FDA recalls HeartMate 3 LV assist device

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The HeartMate 3 left ventricular assist device received a class 1 recall from the Food and Drug Administration on May 17, an action the agency publicly announced on May 22.

The FDA’s step formalized a “corrective action” that the HeartMate 3’s manufacturer, Abbott, first issued in early April and then announced in early May, which said the device used to treat patients with severe advanced heart failure was subject to “outflow graft twist occlusions” that trigger a persistent low-flow alarm and “can result in serious adverse events such as hemodynamic compromise, thrombus, and death,” according to the FDA’s May 17 statement.

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According to Abbott’s May 4 announcement of its corrective action on outflow graft twists, the company learned of the complication in 32 reports received from a total of 4,467 HeartMate 3 devices implanted worldwide, a 0.72% rate. These reports cited three deaths that could have been associated with twists, the company’s statement said. The FDA approved HeartMate 3 for routine U.S. use in August 2017. Since Abbott’s May statement, the company’s count of implanted devices in U.S. patients rose to 4,878, according to a company spokesman, and the FDA cited 5,607 devices as having been sold by Abbott worldwide.

The class 1 recall category the FDA applied means the agency rates the danger posed as a “situation where there is a reasonable chance that a product will cause serious health problems or death.” However, in its statements, the agency has not suggested removing a well-functioning device from patients, nor has the agency called for discontinuing new placements of the HeartMate 3. The FDA gave a full endorsement to the approach Abbott suggested in its April 5 “Dear Physician” letter and then followed with a second letter on May 21.



The first letter attributed development of these twists in the tube that directs blood out from the device to accumulated mechanical forces from heartbeats, respiration, and activity, and also provided some management guidance that Abbott then expanded in its second letter.

The FDA cited some of the key steps Abbott recommended clinicians take with patients who receive a HeartMate 3. This included regular surveillance with transthoracic echocardiography, although echo is not considered definitive for identifying a graft twist obstruction and hence other investigations may also be needed. If the low-flow alarm sounds, a CT scan is “urgently” needed – as long as it’s not contraindicated – to identify a possible outflow twist. Abbott noted that surgical intervention may be needed to correct a twist.

Researchers recently reported 2-year follow-up data from 257 patients in MOMENTUM 3, the randomized pivotal trial for the HeartMate 3 that compared this fully magnetically levitated centrifugal-flow pump to the prior-generation, axial-flow pump. The composite endpoint of freedom from death, stroke, or need for repeat surgery after 2 years was 80% in the HeartMate 3 recipients and 60% among patients in the control arm who received the older-model device (N Engl J Med. 2018 April 12; 378[15]:1386-95).

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The HeartMate 3 left ventricular assist device received a class 1 recall from the Food and Drug Administration on May 17, an action the agency publicly announced on May 22.

The FDA’s step formalized a “corrective action” that the HeartMate 3’s manufacturer, Abbott, first issued in early April and then announced in early May, which said the device used to treat patients with severe advanced heart failure was subject to “outflow graft twist occlusions” that trigger a persistent low-flow alarm and “can result in serious adverse events such as hemodynamic compromise, thrombus, and death,” according to the FDA’s May 17 statement.

Wikimedia Commons/FitzColinGerald/Creative Commons License
According to Abbott’s May 4 announcement of its corrective action on outflow graft twists, the company learned of the complication in 32 reports received from a total of 4,467 HeartMate 3 devices implanted worldwide, a 0.72% rate. These reports cited three deaths that could have been associated with twists, the company’s statement said. The FDA approved HeartMate 3 for routine U.S. use in August 2017. Since Abbott’s May statement, the company’s count of implanted devices in U.S. patients rose to 4,878, according to a company spokesman, and the FDA cited 5,607 devices as having been sold by Abbott worldwide.

The class 1 recall category the FDA applied means the agency rates the danger posed as a “situation where there is a reasonable chance that a product will cause serious health problems or death.” However, in its statements, the agency has not suggested removing a well-functioning device from patients, nor has the agency called for discontinuing new placements of the HeartMate 3. The FDA gave a full endorsement to the approach Abbott suggested in its April 5 “Dear Physician” letter and then followed with a second letter on May 21.



The first letter attributed development of these twists in the tube that directs blood out from the device to accumulated mechanical forces from heartbeats, respiration, and activity, and also provided some management guidance that Abbott then expanded in its second letter.

The FDA cited some of the key steps Abbott recommended clinicians take with patients who receive a HeartMate 3. This included regular surveillance with transthoracic echocardiography, although echo is not considered definitive for identifying a graft twist obstruction and hence other investigations may also be needed. If the low-flow alarm sounds, a CT scan is “urgently” needed – as long as it’s not contraindicated – to identify a possible outflow twist. Abbott noted that surgical intervention may be needed to correct a twist.

Researchers recently reported 2-year follow-up data from 257 patients in MOMENTUM 3, the randomized pivotal trial for the HeartMate 3 that compared this fully magnetically levitated centrifugal-flow pump to the prior-generation, axial-flow pump. The composite endpoint of freedom from death, stroke, or need for repeat surgery after 2 years was 80% in the HeartMate 3 recipients and 60% among patients in the control arm who received the older-model device (N Engl J Med. 2018 April 12; 378[15]:1386-95).

 

The HeartMate 3 left ventricular assist device received a class 1 recall from the Food and Drug Administration on May 17, an action the agency publicly announced on May 22.

The FDA’s step formalized a “corrective action” that the HeartMate 3’s manufacturer, Abbott, first issued in early April and then announced in early May, which said the device used to treat patients with severe advanced heart failure was subject to “outflow graft twist occlusions” that trigger a persistent low-flow alarm and “can result in serious adverse events such as hemodynamic compromise, thrombus, and death,” according to the FDA’s May 17 statement.

