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FDA Panel Backs Somatostatin Analogue for Cushing's
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.
At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.
The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.
Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.
The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).
At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.
The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.
The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.
While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.
She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.
If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.
If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.
If the drug is approved, Novartis plans to market pasireotide as Signifor. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but not at this meeting.
AT A MEETING OF THE FDA’S ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE
Game Changer? First JAK Inhibitor Approved for Rheumatoid Arthritis
The Janus kinase inhibitor tofacitinib, a drug that has the promise to change the treatment experience for some patients with rheumatoid arthritis, has been approved to treat adults with moderately to severely active disease who have not responded adequately to or cannot tolerate methotrexate, the Food and Drug Administration announced on Nov. 6.
Tofacitinib is a small-molecule inhibitor of the Janus kinase (JAK) pathway of inflammatory cytokines that play a role in the pathogenesis of RA, and is the first drug in this class of oral drugs to be approved for RA.
It has been approved with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the serious risks associated with treatment, and a requirement that the manufacturer, Pfizer, conduct a postmarketing study, according to the FDA’s statement announcing the approval.
Approval was based on the results of seven studies, which found that patients with moderately to severely active RA had improvements in clinical response and physical functioning, when compared with those on placebo. Tofacitinib was associated with an increased risk of serious infections, including opportunistic infections; tuberculosis; cancers; and lymphoma, which are described in the boxed warning in the drug’s label, the FDA said.
Treatment was also associated with increases in cholesterol and liver enzymes, and decreased blood counts. The REMS consists of a Medication Guide that includes information for patients about the drug’s safety and a communication plan that will educate health care providers about the serious risks associated with the treatment.
The postmarketing study will compare two doses of tofacitinib with another approved treatment for RA.
At a meeting in May, the FDA’s Arthritis Advisory Committee voted 8 to 2 to recommend approval of tofacitinib for patients with RA, although panel members had lingering safety concerns.
Pfizer is marketing the drug as Xeljanz. Another JAK inhibitor, ruxolitinib (Jakafi), was approved to treat myelofibrosis in 2011.
The Janus kinase inhibitor tofacitinib, a drug that has the promise to change the treatment experience for some patients with rheumatoid arthritis, has been approved to treat adults with moderately to severely active disease who have not responded adequately to or cannot tolerate methotrexate, the Food and Drug Administration announced on Nov. 6.
Tofacitinib is a small-molecule inhibitor of the Janus kinase (JAK) pathway of inflammatory cytokines that play a role in the pathogenesis of RA, and is the first drug in this class of oral drugs to be approved for RA.
It has been approved with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the serious risks associated with treatment, and a requirement that the manufacturer, Pfizer, conduct a postmarketing study, according to the FDA’s statement announcing the approval.
Approval was based on the results of seven studies, which found that patients with moderately to severely active RA had improvements in clinical response and physical functioning, when compared with those on placebo. Tofacitinib was associated with an increased risk of serious infections, including opportunistic infections; tuberculosis; cancers; and lymphoma, which are described in the boxed warning in the drug’s label, the FDA said.
Treatment was also associated with increases in cholesterol and liver enzymes, and decreased blood counts. The REMS consists of a Medication Guide that includes information for patients about the drug’s safety and a communication plan that will educate health care providers about the serious risks associated with the treatment.
The postmarketing study will compare two doses of tofacitinib with another approved treatment for RA.
At a meeting in May, the FDA’s Arthritis Advisory Committee voted 8 to 2 to recommend approval of tofacitinib for patients with RA, although panel members had lingering safety concerns.
Pfizer is marketing the drug as Xeljanz. Another JAK inhibitor, ruxolitinib (Jakafi), was approved to treat myelofibrosis in 2011.
The Janus kinase inhibitor tofacitinib, a drug that has the promise to change the treatment experience for some patients with rheumatoid arthritis, has been approved to treat adults with moderately to severely active disease who have not responded adequately to or cannot tolerate methotrexate, the Food and Drug Administration announced on Nov. 6.
Tofacitinib is a small-molecule inhibitor of the Janus kinase (JAK) pathway of inflammatory cytokines that play a role in the pathogenesis of RA, and is the first drug in this class of oral drugs to be approved for RA.
It has been approved with a Risk Evaluation and Mitigation Strategy (REMS) that addresses the serious risks associated with treatment, and a requirement that the manufacturer, Pfizer, conduct a postmarketing study, according to the FDA’s statement announcing the approval.
Approval was based on the results of seven studies, which found that patients with moderately to severely active RA had improvements in clinical response and physical functioning, when compared with those on placebo. Tofacitinib was associated with an increased risk of serious infections, including opportunistic infections; tuberculosis; cancers; and lymphoma, which are described in the boxed warning in the drug’s label, the FDA said.
Treatment was also associated with increases in cholesterol and liver enzymes, and decreased blood counts. The REMS consists of a Medication Guide that includes information for patients about the drug’s safety and a communication plan that will educate health care providers about the serious risks associated with the treatment.
The postmarketing study will compare two doses of tofacitinib with another approved treatment for RA.
At a meeting in May, the FDA’s Arthritis Advisory Committee voted 8 to 2 to recommend approval of tofacitinib for patients with RA, although panel members had lingering safety concerns.
Pfizer is marketing the drug as Xeljanz. Another JAK inhibitor, ruxolitinib (Jakafi), was approved to treat myelofibrosis in 2011.
Rivaroxaban Now Approved for DVT, PE Treatment
The oral anticoagulant rivaroxaban has been approved for the treatment of deep vein thrombosis or pulmonary embolism and for reducing the recurrence of DVT and PE after initial treatment, the Food and Drug Administration announced Nov. 5.
The expanded approval was based on the results of three studies of almost 9,500 patients with a DVT or PE which found that treatment with rivaroxaban was as effective as the combination of the low molecular weight heparin enoxaparin and a vitamin K antagonist in treating DVT and PE. In one of the studies, continued treatment with rivaroxaban reduced the risk of recurrent DVT and PE, according to an FDA statement.
Rivaroxaban, a factor Xa inhibitor, was initially approved in July 2011 for prophylaxis of DVT or PE in patients undergoing hip replacement or knee-replacement surgery, at a dose of 10 mg orally once a day. Marketed as Xarelto by Janssen Pharmaceuticals, it received in November 2011 a second indication for reducing the risk of stroke in patients with nonvalvular atrial fibrillation.
