the approval is more restrictive than what the company originally proposed, it added, with "elements to ensure safe use to manage…risks."
Cardiovascular Risks: A New Concern?
On the same day Endo announced the FDA approval, the consumer-advocacy group Public Citizen sent a letter to FDA Commissioner Margaret Hamburg, MD, asking that the decision be reversed, noting that cardiovascular concerns regarding testosterone use have arisen since the advisory panel meeting.
The FDA's investigation of cardiovascular safety for all testosterone preparations was triggered by the recent publication of 2 studies suggesting that men taking them may have an increased risk for death, myocardial infarction, or ischemic stroke.
"It is likely, if not certain, that the vote against safety would have been even greater had there been a presentation and discussion of the cardiovascular risks known at that time," writes Public Citizen Health Research Group founder and senior advisor Sidney M. Wolfe, MD.
On February 25, Public Citizen had issued a petition to place a boxed warning on all testosterone products and to delay the decision on approval of Aveed.
In response to a query about this, the FDA told Medscape Medical News that it is "reviewing all relevant data, including new publications. The FDA does not have any evidence that may suggest that the cardiovascular risks, if any, with the use of Aveed are different from that of other approved testosterone products."
Dr. Anawalt agrees. "I believe that the recent brouhaha over concerns of increased cardiovascular risk with testosterone therapy is unfounded. The data do not support the recent conclusions that testosterone might increase cardiovascular risk," he told Medscape Medical News.
He added that although high doses of testosterone therapy might increase the risk of cardiovascular events in elderly, frail men or men with established cardiovascular disease, "that remains unproved by good clinical trials."
He also told Medscape Medical News, "The FDA review will be helpful if it stimulates publicly funded, scientifically sound clinical trials comparing testosterone and placebo in men with hypogonadism.
"In the meantime, physicians should continue to treat men with symptoms, signs, and biochemical evidence of male hypogonadism with physiological doses of testosterone." But "physicians should be cautious about prescribing testosterone to men based solely on low to low-normal testosterone levels," he concluded.
March 07, 2014 The US Food and Drug Administration (FDA) has approved testosterone undecanoate injectable (Aveed, Endo Pharmaceuticals), for the treatment of men with hypogonadism, but with a boxed warning and very strong prescribing restrictions.
Aveed is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. It offers a novel dosing schedule, with a single 3-mL (750 mg) intramuscular injection given once at initiation of therapy, at 4 weeks, and then every 10 weeks thereafter.
The approval follows 3 previous rejections of Aveed by the FDA for safety and risk/benefit concerns and comes just a month after the FDA announced that it is investigating cardiovascular safety data for all testosterone preparations.
The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary-oil microembolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits outweigh the risks.
But one expert, Bradley D. Anawalt, MD, chief of medicine at the University of Washington Medical Center, Seattle, told Medscape Medical News that — despite the cardiovascular concerns, which he says require more investigation — he welcomes the approval. Aveed will offer men with genuinely low testosterone levels and hypogonadism a more convenient treatment option than currently available preparations and has other potential advantages, he observed.
REMS Revised; Aveed Advantages Over Other Products
The REMS requires that patients must be observed for 30 minutes following injection to rule out serious POME or anaphylaxis, that healthcare settings and providers be specially certified in order to prescribe and dispense Aveed, and that they must have on-site equipment and trained personnel to manage such emergencies.
Endo Pharmaceuticals will be required to assess the effectiveness of the REMS and report its findings to the agency on a regular basis.
"I will prescribe [Aveed]. I think that many men will prefer it because of convenience," Dr. Anawalt told Medscape Medical News, noting that the product has been used safely in Europe and elsewhere around the world for many years.
"The safety [issues] relate to cough and concern that the oil that the testosterone is suspended in was being embolized to the lung. Transient cough is a rare side effect with this product and not seen with other testosterone injectables."
Dr. Anawalt, who has no financial ties to Endo Pharmaceuticals or any other company, added that injection-site reactions with Aveed are rare but slightly more common than with other injectable testosterone products because of the larger volumes injected.
And he said that Aveed has "major advantages," including fewer injections (about every 2 to 3 months), less fluctuation in testosterone levels, and possibly less risk of erythrocytosis.
The last time FDA rejected Aveed was in May 2013, following a joint meeting in April of its Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee, in which panel members' votes were evenly split 9-9 on overall safety of the testosterone replacement and 17-1 against the adequacy of the REMS that the company had proposed at the time.
In a statement provided to Medscape Medical News, the FDA said it "had carefully considered the recommendations of the joint advisory committee and approved Aveed with a boxed warning to inform healthcare professionals about the risks of serious POME and anaphylaxis." The REMS for the approval is more restrictive than what the company originally proposed, it added, with "elements to ensure safe use to manage…risks."
Cardiovascular Risks: A New Concern?
On the same day Endo announced the FDA approval, the consumer-advocacy group Public Citizen sent a letter to FDA Commissioner Margaret Hamburg, MD, asking that the decision be reversed, noting that cardiovascular concerns regarding testosterone use have arisen since the advisory panel meeting.
The FDA's investigation of cardiovascular safety for all testosterone preparations was triggered by the recent publication of 2 studies suggesting that men taking them may have an increased risk for death, myocardial infarction, or ischemic stroke.
"It is likely, if not certain, that the vote against safety would have been even greater had there been a presentation and discussion of the cardiovascular risks known at that time," writes Public Citizen Health Research Group founder and senior advisor Sidney M. Wolfe, MD.
On February 25, Public Citizen had issued a petition to place a boxed warning on all testosterone products and to delay the decision on approval of Aveed.
In response to a query about this, the FDA told Medscape Medical News that it is "reviewing all relevant data, including new publications. The FDA does not have any evidence that may suggest that the cardiovascular risks, if any, with the use of Aveed are different from that of other approved testosterone products."
Dr. Anawalt agrees. "I believe that the recent brouhaha over concerns of increased cardiovascular risk with testosterone therapy is unfounded. The data do not support the recent conclusions that testosterone might increase cardiovascular risk," he told Medscape Medical News.
He added that although high doses of testosterone therapy might increase the risk of cardiovascular events in elderly, frail men or men with established cardiovascular disease, "that remains unproved by good clinical trials."
He also told Medscape Medical News, "The FDA review will be helpful if it stimulates publicly funded, scientifically sound clinical trials comparing testosterone and placebo in men with hypogonadism.
"In the meantime, physicians should continue to treat men with symptoms, signs, and biochemical evidence of male hypogonadism with physiological doses of testosterone." But "physicians should be cautious about prescribing testosterone to men based solely on low to low-normal testosterone levels," he concluded.