Wikimedia Commons/FitzColinGerald/Creative Commons License
According to Abbott’s May 4 announcement of its corrective action on outflow graft twists, the company learned of the complication in 32 reports received from a total of 4,467 HeartMate 3 devices implanted worldwide, a 0.72% rate. These reports cited three deaths that could have been associated with twists, the company’s statement said. The FDA approved HeartMate 3 for routine U.S. use in August 2017. Since Abbott’s May statement, the company’s count of implanted devices in U.S. patients rose to 4,878, according to a company spokesman, and the FDA cited 5,607 devices as having been sold by Abbott worldwide.

The class 1 recall category the FDA applied means the agency rates the danger posed as a “situation where there is a reasonable chance that a product will cause serious health problems or death.” However, in its statements, the agency has not suggested removing a well-functioning device from patients, nor has the agency called for discontinuing new placements of the HeartMate 3. The FDA gave a full endorsement to the approach Abbott suggested in its April 5 “Dear Physician” letter and then followed with a second letter on May 21.



The first letter attributed development of these twists in the tube that directs blood out from the device to accumulated mechanical forces from heartbeats, respiration, and activity, and also provided some management guidance that Abbott then expanded in its second letter.

The FDA cited some of the key steps Abbott recommended clinicians take with patients who receive a HeartMate 3. This included regular surveillance with transthoracic echocardiography, although echo is not considered definitive for identifying a graft twist obstruction and hence other investigations may also be needed. If the low-flow alarm sounds, a CT scan is “urgently” needed – as long as it’s not contraindicated – to identify a possible outflow twist. Abbott noted that surgical intervention may be needed to correct a twist.

Researchers recently reported 2-year follow-up data from 257 patients in MOMENTUM 3, the randomized pivotal trial for the HeartMate 3 that compared this fully magnetically levitated centrifugal-flow pump to the prior-generation, axial-flow pump. The composite endpoint of freedom from death, stroke, or need for repeat surgery after 2 years was 80% in the HeartMate 3 recipients and 60% among patients in the control arm who received the older-model device (N Engl J Med. 2018 April 12; 378[15]:1386-95).

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FDA approves Prolia for glucocorticoid-induced osteoporosis

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The Food and Drug Administration has approved Prolia (denosumab) for the treatment of glucocorticoid-induced osteoporosis in adults at high risk of fracture, the drug’s manufacturer Amgen announced May 21.

FDA approval was based on 12-month primary analysis results from a randomized, double-blind, phase 3 trial. Patients who received a 60-mg dose of Prolia subcutaneously every 6 months had greater lumbar spine bone mineral density at 1 year than did those who received a 5-mg dose of risedronate daily in all study subpopulations. These results were maintained after researchers controlled for gender, race, geographic region, and menopausal status, as well as baseline age, lumbar spine bone mineral density T score, and glucocorticoid dose within each subpopulation.

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Prolia is currently approved to treat postmenopausal women with osteoporosis at high fracture risk, to increase bone mass in men with osteoporosis at high fracture risk, and to increase bone mass in women receiving adjuvant aromatase inhibitor therapy for breast cancer and in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.



The most common adverse events associated with Prolia during the phase 3 study were back pain, hypertension, bronchitis, and headache, which are in line with previously reported safety data.

“Patients on long-term systemic glucocorticoid medications can experience a rapid reduction in bone mineral density within a few months of beginning treatment. With this approval, patients who receive treatment with glucocorticoids now have a new option to help improve their bone mineral density,” lead study author Kenneth F. Saag, MD, professor of medicine at the University of Alabama, Birmingham, said in Amgen’s news release.

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The Food and Drug Administration has approved Prolia (denosumab) for the treatment of glucocorticoid-induced osteoporosis in adults at high risk of fracture, the drug’s manufacturer Amgen announced May 21.

FDA approval was based on 12-month primary analysis results from a randomized, double-blind, phase 3 trial. Patients who received a 60-mg dose of Prolia subcutaneously every 6 months had greater lumbar spine bone mineral density at 1 year than did those who received a 5-mg dose of risedronate daily in all study subpopulations. These results were maintained after researchers controlled for gender, race, geographic region, and menopausal status, as well as baseline age, lumbar spine bone mineral density T score, and glucocorticoid dose within each subpopulation.

Wikimedia Commons/FitzColinGerald/Creative Commons License
Prolia is currently approved to treat postmenopausal women with osteoporosis at high fracture risk, to increase bone mass in men with osteoporosis at high fracture risk, and to increase bone mass in women receiving adjuvant aromatase inhibitor therapy for breast cancer and in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.



The most common adverse events associated with Prolia during the phase 3 study were back pain, hypertension, bronchitis, and headache, which are in line with previously reported safety data.

“Patients on long-term systemic glucocorticoid medications can experience a rapid reduction in bone mineral density within a few months of beginning treatment. With this approval, patients who receive treatment with glucocorticoids now have a new option to help improve their bone mineral density,” lead study author Kenneth F. Saag, MD, professor of medicine at the University of Alabama, Birmingham, said in Amgen’s news release.

 

The Food and Drug Administration has approved Prolia (denosumab) for the treatment of glucocorticoid-induced osteoporosis in adults at high risk of fracture, the drug’s manufacturer Amgen announced May 21.

FDA approval was based on 12-month primary analysis results from a randomized, double-blind, phase 3 trial. Patients who received a 60-mg dose of Prolia subcutaneously every 6 months had greater lumbar spine bone mineral density at 1 year than did those who received a 5-mg dose of risedronate daily in all study subpopulations. These results were maintained after researchers controlled for gender, race, geographic region, and menopausal status, as well as baseline age, lumbar spine bone mineral density T score, and glucocorticoid dose within each subpopulation.