The FDA is currently reviewing the company’s applications to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome and for reducing the risk of secondary cardiovascular events in patients with ACS, according to Janssen.
The oral anticoagulant rivaroxaban has been approved for the treatment of deep vein thrombosis or pulmonary embolism and for reducing the recurrence of DVT and PE after initial treatment, the Food and Drug Administration announced Nov. 5.
The expanded approval was based on the results of three studies of almost 9,500 patients with a DVT or PE which found that treatment with rivaroxaban was as effective as the combination of the low molecular weight heparin enoxaparin and a vitamin K antagonist in treating DVT and PE. In one of the studies, continued treatment with rivaroxaban reduced the risk of recurrent DVT and PE, according to an FDA statement.
Rivaroxaban, a factor Xa inhibitor, was initially approved in July 2011 for prophylaxis of DVT or PE in patients undergoing hip replacement or knee-replacement surgery, at a dose of 10 mg orally once a day. Marketed as Xarelto by Janssen Pharmaceuticals, it received in November 2011 a second indication for reducing the risk of stroke in patients with nonvalvular atrial fibrillation.
The FDA is currently reviewing the company’s applications to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome and for reducing the risk of secondary cardiovascular events in patients with ACS, according to Janssen.
The oral anticoagulant rivaroxaban has been approved for the treatment of deep vein thrombosis or pulmonary embolism and for reducing the recurrence of DVT and PE after initial treatment, the Food and Drug Administration announced Nov. 5.
The expanded approval was based on the results of three studies of almost 9,500 patients with a DVT or PE which found that treatment with rivaroxaban was as effective as the combination of the low molecular weight heparin enoxaparin and a vitamin K antagonist in treating DVT and PE. In one of the studies, continued treatment with rivaroxaban reduced the risk of recurrent DVT and PE, according to an FDA statement.
Rivaroxaban, a factor Xa inhibitor, was initially approved in July 2011 for prophylaxis of DVT or PE in patients undergoing hip replacement or knee-replacement surgery, at a dose of 10 mg orally once a day. Marketed as Xarelto by Janssen Pharmaceuticals, it received in November 2011 a second indication for reducing the risk of stroke in patients with nonvalvular atrial fibrillation.
The FDA is currently reviewing the company’s applications to approve rivaroxaban for reducing the risk of stent thrombosis in patients with acute coronary syndrome and for reducing the risk of secondary cardiovascular events in patients with ACS, according to Janssen.
FDA Reports Dabigatran Bleeds Don't Exceed Warfarin Bleeds
The Food and Drug Administration is satisfied that dabigatran’s bleeding risk is no greater than that of warfarin and will not change the drug’s label.
The rates of gastrointestinal and intracranial bleeding among patients who have been prescribed the anticoagulant dabigatran "do not appear to be higher" than the rates among patients who have been prescribed warfarin, according to an analysis of insurance claims and administrative data conducted by the agency.
The results of this analysis, conducted in response to postmarketing reports of bleeding among people treated with dabigatran, are "consistent with observations" in the RE-LY trial, the study of 18,000 patients that was the basis of the approval of the anticoagulant for reducing the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation (AF), the FDA said in the MedWatch safety alert, released on Nov. 2. In the RE-LY study, the rates of serious bleeding was similar among those treated with dabigatran and those with warfarin (N. Engl. J. Med. 2009;361:1139-51).
The agency is evaluating different sources of data in its review of this safety issue, which is ongoing. Dabigatran, an orally administered direct thrombin inhibitor, was approved in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and is marketed as Pradaxa by Boehringer Ingelheim.
The FDA’s analysis found that the rates of bleeding were actually higher among those on warfarin, although the statement does not point this out. The FDA analyzed data from a database of nearly 100 million patients and determined that the combined incidence of intracranial and gastrointestinal hemorrhages per 100,000 days at risk was 1.8-2.6 times higher for new users of warfarin than for new users of dabigatran. When they analyzed the two events separately, they found that the incidence rate of gastrointestinal hemorrhage events per 100,000 days at risk was 1.6-2.2 times higher for new users of warfarin than for new users of dabigatran. The incidence rate of intracranial hemorrhage events per 100,000 days at risk was 2.1-3.0 times higher for new users of warfarin than for those on dabigatran.
These estimates do not account for age, medical conditions, or other differences between the patients on warfarin and dabigatran that could affect bleeding outcomes, according to the FDA. In addition, although a "large" number of reports of bleeding in treated patients were submitted to the FDA’s Adverse Events Reporting System (FAERS) after dabigatran was approved, the agency believes that a "simple comparison" between the number of postmarketing bleeding events associated with dabigatran and warfarin is "misleading" because it is likely that bleeding events associated with warfarin are under reported, since the drug has been available for so long and bleeding is a well-recognized consequence of warfarin treatment.
At this time, the FDA is not changing any recommendations on the dabigatran label and is continuing to monitor postmarketing reports of bleeding in patients on dabigatran "for evidence of inappropriate dosing, use of interacting drugs, and other clinical factors that might lead to a bleeding event," according to the statement. The recommendations in the statement include advice to clinicians that they evaluate a patient’s renal function before prescribing dabigatran, which is eliminated by the kidneys, and the dosing regimens for patients with severe renal impairment and those with a creatinine clearance above 30 mL/min.
Click here for the Medwatch safety alert. Adverse events associated with dabigatran should be reported here or to the FDA at 800-332-0178.
The Food and Drug Administration is satisfied that dabigatran’s bleeding risk is no greater than that of warfarin and will not change the drug’s label.
The rates of gastrointestinal and intracranial bleeding among patients who have been prescribed the anticoagulant dabigatran "do not appear to be higher" than the rates among patients who have been prescribed warfarin, according to an analysis of insurance claims and administrative data conducted by the agency.
The results of this analysis, conducted in response to postmarketing reports of bleeding among people treated with dabigatran, are "consistent with observations" in the RE-LY trial, the study of 18,000 patients that was the basis of the approval of the anticoagulant for reducing the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation (AF), the FDA said in the MedWatch safety alert, released on Nov. 2. In the RE-LY study, the rates of serious bleeding was similar among those treated with dabigatran and those with warfarin (N. Engl. J. Med. 2009;361:1139-51).
The agency is evaluating different sources of data in its review of this safety issue, which is ongoing. Dabigatran, an orally administered direct thrombin inhibitor, was approved in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and is marketed as Pradaxa by Boehringer Ingelheim.