Wikimedia Commons/FitzColinGerald/Creative Commons License
Prolia is currently approved to treat postmenopausal women with osteoporosis at high fracture risk, to increase bone mass in men with osteoporosis at high fracture risk, and to increase bone mass in women receiving adjuvant aromatase inhibitor therapy for breast cancer and in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.



The most common adverse events associated with Prolia during the phase 3 study were back pain, hypertension, bronchitis, and headache, which are in line with previously reported safety data.

“Patients on long-term systemic glucocorticoid medications can experience a rapid reduction in bone mineral density within a few months of beginning treatment. With this approval, patients who receive treatment with glucocorticoids now have a new option to help improve their bone mineral density,” lead study author Kenneth F. Saag, MD, professor of medicine at the University of Alabama, Birmingham, said in Amgen’s news release.

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FDA advisory panelists reject Buvaya for acute pain

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HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

 


The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.
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HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

 


The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.

 

HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.

At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.

The rejection of Buvaya by the committees is consistent with the views of FDA reviewers who expressed concerns with particularly high rates of nausea, vomiting, and dizziness. Sublingual buprenorphine also had significant delays to time of meaningful pain reduction, compared with similar opioids like oxymorphone and oxycodone. In fact, more than half of the patients treated with lower doses of Buvaya never experienced any level of pain relief. The FDA reviewers’ views were echoed by several advisory committee members.

“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”

According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.

Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.

One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.

 

 


The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.

The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.

Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”

Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.
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FDA approves Aimovig for migraine prevention

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The Food and Drug Administration has approved Aimovig (erenumab-aooe), delivered once a month via injection, for the prevention of migraines in adults.

Aimovig is the first FDA-approved treatment developed to prevent migraines by blocking the calcitonin gene–related peptide receptor.

Wikimedia Commons/FitzColinGerald/Creative Commons License
Approval for the drug was based on results from three clinical trials. In the first, which included 955 patients with episodic migraine, patients treated with Aimovig over a 6-month period had, on average, 1-2 fewer migraine days per month than those who received placebo. In the second, which included 577 patients with episodic migraine, those treated with Aimovig over a 3-month period had, on average, 1 fewer migraine day per month versus those who received placebo.

The final clinical trial included 667 chronic migraine patients, and over a 3-month period, those treated with Aimovig had, on average, 2.5 fewer migraine days per month, compared with those who received placebo.

The most commonly reported adverse events were injection-site reactions and constipation.

“Aimovig provides patients with a novel option for reducing the number of days with migraine. We need new treatments for this painful and often debilitating condition,” Eric Bastings, MD, deputy director of the division of neurology products in the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

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The Food and Drug Administration has approved Aimovig (erenumab-aooe), delivered once a month via injection, for the prevention of migraines in adults.

Aimovig is the first FDA-approved treatment developed to prevent migraines by blocking the calcitonin gene–related peptide receptor.

Wikimedia Commons/FitzColinGerald/Creative Commons License
Approval for the drug was based on results from three clinical trials. In the first, which included 955 patients with episodic migraine, patients treated with Aimovig over a 6-month period had, on average, 1-2 fewer migraine days per month than those who received placebo. In the second, which included 577 patients with episodic migraine, those treated with Aimovig over a 3-month period had, on average, 1 fewer migraine day per month versus those who received placebo.

The final clinical trial included 667 chronic migraine patients, and over a 3-month period, those treated with Aimovig had, on average, 2.5 fewer migraine days per month, compared with those who received placebo.

The most commonly reported adverse events were injection-site reactions and constipation.

“Aimovig provides patients with a novel option for reducing the number of days with migraine. We need new treatments for this painful and often debilitating condition,” Eric Bastings, MD, deputy director of the division of neurology products in the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

 

The Food and Drug Administration has approved Aimovig (erenumab-aooe), delivered once a month via injection, for the prevention of migraines in adults.

Aimovig is the first FDA-approved treatment developed to prevent migraines by blocking the calcitonin gene–related peptide receptor.

Wikimedia Commons/FitzColinGerald/Creative Commons License
Approval for the drug was based on results from three clinical trials. In the first, which included 955 patients with episodic migraine, patients treated with Aimovig over a 6-month period had, on average, 1-2 fewer migraine days per month than those who received placebo. In the second, which included 577 patients with episodic migraine, those treated with Aimovig over a 3-month period had, on average, 1 fewer migraine day per month versus those who received placebo.

The final clinical trial included 667 chronic migraine patients, and over a 3-month period, those treated with Aimovig had, on average, 2.5 fewer migraine days per month, compared with those who received placebo.

The most commonly reported adverse events were injection-site reactions and constipation.

“Aimovig provides patients with a novel option for reducing the number of days with migraine. We need new treatments for this painful and often debilitating condition,” Eric Bastings, MD, deputy director of the division of neurology products in the FDA’s Center for Drug Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

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FDA warns of birth defect risks from dolutegravir

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The Food and Drug Administration has issued a Drug Safety Communication alert that serious cases of neural tube birth defects have been reported in babies born to women treated with dolutegravir for human immunodeficiency virus. Reported defects have involved the brain, spine, and spinal cord.

copyright alexskopje/Thinkstock
Evidence of a higher risk of these defects was seen in the preliminary results of an ongoing observational study in Botswana of women treated with the drug from the initiation of pregnancy through early in the first trimester, a critical period in neural tube development. Such birth defects can occur early in pregnancy when the spinal cord, brain, and related structures do not form properly.

To date, in this observational study, there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy, according to the FDA. “We are investigating this new safety issue and will update the public when we have more information,” the alert stated.

Dolutegravir is an FDA-approved antiretroviral used to treat HIV. The drug is available as a single ingredient under the brand name Tivicay and as a combination tablet with other HIV medicines under the brand names Juluca and Triumeq.