The FDA’s analysis found that the rates of bleeding were actually higher among those on warfarin, although the statement does not point this out. The FDA analyzed data from a database of nearly 100 million patients and determined that the combined incidence of intracranial and gastrointestinal hemorrhages per 100,000 days at risk was 1.8-2.6 times higher for new users of warfarin than for new users of dabigatran. When they analyzed the two events separately, they found that the incidence rate of gastrointestinal hemorrhage events per 100,000 days at risk was 1.6-2.2 times higher for new users of warfarin than for new users of dabigatran. The incidence rate of intracranial hemorrhage events per 100,000 days at risk was 2.1-3.0 times higher for new users of warfarin than for those on dabigatran.
These estimates do not account for age, medical conditions, or other differences between the patients on warfarin and dabigatran that could affect bleeding outcomes, according to the FDA. In addition, although a "large" number of reports of bleeding in treated patients were submitted to the FDA’s Adverse Events Reporting System (FAERS) after dabigatran was approved, the agency believes that a "simple comparison" between the number of postmarketing bleeding events associated with dabigatran and warfarin is "misleading" because it is likely that bleeding events associated with warfarin are under reported, since the drug has been available for so long and bleeding is a well-recognized consequence of warfarin treatment.
At this time, the FDA is not changing any recommendations on the dabigatran label and is continuing to monitor postmarketing reports of bleeding in patients on dabigatran "for evidence of inappropriate dosing, use of interacting drugs, and other clinical factors that might lead to a bleeding event," according to the statement. The recommendations in the statement include advice to clinicians that they evaluate a patient’s renal function before prescribing dabigatran, which is eliminated by the kidneys, and the dosing regimens for patients with severe renal impairment and those with a creatinine clearance above 30 mL/min.
Click here for the Medwatch safety alert. Adverse events associated with dabigatran should be reported here or to the FDA at 800-332-0178.
The Food and Drug Administration is satisfied that dabigatran’s bleeding risk is no greater than that of warfarin and will not change the drug’s label.
The rates of gastrointestinal and intracranial bleeding among patients who have been prescribed the anticoagulant dabigatran "do not appear to be higher" than the rates among patients who have been prescribed warfarin, according to an analysis of insurance claims and administrative data conducted by the agency.
The results of this analysis, conducted in response to postmarketing reports of bleeding among people treated with dabigatran, are "consistent with observations" in the RE-LY trial, the study of 18,000 patients that was the basis of the approval of the anticoagulant for reducing the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation (AF), the FDA said in the MedWatch safety alert, released on Nov. 2. In the RE-LY study, the rates of serious bleeding was similar among those treated with dabigatran and those with warfarin (N. Engl. J. Med. 2009;361:1139-51).
The agency is evaluating different sources of data in its review of this safety issue, which is ongoing. Dabigatran, an orally administered direct thrombin inhibitor, was approved in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and is marketed as Pradaxa by Boehringer Ingelheim.
The FDA’s analysis found that the rates of bleeding were actually higher among those on warfarin, although the statement does not point this out. The FDA analyzed data from a database of nearly 100 million patients and determined that the combined incidence of intracranial and gastrointestinal hemorrhages per 100,000 days at risk was 1.8-2.6 times higher for new users of warfarin than for new users of dabigatran. When they analyzed the two events separately, they found that the incidence rate of gastrointestinal hemorrhage events per 100,000 days at risk was 1.6-2.2 times higher for new users of warfarin than for new users of dabigatran. The incidence rate of intracranial hemorrhage events per 100,000 days at risk was 2.1-3.0 times higher for new users of warfarin than for those on dabigatran.
These estimates do not account for age, medical conditions, or other differences between the patients on warfarin and dabigatran that could affect bleeding outcomes, according to the FDA. In addition, although a "large" number of reports of bleeding in treated patients were submitted to the FDA’s Adverse Events Reporting System (FAERS) after dabigatran was approved, the agency believes that a "simple comparison" between the number of postmarketing bleeding events associated with dabigatran and warfarin is "misleading" because it is likely that bleeding events associated with warfarin are under reported, since the drug has been available for so long and bleeding is a well-recognized consequence of warfarin treatment.
At this time, the FDA is not changing any recommendations on the dabigatran label and is continuing to monitor postmarketing reports of bleeding in patients on dabigatran "for evidence of inappropriate dosing, use of interacting drugs, and other clinical factors that might lead to a bleeding event," according to the statement. The recommendations in the statement include advice to clinicians that they evaluate a patient’s renal function before prescribing dabigatran, which is eliminated by the kidneys, and the dosing regimens for patients with severe renal impairment and those with a creatinine clearance above 30 mL/min.
Click here for the Medwatch safety alert. Adverse events associated with dabigatran should be reported here or to the FDA at 800-332-0178.
FDA Approves Omacetaxine for Chronic Myeloid Leukemia
Omacetaxine mepesuccinate has been approved for treating adults with chronic myeloid leukemia that has progressed after treatment with at least two tyrosine kinase inhibitors, the Food and Drug Administration announced on Oct. 26.
The new agent will be marketed as Synribo by Teva Pharmaceuticals, an Israel-based company with a U.S. presence in Frazer, Pa.
It is the second drug approved this fall for patients who are not being helped by standard treatments for chronic myeloid leukemia (CML). On Sept. 4, the FDA approved bosutinib (Bosulif) to treat patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies
Synribo is the latest name for omacetaxine, a synthetic formulation of homoharringtonine, a drug used in China, where it was first extracted from an evergreen tree (Cephalotaxus). It had been studied for acute and chronic myeloid leukemias before imatinib (Gleevec) emerged as a standard therapy in CML, but interest flagged after imatinib was approved.
More recently, another manufacturer sought approval of omacetaxine under the brand name Omapro for CML patients after failure of prior therapy with imatinib in patients with the Bcr-Abl T3151 mutation, which is highly resistant to current treatments.
In 2010, however, the FDA’s Oncologic Drugs Advisory Committee agreed with the FDA that a validated test for the T3151 mutation was needed before the drug could be indicated for patients with the mutation. The FDA statement announcing approval of omacetaxine makes no mention of T3151.
Omacetaxine was designated as an orphan drug and was approved under the FDA’s accelerated approval program, "which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients," the statement said.
Dr. Jorge Cortes discussed omacetaxine at the 2009 meeting of the American Society of Hematology
The approved indication is in patients with chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval is based on response rate, according to the drug’s prescribing information, which states that "there are no trials verifying an improvement in disease-related symptoms or increased survival" with omacetaxine.
A protein synthesis inhibitor omacetaxine is administered at a dose of 1.25 mg/m2 subcutaneously twice daily for 14 days over a 28-day-cycle for the induction phase, after which it is administered twice daily for 7 consecutive days over a 28-day cycle, for a maintenance phase.
Approval was based on the combined results of two studies of patients with CML who had received at least two approved TKIs and had documented evidence of resistance or intolerance to dasatinib (Sprycel) and/or nilotinib (Tasigna) at a minimum, according to the statement. Teva said many of the patients had also been treated with imatinib and other treatments, including hydroxyurea, interferon, and cytarabine.
Among 76 patients with chronic phase CML, 14 (18.4%) achieved a major cytogenic response, the primary efficacy end point, in a mean of 3.5 months; the median duration of the response was 12.5 months.
Among the 35 patients with accelerated phase CML, 5 (14.3%) achieved a major hematologic response (a complete hematologic response or no evidence of leukemia, lasting for a median of 4.7 months. The mean time to the onset of the response in the 5 patients was 2.3 months, according to the prescribing information. None of the patients had a major cytogenic response.
In studies, the most common grade 1-4 adverse reactions (affecting 20% or more of treated patients) included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness and fatigue, injection site reactions, pyrexia, infection, and lymphopenia, according to the FDA.
Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia and diarrhea, were the most common grade 3/4 adverse reactions, affecting 5% or more of treated patients.
"Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.
The FDA cited the National Institutes of Health estimate that about 5,430 people will be diagnosed with CML this year.
The drug’s prescribing information is available here.
Omacetaxine mepesuccinate has been approved for treating adults with chronic myeloid leukemia that has progressed after treatment with at least two tyrosine kinase inhibitors, the Food and Drug Administration announced on Oct. 26.
The new agent will be marketed as Synribo by Teva Pharmaceuticals, an Israel-based company with a U.S. presence in Frazer, Pa.
It is the second drug approved this fall for patients who are not being helped by standard treatments for chronic myeloid leukemia (CML). On Sept. 4, the FDA approved bosutinib (Bosulif) to treat patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies
Synribo is the latest name for omacetaxine, a synthetic formulation of homoharringtonine, a drug used in China, where it was first extracted from an evergreen tree (Cephalotaxus). It had been studied for acute and chronic myeloid leukemias before imatinib (Gleevec) emerged as a standard therapy in CML, but interest flagged after imatinib was approved.
More recently, another manufacturer sought approval of omacetaxine under the brand name Omapro for CML patients after failure of prior therapy with imatinib in patients with the Bcr-Abl T3151 mutation, which is highly resistant to current treatments.
In 2010, however, the FDA’s Oncologic Drugs Advisory Committee agreed with the FDA that a validated test for the T3151 mutation was needed before the drug could be indicated for patients with the mutation. The FDA statement announcing approval of omacetaxine makes no mention of T3151.
Omacetaxine was designated as an orphan drug and was approved under the FDA’s accelerated approval program, "which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients," the statement said.
Dr. Jorge Cortes discussed omacetaxine at the 2009 meeting of the American Society of Hematology
The approved indication is in patients with chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval is based on response rate, according to the drug’s prescribing information, which states that "there are no trials verifying an improvement in disease-related symptoms or increased survival" with omacetaxine.
A protein synthesis inhibitor omacetaxine is administered at a dose of 1.25 mg/m2 subcutaneously twice daily for 14 days over a 28-day-cycle for the induction phase, after which it is administered twice daily for 7 consecutive days over a 28-day cycle, for a maintenance phase.
Approval was based on the combined results of two studies of patients with CML who had received at least two approved TKIs and had documented evidence of resistance or intolerance to dasatinib (Sprycel) and/or nilotinib (Tasigna) at a minimum, according to the statement. Teva said many of the patients had also been treated with imatinib and other treatments, including hydroxyurea, interferon, and cytarabine.
Among 76 patients with chronic phase CML, 14 (18.4%) achieved a major cytogenic response, the primary efficacy end point, in a mean of 3.5 months; the median duration of the response was 12.5 months.
Among the 35 patients with accelerated phase CML, 5 (14.3%) achieved a major hematologic response (a complete hematologic response or no evidence of leukemia, lasting for a median of 4.7 months. The mean time to the onset of the response in the 5 patients was 2.3 months, according to the prescribing information. None of the patients had a major cytogenic response.
In studies, the most common grade 1-4 adverse reactions (affecting 20% or more of treated patients) included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness and fatigue, injection site reactions, pyrexia, infection, and lymphopenia, according to the FDA.
Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia and diarrhea, were the most common grade 3/4 adverse reactions, affecting 5% or more of treated patients.
"Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.
The FDA cited the National Institutes of Health estimate that about 5,430 people will be diagnosed with CML this year.
The drug’s prescribing information is available here.
Omacetaxine mepesuccinate has been approved for treating adults with chronic myeloid leukemia that has progressed after treatment with at least two tyrosine kinase inhibitors, the Food and Drug Administration announced on Oct. 26.
The new agent will be marketed as Synribo by Teva Pharmaceuticals, an Israel-based company with a U.S. presence in Frazer, Pa.
It is the second drug approved this fall for patients who are not being helped by standard treatments for chronic myeloid leukemia (CML). On Sept. 4, the FDA approved bosutinib (Bosulif) to treat patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies
Synribo is the latest name for omacetaxine, a synthetic formulation of homoharringtonine, a drug used in China, where it was first extracted from an evergreen tree (Cephalotaxus). It had been studied for acute and chronic myeloid leukemias before imatinib (Gleevec) emerged as a standard therapy in CML, but interest flagged after imatinib was approved.
More recently, another manufacturer sought approval of omacetaxine under the brand name Omapro for CML patients after failure of prior therapy with imatinib in patients with the Bcr-Abl T3151 mutation, which is highly resistant to current treatments.
In 2010, however, the FDA’s Oncologic Drugs Advisory Committee agreed with the FDA that a validated test for the T3151 mutation was needed before the drug could be indicated for patients with the mutation. The FDA statement announcing approval of omacetaxine makes no mention of T3151.
Omacetaxine was designated as an orphan drug and was approved under the FDA’s accelerated approval program, "which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate end point that is reasonably likely to predict a clinical benefit to patients," the statement said.