Medwatch also released an alert for medical practitioners to report adverse events related to this issue.

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The Food and Drug Administration has issued a Drug Safety Communication alert that serious cases of neural tube birth defects have been reported in babies born to women treated with dolutegravir for human immunodeficiency virus. Reported defects have involved the brain, spine, and spinal cord.

copyright alexskopje/Thinkstock
Evidence of a higher risk of these defects was seen in the preliminary results of an ongoing observational study in Botswana of women treated with the drug from the initiation of pregnancy through early in the first trimester, a critical period in neural tube development. Such birth defects can occur early in pregnancy when the spinal cord, brain, and related structures do not form properly.

To date, in this observational study, there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy, according to the FDA. “We are investigating this new safety issue and will update the public when we have more information,” the alert stated.

Dolutegravir is an FDA-approved antiretroviral used to treat HIV. The drug is available as a single ingredient under the brand name Tivicay and as a combination tablet with other HIV medicines under the brand names Juluca and Triumeq.

Medwatch also released an alert for medical practitioners to report adverse events related to this issue.

 

The Food and Drug Administration has issued a Drug Safety Communication alert that serious cases of neural tube birth defects have been reported in babies born to women treated with dolutegravir for human immunodeficiency virus. Reported defects have involved the brain, spine, and spinal cord.

copyright alexskopje/Thinkstock
Evidence of a higher risk of these defects was seen in the preliminary results of an ongoing observational study in Botswana of women treated with the drug from the initiation of pregnancy through early in the first trimester, a critical period in neural tube development. Such birth defects can occur early in pregnancy when the spinal cord, brain, and related structures do not form properly.

To date, in this observational study, there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy, according to the FDA. “We are investigating this new safety issue and will update the public when we have more information,” the alert stated.

Dolutegravir is an FDA-approved antiretroviral used to treat HIV. The drug is available as a single ingredient under the brand name Tivicay and as a combination tablet with other HIV medicines under the brand names Juluca and Triumeq.

Medwatch also released an alert for medical practitioners to report adverse events related to this issue.

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FDA queries more companies about youth e-cig use

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Four more e-cigarette manufacturers are facing Food and Drug Administration scrutiny in an effort for the agency to better understand youth appeal and usage of e-cigarettes.

“Too many kids continue to experiment with e-cigarette and vaping products, putting them at risk for developing a lifelong nicotine addiction,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “These products should never be marketed to, sold to, or used by kids, and it’s critical that we take aggressive steps to address the youth use of these products.”

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The agency sent letters May 17 to four manufacturers: J Well; YGT Investment and 7 Daze; Liquid Filling Solutions; and SRV. This latest round of inquiries follows a similar request for information letter sent April 24 to JUUL Labs.

The agency is seeking information including, but not limited to, “documents related to product marketing, documents related to research on product design (as it may relate to the appeal or addictive potential for youth, youth-related adverse experiences), and consumer complaints associated with products,” the agency said in a statement.



The May 17 letters note that the four companies manufacture products similar to JUUL’s product offering, sharing similar characteristics, “including e-liquids that contain nicotine salts with corresponding high nicotine concentration, small size which makes them easily concealable, and product design features that are intuitive, even for novice [electronic nicotine delivery system] users. These attributes may relate to the appeal and addictiveness of the product, particularly for youth who may be experimenting with tobacco products.”

The action is the latest in the agency’s effort to combat nicotine addiction. In March, the agency issues an advanced notice of proposed rule making seeking information on the role flavoring plays in youth tobacco consumption.

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Four more e-cigarette manufacturers are facing Food and Drug Administration scrutiny in an effort for the agency to better understand youth appeal and usage of e-cigarettes.

“Too many kids continue to experiment with e-cigarette and vaping products, putting them at risk for developing a lifelong nicotine addiction,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “These products should never be marketed to, sold to, or used by kids, and it’s critical that we take aggressive steps to address the youth use of these products.”

Thinkstockphotos.com
The agency sent letters May 17 to four manufacturers: J Well; YGT Investment and 7 Daze; Liquid Filling Solutions; and SRV. This latest round of inquiries follows a similar request for information letter sent April 24 to JUUL Labs.

The agency is seeking information including, but not limited to, “documents related to product marketing, documents related to research on product design (as it may relate to the appeal or addictive potential for youth, youth-related adverse experiences), and consumer complaints associated with products,” the agency said in a statement.



The May 17 letters note that the four companies manufacture products similar to JUUL’s product offering, sharing similar characteristics, “including e-liquids that contain nicotine salts with corresponding high nicotine concentration, small size which makes them easily concealable, and product design features that are intuitive, even for novice [electronic nicotine delivery system] users. These attributes may relate to the appeal and addictiveness of the product, particularly for youth who may be experimenting with tobacco products.”

The action is the latest in the agency’s effort to combat nicotine addiction. In March, the agency issues an advanced notice of proposed rule making seeking information on the role flavoring plays in youth tobacco consumption.

 

Four more e-cigarette manufacturers are facing Food and Drug Administration scrutiny in an effort for the agency to better understand youth appeal and usage of e-cigarettes.

“Too many kids continue to experiment with e-cigarette and vaping products, putting them at risk for developing a lifelong nicotine addiction,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “These products should never be marketed to, sold to, or used by kids, and it’s critical that we take aggressive steps to address the youth use of these products.”

Thinkstockphotos.com
The agency sent letters May 17 to four manufacturers: J Well; YGT Investment and 7 Daze; Liquid Filling Solutions; and SRV. This latest round of inquiries follows a similar request for information letter sent April 24 to JUUL Labs.

The agency is seeking information including, but not limited to, “documents related to product marketing, documents related to research on product design (as it may relate to the appeal or addictive potential for youth, youth-related adverse experiences), and consumer complaints associated with products,” the agency said in a statement.



The May 17 letters note that the four companies manufacture products similar to JUUL’s product offering, sharing similar characteristics, “including e-liquids that contain nicotine salts with corresponding high nicotine concentration, small size which makes them easily concealable, and product design features that are intuitive, even for novice [electronic nicotine delivery system] users. These attributes may relate to the appeal and addictiveness of the product, particularly for youth who may be experimenting with tobacco products.”

The action is the latest in the agency’s effort to combat nicotine addiction. In March, the agency issues an advanced notice of proposed rule making seeking information on the role flavoring plays in youth tobacco consumption.

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FDA: PrEP indication updated to include adolescents at risk of HIV infection

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The following is the text of an announcement by the U.S. Food and Drug Administration regarding a revision in the Truvada label to expand the PrEP indication to include at-risk adolescents. The new label change has not yet been posted.



The Food and Drug Administration approved revisions to the Truvada (emtricitabine and tenofovir disoproxil fumarate) labeling to expand the Pre-Exposure Prophylaxis (PrEP) indication to include adolescents weighing at least 35 kg who are at risk of HIV-1 acquisition. The major labeling changes with respect to this expanded indication are summarized below. In addition, Section 8 was reformatted per the Pregnancy and Lactation Labeling Rule (PLLR) and includes updated information specific to the use of Truvada for PrEP during pregnancy and breastfeeding. Other sections of labeling were reformatted for consistency with current and best labeling practices, as well as with labeling for other HIV fixed-dose combination products.

Indications and usage

1.2 HIV-1 pre-exposure prophylaxis (PrEP)

Truvada is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating Truvada for HIV-1 PrEP.

If clinical symptoms consistent with acute viral infection are present and recent (less than 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection

When considering Truvada for HIV-1 PrEP, factors that help to identify individuals at risk may include:

– has partner(s) known to be HIV-1 infected, or

– engages in sexual activity within a high prevalence area or social network and has additional risk factors for HIV-1 acquisition, such as:

 

 

  • inconsistent or no condom use.
  • diagnosis of sexually transmitted infections.
  • exchange of sex for commodities (such as money, food, shelter, or drugs).
  • use of illicit drugs or alcohol dependence.
  • incarceration.
  • partner(s) of unknown HIV-1 status with any of the factors listed above.

Dosage and administration

2.1 Testing prior to initiation of Truvada for treatment of HIV-1 infection or for HIV-1 PrEP

Prior to or when initiating Truvada, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of Truvada, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus

 

 


2.2 HIV-1 screening for individuals receiving Truvada for HIV-1 PrEP

Screen all patients for HIV-1 infection before initiating Truvada for HIV-1 PrEP and at least once every 3 months while taking Truvada



2.5 Recommended dosage for HIV-1 PrEP

The dosage of Truvada in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.
 

 

6.0 Adverse reactions

Clinical trials in adolescent subjects

In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received Truvada once daily for HIV-1 PrEP, the safety profile of Truvada was similar to that observed in adults. Median duration to exposure of Truvada was 47 weeks.

In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from greater than −2 to less than or equal to −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to Truvada by Week 48.

8.4 Pediatric use

HIV-1 PrEP

The safety and effectiveness of Truvada for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of Truvada for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects.

 

 

Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received Truvada once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range, 15-18 years); 46% were Hispanic, 52% black, and 37% white. The safety profile of Truvada in ATN113 was similar to that observed in the adult HIV-1 PrEP trials.

In the ATN113 trial, HIV-1 seroconversion occurred in three subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the three subjects who seroconverted.

Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling.

12.0 Clinical pharmacology

HIV-1 PrEP

The pharmacokinetic data for tenofovir and FTC following administration of Truvada in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of Truvada for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.

 

 


ResistanceATN113 Trial

In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4)], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended Truvada dosage.


The updated label will soon be available at drugs@fda or DailyMed.
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The following is the text of an announcement by the U.S. Food and Drug Administration regarding a revision in the Truvada label to expand the PrEP indication to include at-risk adolescents. The new label change has not yet been posted.



The Food and Drug Administration approved revisions to the Truvada (emtricitabine and tenofovir disoproxil fumarate) labeling to expand the Pre-Exposure Prophylaxis (PrEP) indication to include adolescents weighing at least 35 kg who are at risk of HIV-1 acquisition. The major labeling changes with respect to this expanded indication are summarized below. In addition, Section 8 was reformatted per the Pregnancy and Lactation Labeling Rule (PLLR) and includes updated information specific to the use of Truvada for PrEP during pregnancy and breastfeeding. Other sections of labeling were reformatted for consistency with current and best labeling practices, as well as with labeling for other HIV fixed-dose combination products.

Indications and usage

1.2 HIV-1 pre-exposure prophylaxis (PrEP)

Truvada is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating Truvada for HIV-1 PrEP.

If clinical symptoms consistent with acute viral infection are present and recent (less than 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection

When considering Truvada for HIV-1 PrEP, factors that help to identify individuals at risk may include:

– has partner(s) known to be HIV-1 infected, or

– engages in sexual activity within a high prevalence area or social network and has additional risk factors for HIV-1 acquisition, such as:

 

 

  • inconsistent or no condom use.
  • diagnosis of sexually transmitted infections.
  • exchange of sex for commodities (such as money, food, shelter, or drugs).
  • use of illicit drugs or alcohol dependence.
  • incarceration.
  • partner(s) of unknown HIV-1 status with any of the factors listed above.