Dr. Jorge Cortes discussed omacetaxine at the 2009 meeting of the American Society of Hematology
The approved indication is in patients with chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval is based on response rate, according to the drug’s prescribing information, which states that "there are no trials verifying an improvement in disease-related symptoms or increased survival" with omacetaxine.
A protein synthesis inhibitor omacetaxine is administered at a dose of 1.25 mg/m2 subcutaneously twice daily for 14 days over a 28-day-cycle for the induction phase, after which it is administered twice daily for 7 consecutive days over a 28-day cycle, for a maintenance phase.
Approval was based on the combined results of two studies of patients with CML who had received at least two approved TKIs and had documented evidence of resistance or intolerance to dasatinib (Sprycel) and/or nilotinib (Tasigna) at a minimum, according to the statement. Teva said many of the patients had also been treated with imatinib and other treatments, including hydroxyurea, interferon, and cytarabine.
Among 76 patients with chronic phase CML, 14 (18.4%) achieved a major cytogenic response, the primary efficacy end point, in a mean of 3.5 months; the median duration of the response was 12.5 months.
Among the 35 patients with accelerated phase CML, 5 (14.3%) achieved a major hematologic response (a complete hematologic response or no evidence of leukemia, lasting for a median of 4.7 months. The mean time to the onset of the response in the 5 patients was 2.3 months, according to the prescribing information. None of the patients had a major cytogenic response.
In studies, the most common grade 1-4 adverse reactions (affecting 20% or more of treated patients) included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness and fatigue, injection site reactions, pyrexia, infection, and lymphopenia, according to the FDA.
Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia and diarrhea, were the most common grade 3/4 adverse reactions, affecting 5% or more of treated patients.
"Today’s approval provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML," said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.
The FDA cited the National Institutes of Health estimate that about 5,430 people will be diagnosed with CML this year.
The drug’s prescribing information is available here.
ACOG Encourages Long-Acting Contraceptives for Sexually Active Teens
Health care professionals should encourage sexually active adolescents to consider long-acting reversible contraceptive methods when counseling them about contraceptive choices, according to an American College of Obstetricians and Gynecologists’ committee opinion.
With pregnancy rates less than 1% with perfect and typical use, long-acting reversible contraception (LARC) methods "are the best reversible methods for preventing unintended pregnancy, rapid repeat pregnancy, and abortion in young women," the opinion states. Although the complications of these methods – intrauterine devices and the contraceptive implant – are rare and are similar in adolescents and older women, they are underused in the younger age group, according to ACOG committee opinion No. 539, written by the Committee on Adolescent Health Care’s Long-Acting Reversible Contraception Working Group. The opinion was published in the October issue of Obstetrics & Gynecology (2012;120:983-8).
"Increasing adolescent access to LARC is a clinical and public health opportunity for obstetrician-gynecologists," the opinion says, adding: "With top-tier effectiveness, high rates of satisfaction and continuation, and no need for daily adherence, LARC methods should be first-line recommendations for all women and adolescents," combined with the use of consistent use of condoms to reduce the risk of sexually transmitted infections.
The new opinion is a reaffirmation of the committee opinion issued in 2007. "We’ve had the support to offer these top-tier methods as first line for adolescents for years ... and yet teens are largely using condoms, oral contraceptive pills, and withdrawal – methods with much, much higher failure rates – for contraception, if they are using anything at all," said Dr. Melissa Kottke, a member of the committee and medical director of the Jane Fonda Center for Adolescent Reproductive Health at Emory University in Atlanta.
Health care providers are not routinely offering these methods to teens, possibly because they mistakenly think that teens will not choose these methods, which data indicate is not the case; and they may not have the training or comfort level to provide them, she said in an interview. Clinicians may also believe that LARCs are only appropriate for parous teens and there is a "lingering fear of infection," but there are data that support the safe use of IUDs and the implant in both parous and nulligravid teens, she said, adding that all women, including adolescents, should be counseled on condom use and other approaches to decrease their risk of sexually transmitted infections.
The opinion recommends that adolescents should be routinely screened for sexually transmitted infections when or before an IUD is inserted.
Among the statistics cited in the ACOG opinion is that 42% of all adolescents aged 15-19 years have had intercourse and 82% of adolescent pregnancies are not planned.
The opinion refers to depot medroxyprogesterone acetate (DMPA) injection, the contraceptive patch, vaginal ring, and OCs, as well as condoms and other short-acting methods, as adolescent contraceptive "mainstays," but points out that these methods are associated with lower continuation rates and higher pregnancy rates among adolescents than LARC methods. For example, a study published in 2011 found that 1 year after starting a short-acting contraceptive, continuation rates among women 15-24 were as low as 11% for the contraceptive patch, 16% for DMPA, and about 30% for OCs and the vaginal ring. But in another study, continuation rates for the levonorgestrel intrauterine system and contraceptive implant among women under aged 20 at 1 year were 85%, and copper IUD continuation rates at 1 year among adolescents were 72%.
The use of LARC methods have increased in the United States, from 22.4% in 2002 and 8.5% in 2009. But among teenagers, about 4.5% of adolescents use LARC, mostly IUDs. Use of the contraceptive implant, the etonogestrel single-rod contraceptive approved in 2006, is low in all age groups (less than 1% of the women in the United States using contraception and 0.5% of those aged 15-19 years), according to the opinion.
The committee cites barriers to use of LARCs by adolescents – including cost, lack of access, and concerns among health care providers about their safety in younger patients – and note that training and education programs "should address common misconceptions and review the key evidence and benefits of adolescent LARC use."
In the interview, Dr. Kottke, also with the department of gynecology and obstetrics at Emory, said that she believed that many of these barriers "can be overcome with clinician support, education and training ... and the impact on the health and wellness of our adolescent patients and our communities will be substantial."
She disclosed that she has been an Implanon trainer in the past. (Nexplanon, the etonogestrel implant, is the only contraceptive implant currently on the market; it is a radiopaque version of Implanon, which is no longer available.)
This opinion replaces ACOG committee opinion No. 392, published in December 2007.
This committee opinion is an excellent resource for clinicians taking care of adolescents. It succinctly and comprehensively provides the evidence to show that long acting reversible contraceptives (IUD and implant) should be offered as first line methods to adolescents.