Dosage and administration

2.1 Testing prior to initiation of Truvada for treatment of HIV-1 infection or for HIV-1 PrEP

Prior to or when initiating Truvada, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of Truvada, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus

 

 


2.2 HIV-1 screening for individuals receiving Truvada for HIV-1 PrEP

Screen all patients for HIV-1 infection before initiating Truvada for HIV-1 PrEP and at least once every 3 months while taking Truvada



2.5 Recommended dosage for HIV-1 PrEP

The dosage of Truvada in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.
 

 

6.0 Adverse reactions

Clinical trials in adolescent subjects

In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received Truvada once daily for HIV-1 PrEP, the safety profile of Truvada was similar to that observed in adults. Median duration to exposure of Truvada was 47 weeks.

In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from greater than −2 to less than or equal to −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to Truvada by Week 48.

8.4 Pediatric use

HIV-1 PrEP

The safety and effectiveness of Truvada for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of Truvada for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects.

 

 

Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received Truvada once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range, 15-18 years); 46% were Hispanic, 52% black, and 37% white. The safety profile of Truvada in ATN113 was similar to that observed in the adult HIV-1 PrEP trials.

In the ATN113 trial, HIV-1 seroconversion occurred in three subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the three subjects who seroconverted.

Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling.

12.0 Clinical pharmacology

HIV-1 PrEP

The pharmacokinetic data for tenofovir and FTC following administration of Truvada in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of Truvada for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.

 

 


ResistanceATN113 Trial

In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4)], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended Truvada dosage.


The updated label will soon be available at drugs@fda or DailyMed.

 

The following is the text of an announcement by the U.S. Food and Drug Administration regarding a revision in the Truvada label to expand the PrEP indication to include at-risk adolescents. The new label change has not yet been posted.



The Food and Drug Administration approved revisions to the Truvada (emtricitabine and tenofovir disoproxil fumarate) labeling to expand the Pre-Exposure Prophylaxis (PrEP) indication to include adolescents weighing at least 35 kg who are at risk of HIV-1 acquisition. The major labeling changes with respect to this expanded indication are summarized below. In addition, Section 8 was reformatted per the Pregnancy and Lactation Labeling Rule (PLLR) and includes updated information specific to the use of Truvada for PrEP during pregnancy and breastfeeding. Other sections of labeling were reformatted for consistency with current and best labeling practices, as well as with labeling for other HIV fixed-dose combination products.

Indications and usage

1.2 HIV-1 pre-exposure prophylaxis (PrEP)

Truvada is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating Truvada for HIV-1 PrEP.

If clinical symptoms consistent with acute viral infection are present and recent (less than 1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection

When considering Truvada for HIV-1 PrEP, factors that help to identify individuals at risk may include:

– has partner(s) known to be HIV-1 infected, or

– engages in sexual activity within a high prevalence area or social network and has additional risk factors for HIV-1 acquisition, such as:

 

 

  • inconsistent or no condom use.
  • diagnosis of sexually transmitted infections.
  • exchange of sex for commodities (such as money, food, shelter, or drugs).
  • use of illicit drugs or alcohol dependence.
  • incarceration.
  • partner(s) of unknown HIV-1 status with any of the factors listed above.

Dosage and administration

2.1 Testing prior to initiation of Truvada for treatment of HIV-1 infection or for HIV-1 PrEP

Prior to or when initiating Truvada, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of Truvada, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus

 

 


2.2 HIV-1 screening for individuals receiving Truvada for HIV-1 PrEP

Screen all patients for HIV-1 infection before initiating Truvada for HIV-1 PrEP and at least once every 3 months while taking Truvada



2.5 Recommended dosage for HIV-1 PrEP

The dosage of Truvada in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food.
 

 

6.0 Adverse reactions

Clinical trials in adolescent subjects

In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received Truvada once daily for HIV-1 PrEP, the safety profile of Truvada was similar to that observed in adults. Median duration to exposure of Truvada was 47 weeks.

In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from greater than −2 to less than or equal to −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to Truvada by Week 48.

8.4 Pediatric use

HIV-1 PrEP

The safety and effectiveness of Truvada for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of Truvada for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects.

 

 

Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received Truvada once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range, 15-18 years); 46% were Hispanic, 52% black, and 37% white. The safety profile of Truvada in ATN113 was similar to that observed in the adult HIV-1 PrEP trials.

In the ATN113 trial, HIV-1 seroconversion occurred in three subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the three subjects who seroconverted.

Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling.

12.0 Clinical pharmacology

HIV-1 PrEP

The pharmacokinetic data for tenofovir and FTC following administration of Truvada in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of Truvada for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.

 

 


ResistanceATN113 Trial

In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4)], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended Truvada dosage.


The updated label will soon be available at drugs@fda or DailyMed.
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FDA’s Gottlieb floats ideas on Medicare drug coverage

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– Trump administration officials are eying office-administered drugs in crowded therapeutic categories for the switch from Medicare Part B to Medicare Part D as an early way to reduce spending on prescription drugs.

When the current Part B drug reimbursement scheme – average sales price plus an additional 6% to cover administration and storage – was developed, there was little competition in most of the covered therapeutic categories, Scott Gottlieb, MD, Food and Drug Administration commissioner, said May 15 at an event hosted by the Alliance for Health Policy.

Gregory Twachtman, MDEdge News
Dr. Scott Gottlieb, FDA Commissioner
“If you look within the categories of the TNF inhibitors and a lot of monoclonal antibodies, there wasn’t product competition in those categories,” Dr. Gottlieb said. “These were very novel drugs. They hadn’t been on the market, in many cases, for many years.”

The situation is different now. “Not only are these product categories multisource and in some cases quite crowded, but there is also a lot of therapeutic equivalence,” Dr. Gottlieb said. “There are a lot of other types of drugs [physicians] might use to try to address the same clinical condition.”

He specifically noted that autoimmune and inflammatory conditions have a wealth of products that address them in different ways, with the opportunity for therapeutic substitutions. He also mentioned drugs that are delivered through durable medical equipment as another area open to being moved into a more price-competitive space.