In 2008, twice as many teenagers in the United States became pregnant, compared with Sweden. Birth control pills and condoms are the most popular forms of contraceptives used by teens in the United States, and have higher failure rates compared with LARC methods and high discontinuation rates. While the uptake of LARC nationally has been low in the adolescent population, data from the contraceptive CHOICE study found that with appropriate counseling, and no financial, logistical, provider or other barriers to use, over 40% of females aged 14-17 years chose the implant and over 40% of those aged 18-20 years chose an IUD. The study is a prospective cohort of more than 9,000 women aged 14-45 years who desired contraception, and after enrolling in the study were given comprehensive contraceptive counseling and their choice of contraception free of cost for a specified duration, after enrollment.
Another study of teens attending a family planning clinic showed that more than half had not heard of intrauterine contraceptives and when counseled appropriately by health care providers, they were three times more likely to be interested in using it.
LARC methods have both contraceptive and noncontraceptive benefits. There are few absolute contraindications to using LARC methods, and increasing their use has the potential to reduce unintended pregnancy in the U.S. adolescent population with appropriate counseling and in the absence of financial, logistical, provider or other barriers.
Dr. Rameet H. Singh, assistant professor of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Singh said she had no relevant financial disclosures.
This committee opinion is an excellent resource for clinicians taking care of adolescents. It succinctly and comprehensively provides the evidence to show that long acting reversible contraceptives (IUD and implant) should be offered as first line methods to adolescents.
In 2008, twice as many teenagers in the United States became pregnant, compared with Sweden. Birth control pills and condoms are the most popular forms of contraceptives used by teens in the United States, and have higher failure rates compared with LARC methods and high discontinuation rates. While the uptake of LARC nationally has been low in the adolescent population, data from the contraceptive CHOICE study found that with appropriate counseling, and no financial, logistical, provider or other barriers to use, over 40% of females aged 14-17 years chose the implant and over 40% of those aged 18-20 years chose an IUD. The study is a prospective cohort of more than 9,000 women aged 14-45 years who desired contraception, and after enrolling in the study were given comprehensive contraceptive counseling and their choice of contraception free of cost for a specified duration, after enrollment.
Another study of teens attending a family planning clinic showed that more than half had not heard of intrauterine contraceptives and when counseled appropriately by health care providers, they were three times more likely to be interested in using it.
LARC methods have both contraceptive and noncontraceptive benefits. There are few absolute contraindications to using LARC methods, and increasing their use has the potential to reduce unintended pregnancy in the U.S. adolescent population with appropriate counseling and in the absence of financial, logistical, provider or other barriers.
Dr. Rameet H. Singh, assistant professor of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Singh said she had no relevant financial disclosures.
This committee opinion is an excellent resource for clinicians taking care of adolescents. It succinctly and comprehensively provides the evidence to show that long acting reversible contraceptives (IUD and implant) should be offered as first line methods to adolescents.
In 2008, twice as many teenagers in the United States became pregnant, compared with Sweden. Birth control pills and condoms are the most popular forms of contraceptives used by teens in the United States, and have higher failure rates compared with LARC methods and high discontinuation rates. While the uptake of LARC nationally has been low in the adolescent population, data from the contraceptive CHOICE study found that with appropriate counseling, and no financial, logistical, provider or other barriers to use, over 40% of females aged 14-17 years chose the implant and over 40% of those aged 18-20 years chose an IUD. The study is a prospective cohort of more than 9,000 women aged 14-45 years who desired contraception, and after enrolling in the study were given comprehensive contraceptive counseling and their choice of contraception free of cost for a specified duration, after enrollment.
Another study of teens attending a family planning clinic showed that more than half had not heard of intrauterine contraceptives and when counseled appropriately by health care providers, they were three times more likely to be interested in using it.
LARC methods have both contraceptive and noncontraceptive benefits. There are few absolute contraindications to using LARC methods, and increasing their use has the potential to reduce unintended pregnancy in the U.S. adolescent population with appropriate counseling and in the absence of financial, logistical, provider or other barriers.
Dr. Rameet H. Singh, assistant professor of obstetrics and gynecology at the University of New Mexico, Albuquerque. Dr. Singh said she had no relevant financial disclosures.
Health care professionals should encourage sexually active adolescents to consider long-acting reversible contraceptive methods when counseling them about contraceptive choices, according to an American College of Obstetricians and Gynecologists’ committee opinion.
With pregnancy rates less than 1% with perfect and typical use, long-acting reversible contraception (LARC) methods "are the best reversible methods for preventing unintended pregnancy, rapid repeat pregnancy, and abortion in young women," the opinion states. Although the complications of these methods – intrauterine devices and the contraceptive implant – are rare and are similar in adolescents and older women, they are underused in the younger age group, according to ACOG committee opinion No. 539, written by the Committee on Adolescent Health Care’s Long-Acting Reversible Contraception Working Group. The opinion was published in the October issue of Obstetrics & Gynecology (2012;120:983-8).
"Increasing adolescent access to LARC is a clinical and public health opportunity for obstetrician-gynecologists," the opinion says, adding: "With top-tier effectiveness, high rates of satisfaction and continuation, and no need for daily adherence, LARC methods should be first-line recommendations for all women and adolescents," combined with the use of consistent use of condoms to reduce the risk of sexually transmitted infections.
The new opinion is a reaffirmation of the committee opinion issued in 2007. "We’ve had the support to offer these top-tier methods as first line for adolescents for years ... and yet teens are largely using condoms, oral contraceptive pills, and withdrawal – methods with much, much higher failure rates – for contraception, if they are using anything at all," said Dr. Melissa Kottke, a member of the committee and medical director of the Jane Fonda Center for Adolescent Reproductive Health at Emory University in Atlanta.
Health care providers are not routinely offering these methods to teens, possibly because they mistakenly think that teens will not choose these methods, which data indicate is not the case; and they may not have the training or comfort level to provide them, she said in an interview. Clinicians may also believe that LARCs are only appropriate for parous teens and there is a "lingering fear of infection," but there are data that support the safe use of IUDs and the implant in both parous and nulligravid teens, she said, adding that all women, including adolescents, should be counseled on condom use and other approaches to decrease their risk of sexually transmitted infections.
The opinion recommends that adolescents should be routinely screened for sexually transmitted infections when or before an IUD is inserted.
Among the statistics cited in the ACOG opinion is that 42% of all adolescents aged 15-19 years have had intercourse and 82% of adolescent pregnancies are not planned.