“I don’t think anyone envisioned how competitive these categories would become,” he said.

Switching drug coverage from Medicare Part B to Part D is just one of more than 50 proposals contained in a broad package introduced by the White House on May 11 to address the rising prices of prescription drugs.

“In situations where you have a lot of therapeutic variety ... you have [insurance] plans negotiating pricing using formularies and using things like step therapy, putting drugs on preferred tiers relative to the price concessions they are able to extract,” Dr. Gottlieb said.
 

 


In contrast, the current Part B [program], “looks like the small molecule world with respect to how much competition we see within some of these categories, but you don’t have the same structure. Times have changed, and I think that is why you see Secretary [Alex Azar of the Health & Human Services department] rethinking how we bid out those Part B drugs into a competitive scheme.”

Dr. Gottlieb suggested that more competition could come from the moving coverage to Medicare Part D or possibly through a reinvigorated competitive acquisition program for Part B.
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– Trump administration officials are eying office-administered drugs in crowded therapeutic categories for the switch from Medicare Part B to Medicare Part D as an early way to reduce spending on prescription drugs.

When the current Part B drug reimbursement scheme – average sales price plus an additional 6% to cover administration and storage – was developed, there was little competition in most of the covered therapeutic categories, Scott Gottlieb, MD, Food and Drug Administration commissioner, said May 15 at an event hosted by the Alliance for Health Policy.

Gregory Twachtman, MDEdge News
Dr. Scott Gottlieb, FDA Commissioner
“If you look within the categories of the TNF inhibitors and a lot of monoclonal antibodies, there wasn’t product competition in those categories,” Dr. Gottlieb said. “These were very novel drugs. They hadn’t been on the market, in many cases, for many years.”

The situation is different now. “Not only are these product categories multisource and in some cases quite crowded, but there is also a lot of therapeutic equivalence,” Dr. Gottlieb said. “There are a lot of other types of drugs [physicians] might use to try to address the same clinical condition.”

He specifically noted that autoimmune and inflammatory conditions have a wealth of products that address them in different ways, with the opportunity for therapeutic substitutions. He also mentioned drugs that are delivered through durable medical equipment as another area open to being moved into a more price-competitive space.

“I don’t think anyone envisioned how competitive these categories would become,” he said.

Switching drug coverage from Medicare Part B to Part D is just one of more than 50 proposals contained in a broad package introduced by the White House on May 11 to address the rising prices of prescription drugs.

“In situations where you have a lot of therapeutic variety ... you have [insurance] plans negotiating pricing using formularies and using things like step therapy, putting drugs on preferred tiers relative to the price concessions they are able to extract,” Dr. Gottlieb said.
 

 


In contrast, the current Part B [program], “looks like the small molecule world with respect to how much competition we see within some of these categories, but you don’t have the same structure. Times have changed, and I think that is why you see Secretary [Alex Azar of the Health & Human Services department] rethinking how we bid out those Part B drugs into a competitive scheme.”

Dr. Gottlieb suggested that more competition could come from the moving coverage to Medicare Part D or possibly through a reinvigorated competitive acquisition program for Part B.

 

– Trump administration officials are eying office-administered drugs in crowded therapeutic categories for the switch from Medicare Part B to Medicare Part D as an early way to reduce spending on prescription drugs.

When the current Part B drug reimbursement scheme – average sales price plus an additional 6% to cover administration and storage – was developed, there was little competition in most of the covered therapeutic categories, Scott Gottlieb, MD, Food and Drug Administration commissioner, said May 15 at an event hosted by the Alliance for Health Policy.

Gregory Twachtman, MDEdge News
Dr. Scott Gottlieb, FDA Commissioner
“If you look within the categories of the TNF inhibitors and a lot of monoclonal antibodies, there wasn’t product competition in those categories,” Dr. Gottlieb said. “These were very novel drugs. They hadn’t been on the market, in many cases, for many years.”

The situation is different now. “Not only are these product categories multisource and in some cases quite crowded, but there is also a lot of therapeutic equivalence,” Dr. Gottlieb said. “There are a lot of other types of drugs [physicians] might use to try to address the same clinical condition.”

He specifically noted that autoimmune and inflammatory conditions have a wealth of products that address them in different ways, with the opportunity for therapeutic substitutions. He also mentioned drugs that are delivered through durable medical equipment as another area open to being moved into a more price-competitive space.

“I don’t think anyone envisioned how competitive these categories would become,” he said.

Switching drug coverage from Medicare Part B to Part D is just one of more than 50 proposals contained in a broad package introduced by the White House on May 11 to address the rising prices of prescription drugs.

“In situations where you have a lot of therapeutic variety ... you have [insurance] plans negotiating pricing using formularies and using things like step therapy, putting drugs on preferred tiers relative to the price concessions they are able to extract,” Dr. Gottlieb said.
 

 


In contrast, the current Part B [program], “looks like the small molecule world with respect to how much competition we see within some of these categories, but you don’t have the same structure. Times have changed, and I think that is why you see Secretary [Alex Azar of the Health & Human Services department] rethinking how we bid out those Part B drugs into a competitive scheme.”

Dr. Gottlieb suggested that more competition could come from the moving coverage to Medicare Part D or possibly through a reinvigorated competitive acquisition program for Part B.
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FDA approves epoetin alfa biosimilar to treat anemia

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The Food and Drug Administration has approved epoetin alfa-epbx (Retacrit) as the first biosimilar to epoetin alfa (Epogen/Procrit), a treatment for anemia brought on by chronic kidney disease, chemotherapy, or use of zidovudine.

The biosimilar product is also approved to reduce the chance of red blood cell transfusion before and after surgery.