The opinion refers to depot medroxyprogesterone acetate (DMPA) injection, the contraceptive patch, vaginal ring, and OCs, as well as condoms and other short-acting methods, as adolescent contraceptive "mainstays," but points out that these methods are associated with lower continuation rates and higher pregnancy rates among adolescents than LARC methods. For example, a study published in 2011 found that 1 year after starting a short-acting contraceptive, continuation rates among women 15-24 were as low as 11% for the contraceptive patch, 16% for DMPA, and about 30% for OCs and the vaginal ring. But in another study, continuation rates for the levonorgestrel intrauterine system and contraceptive implant among women under aged 20 at 1 year were 85%, and copper IUD continuation rates at 1 year among adolescents were 72%.
The use of LARC methods have increased in the United States, from 22.4% in 2002 and 8.5% in 2009. But among teenagers, about 4.5% of adolescents use LARC, mostly IUDs. Use of the contraceptive implant, the etonogestrel single-rod contraceptive approved in 2006, is low in all age groups (less than 1% of the women in the United States using contraception and 0.5% of those aged 15-19 years), according to the opinion.
The committee cites barriers to use of LARCs by adolescents – including cost, lack of access, and concerns among health care providers about their safety in younger patients – and note that training and education programs "should address common misconceptions and review the key evidence and benefits of adolescent LARC use."
In the interview, Dr. Kottke, also with the department of gynecology and obstetrics at Emory, said that she believed that many of these barriers "can be overcome with clinician support, education and training ... and the impact on the health and wellness of our adolescent patients and our communities will be substantial."
She disclosed that she has been an Implanon trainer in the past. (Nexplanon, the etonogestrel implant, is the only contraceptive implant currently on the market; it is a radiopaque version of Implanon, which is no longer available.)
This opinion replaces ACOG committee opinion No. 392, published in December 2007.
Health care professionals should encourage sexually active adolescents to consider long-acting reversible contraceptive methods when counseling them about contraceptive choices, according to an American College of Obstetricians and Gynecologists’ committee opinion.
With pregnancy rates less than 1% with perfect and typical use, long-acting reversible contraception (LARC) methods "are the best reversible methods for preventing unintended pregnancy, rapid repeat pregnancy, and abortion in young women," the opinion states. Although the complications of these methods – intrauterine devices and the contraceptive implant – are rare and are similar in adolescents and older women, they are underused in the younger age group, according to ACOG committee opinion No. 539, written by the Committee on Adolescent Health Care’s Long-Acting Reversible Contraception Working Group. The opinion was published in the October issue of Obstetrics & Gynecology (2012;120:983-8).
"Increasing adolescent access to LARC is a clinical and public health opportunity for obstetrician-gynecologists," the opinion says, adding: "With top-tier effectiveness, high rates of satisfaction and continuation, and no need for daily adherence, LARC methods should be first-line recommendations for all women and adolescents," combined with the use of consistent use of condoms to reduce the risk of sexually transmitted infections.
The new opinion is a reaffirmation of the committee opinion issued in 2007. "We’ve had the support to offer these top-tier methods as first line for adolescents for years ... and yet teens are largely using condoms, oral contraceptive pills, and withdrawal – methods with much, much higher failure rates – for contraception, if they are using anything at all," said Dr. Melissa Kottke, a member of the committee and medical director of the Jane Fonda Center for Adolescent Reproductive Health at Emory University in Atlanta.
Health care providers are not routinely offering these methods to teens, possibly because they mistakenly think that teens will not choose these methods, which data indicate is not the case; and they may not have the training or comfort level to provide them, she said in an interview. Clinicians may also believe that LARCs are only appropriate for parous teens and there is a "lingering fear of infection," but there are data that support the safe use of IUDs and the implant in both parous and nulligravid teens, she said, adding that all women, including adolescents, should be counseled on condom use and other approaches to decrease their risk of sexually transmitted infections.
The opinion recommends that adolescents should be routinely screened for sexually transmitted infections when or before an IUD is inserted.
Among the statistics cited in the ACOG opinion is that 42% of all adolescents aged 15-19 years have had intercourse and 82% of adolescent pregnancies are not planned.
The opinion refers to depot medroxyprogesterone acetate (DMPA) injection, the contraceptive patch, vaginal ring, and OCs, as well as condoms and other short-acting methods, as adolescent contraceptive "mainstays," but points out that these methods are associated with lower continuation rates and higher pregnancy rates among adolescents than LARC methods. For example, a study published in 2011 found that 1 year after starting a short-acting contraceptive, continuation rates among women 15-24 were as low as 11% for the contraceptive patch, 16% for DMPA, and about 30% for OCs and the vaginal ring. But in another study, continuation rates for the levonorgestrel intrauterine system and contraceptive implant among women under aged 20 at 1 year were 85%, and copper IUD continuation rates at 1 year among adolescents were 72%.
The use of LARC methods have increased in the United States, from 22.4% in 2002 and 8.5% in 2009. But among teenagers, about 4.5% of adolescents use LARC, mostly IUDs. Use of the contraceptive implant, the etonogestrel single-rod contraceptive approved in 2006, is low in all age groups (less than 1% of the women in the United States using contraception and 0.5% of those aged 15-19 years), according to the opinion.
The committee cites barriers to use of LARCs by adolescents – including cost, lack of access, and concerns among health care providers about their safety in younger patients – and note that training and education programs "should address common misconceptions and review the key evidence and benefits of adolescent LARC use."
In the interview, Dr. Kottke, also with the department of gynecology and obstetrics at Emory, said that she believed that many of these barriers "can be overcome with clinician support, education and training ... and the impact on the health and wellness of our adolescent patients and our communities will be substantial."
She disclosed that she has been an Implanon trainer in the past. (Nexplanon, the etonogestrel implant, is the only contraceptive implant currently on the market; it is a radiopaque version of Implanon, which is no longer available.)
This opinion replaces ACOG committee opinion No. 392, published in December 2007.
FROM OBSTETRICS & GYNECOLOGY
ACIP Backs Meningococcal Vaccine for High-Risk Infants Only
Infants at increased risk for meningococcal disease should receive four doses of the Hib-MenCY-TT vaccine at ages 2, 4, 6 months and between 12-15 months, according to the majority of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting on Oct. 24, the committee voted 13-1, with one abstention, to support this proposal by ACIP’s meningococcal vaccines work group. Children at risk include those with recognized persistent complement pathway deficiencies and those with anatomic or functional asplenia including sickle cell disease. The vaccine also can be used in infants aged 2-18 months who live in communities with outbreaks of serogroup C and Y meningococcal disease, according to the proposal.