FDA’s approval, issued on May 15, is based on review of structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other safety and effectiveness information showing that the epoetin alfa-epbx is biosimilar to the reference product epoetin alfa. By approving epoetin alfa-epbx as a biosimilar, the FDA is saying that there are “no clinically meaningful differences in safety, purity, and potency” from epoetin alfa.

The agency’s approval comes almost a year after the Oncologic Drugs Advisory Committee voted 14-1 to support approval of the biosimilar. The FDA had rejected the application in 2017, citing manufacturing issues at a facility in Kansas, before ultimately approving the product in 2018.

The biosimilar product must be dispensed with a patient Medication Guide with information about uses and risks and carries a boxed warning about an increased risk of death, heart problems, stroke, and tumor growth or recurrence.

The biosimilar product is marketed by Hospira Inc., a Pfizer company.

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The Food and Drug Administration has approved epoetin alfa-epbx (Retacrit) as the first biosimilar to epoetin alfa (Epogen/Procrit), a treatment for anemia brought on by chronic kidney disease, chemotherapy, or use of zidovudine.

The biosimilar product is also approved to reduce the chance of red blood cell transfusion before and after surgery.

FDA’s approval, issued on May 15, is based on review of structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other safety and effectiveness information showing that the epoetin alfa-epbx is biosimilar to the reference product epoetin alfa. By approving epoetin alfa-epbx as a biosimilar, the FDA is saying that there are “no clinically meaningful differences in safety, purity, and potency” from epoetin alfa.

The agency’s approval comes almost a year after the Oncologic Drugs Advisory Committee voted 14-1 to support approval of the biosimilar. The FDA had rejected the application in 2017, citing manufacturing issues at a facility in Kansas, before ultimately approving the product in 2018.

The biosimilar product must be dispensed with a patient Medication Guide with information about uses and risks and carries a boxed warning about an increased risk of death, heart problems, stroke, and tumor growth or recurrence.

The biosimilar product is marketed by Hospira Inc., a Pfizer company.

 

The Food and Drug Administration has approved epoetin alfa-epbx (Retacrit) as the first biosimilar to epoetin alfa (Epogen/Procrit), a treatment for anemia brought on by chronic kidney disease, chemotherapy, or use of zidovudine.

The biosimilar product is also approved to reduce the chance of red blood cell transfusion before and after surgery.

FDA’s approval, issued on May 15, is based on review of structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other safety and effectiveness information showing that the epoetin alfa-epbx is biosimilar to the reference product epoetin alfa. By approving epoetin alfa-epbx as a biosimilar, the FDA is saying that there are “no clinically meaningful differences in safety, purity, and potency” from epoetin alfa.

The agency’s approval comes almost a year after the Oncologic Drugs Advisory Committee voted 14-1 to support approval of the biosimilar. The FDA had rejected the application in 2017, citing manufacturing issues at a facility in Kansas, before ultimately approving the product in 2018.

The biosimilar product must be dispensed with a patient Medication Guide with information about uses and risks and carries a boxed warning about an increased risk of death, heart problems, stroke, and tumor growth or recurrence.

The biosimilar product is marketed by Hospira Inc., a Pfizer company.

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FDA seeks comments on pediatric HIV product development

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The U.S. Food and Drug Administration announced a draft guidance for industry entitled “Pediatric HIV Infection: Drug Development for Treatment.” This draft guidance provides general recommendations for developing products to treat HIV infections in pediatric patients (from birth to younger than 17 years of age).

This guidance document is being distributed for comment purposes only, according to the FDA. Comments and suggestions should be submitted by July 13. Electronic comments should be submitted to www.regulations.gov, while written comments should be submitted to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number (Docket No. FDA-2018-D-1638) as described in the May 14 Federal Register announcement.

According to the FDA announcement, the draft includes recommendations on when sponsors should initiate pediatric formulation development and when to begin pediatric studies to evaluate antiretroviral drug products for the treatment of HIV infection.

SOURCE: Federal Register May 14. Pediatric HIV Infection: Drug Development for Treatment; Draft Guidance for Industry; Availability.

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The U.S. Food and Drug Administration announced a draft guidance for industry entitled “Pediatric HIV Infection: Drug Development for Treatment.” This draft guidance provides general recommendations for developing products to treat HIV infections in pediatric patients (from birth to younger than 17 years of age).

This guidance document is being distributed for comment purposes only, according to the FDA. Comments and suggestions should be submitted by July 13. Electronic comments should be submitted to www.regulations.gov, while written comments should be submitted to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number (Docket No. FDA-2018-D-1638) as described in the May 14 Federal Register announcement.

According to the FDA announcement, the draft includes recommendations on when sponsors should initiate pediatric formulation development and when to begin pediatric studies to evaluate antiretroviral drug products for the treatment of HIV infection.

SOURCE: Federal Register May 14. Pediatric HIV Infection: Drug Development for Treatment; Draft Guidance for Industry; Availability.

 

The U.S. Food and Drug Administration announced a draft guidance for industry entitled “Pediatric HIV Infection: Drug Development for Treatment.” This draft guidance provides general recommendations for developing products to treat HIV infections in pediatric patients (from birth to younger than 17 years of age).

This guidance document is being distributed for comment purposes only, according to the FDA. Comments and suggestions should be submitted by July 13. Electronic comments should be submitted to www.regulations.gov, while written comments should be submitted to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number (Docket No. FDA-2018-D-1638) as described in the May 14 Federal Register announcement.

According to the FDA announcement, the draft includes recommendations on when sponsors should initiate pediatric formulation development and when to begin pediatric studies to evaluate antiretroviral drug products for the treatment of HIV infection.

SOURCE: Federal Register May 14. Pediatric HIV Infection: Drug Development for Treatment; Draft Guidance for Industry; Availability.

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