ACIP is not recommending routine meningococcal vaccination for infants.
The meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (MenHibrix) was approved in June 2012 to prevent invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b in children aged 6 weeks through 18 months.
Current ACIP recommendations for routine meningococcal vaccination recommend vaccination at ages 11-12 years with a booster dose at age 16 years. For younger children, the schedule recommends one of the quadrivalent meningococcal conjugate vaccines for children at high risk including those with persistent complement component deficiency; the minimum age for Menactra (MenACWY-D) is 9 months and is 2 years for Menveo (MenACWY-CRM).
The work group considered two options: a recommendation for all infants or vaccination only or for those at increased risk for meningococcal disease, said Dr. Amanda Cohn, a medical officer in the CDC’s National Center for Immunization and Respiratory Diseases. The work group concluded that the data do not currently support routine infant meningococcal vaccination.
But the group recommended vaccination for high-risk infants, a small group (about 5,000 infants a year), who are a "feasible target for vaccination," she said, adding that this approach was consistent with current recommendations for other age groups.
N. meningitidis is the third most common cause of sepsis in people with asplenia, and Hib-MenCY-TT provides an alternative to using MenACWY-D with PCV13 during the second year of life, providing protection for children with sickle cell disease detected on newborn screening before they develop functional asplenia, she said.
In a community outbreak, the need for multiple doses of Hib-MenCY-TT would limit the benefit of the vaccine, but having the vaccine available for infants would be useful if infants are targeted for vaccination in an outbreak. N. meningitidis is also the primary pathogen with late component complement deficiency, she said.
The work group noted that the amount of preventable meningococcal disease cases in children under age 5 years is low, because currently rates are low, and under age 1, most cases are caused by serogroup B, which is not covered by the new vaccine, she said. Most meningococcal disease in this age group is caused by serogroup B, and the incidence declines after 6- 8 months.
About 50%-60% of meningococcal disease in children under 5 years is due to serogroup B. The proportion caused by serogroups C, Y and w135 increases with age. Between 2007 to 2009 (considered "low incidence years"), there were 77 cases of serogroup Y and C meningococcal cases among children under age 5 in the United States and 4-8 deaths, considerably lower than the rates in the late 1990s, she said. Of these cases, 44 cases and 2-4 deaths were potentially preventable.
Meningococcal disease is cyclical, but because it last peaked in the late 1990s, the incidence has declined to historically low levels, and there is no indication that rates are starting to increase. Rates have declined in all age groups, Dr. Cohn said.
So far this year, meningococcal disease appears to be lower that last year, with 407 cases under age 5 years reported by week 41 this year, compared with 541 at the same time last year. So far this year, there have been seven cases and two deaths from serogroup C and Y in children aged 6-59 months, and the working group believes that there is no evidence that this will increase in the near future, she said.
ACIP will review the use of MenHibrix for Hib vaccination at the next meeting, when Hib recommendations will be on the agenda.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
Infants at increased risk for meningococcal disease should receive four doses of the Hib-MenCY-TT vaccine at ages 2, 4, 6 months and between 12-15 months, according to the majority of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting on Oct. 24, the committee voted 13-1, with one abstention, to support this proposal by ACIP’s meningococcal vaccines work group. Children at risk include those with recognized persistent complement pathway deficiencies and those with anatomic or functional asplenia including sickle cell disease. The vaccine also can be used in infants aged 2-18 months who live in communities with outbreaks of serogroup C and Y meningococcal disease, according to the proposal.
ACIP is not recommending routine meningococcal vaccination for infants.
The meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (MenHibrix) was approved in June 2012 to prevent invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b in children aged 6 weeks through 18 months.
Current ACIP recommendations for routine meningococcal vaccination recommend vaccination at ages 11-12 years with a booster dose at age 16 years. For younger children, the schedule recommends one of the quadrivalent meningococcal conjugate vaccines for children at high risk including those with persistent complement component deficiency; the minimum age for Menactra (MenACWY-D) is 9 months and is 2 years for Menveo (MenACWY-CRM).
The work group considered two options: a recommendation for all infants or vaccination only or for those at increased risk for meningococcal disease, said Dr. Amanda Cohn, a medical officer in the CDC’s National Center for Immunization and Respiratory Diseases. The work group concluded that the data do not currently support routine infant meningococcal vaccination.
But the group recommended vaccination for high-risk infants, a small group (about 5,000 infants a year), who are a "feasible target for vaccination," she said, adding that this approach was consistent with current recommendations for other age groups.
N. meningitidis is the third most common cause of sepsis in people with asplenia, and Hib-MenCY-TT provides an alternative to using MenACWY-D with PCV13 during the second year of life, providing protection for children with sickle cell disease detected on newborn screening before they develop functional asplenia, she said.
In a community outbreak, the need for multiple doses of Hib-MenCY-TT would limit the benefit of the vaccine, but having the vaccine available for infants would be useful if infants are targeted for vaccination in an outbreak. N. meningitidis is also the primary pathogen with late component complement deficiency, she said.
The work group noted that the amount of preventable meningococcal disease cases in children under age 5 years is low, because currently rates are low, and under age 1, most cases are caused by serogroup B, which is not covered by the new vaccine, she said. Most meningococcal disease in this age group is caused by serogroup B, and the incidence declines after 6- 8 months.
About 50%-60% of meningococcal disease in children under 5 years is due to serogroup B. The proportion caused by serogroups C, Y and w135 increases with age. Between 2007 to 2009 (considered "low incidence years"), there were 77 cases of serogroup Y and C meningococcal cases among children under age 5 in the United States and 4-8 deaths, considerably lower than the rates in the late 1990s, she said. Of these cases, 44 cases and 2-4 deaths were potentially preventable.
Meningococcal disease is cyclical, but because it last peaked in the late 1990s, the incidence has declined to historically low levels, and there is no indication that rates are starting to increase. Rates have declined in all age groups, Dr. Cohn said.
So far this year, meningococcal disease appears to be lower that last year, with 407 cases under age 5 years reported by week 41 this year, compared with 541 at the same time last year. So far this year, there have been seven cases and two deaths from serogroup C and Y in children aged 6-59 months, and the working group believes that there is no evidence that this will increase in the near future, she said.
ACIP will review the use of MenHibrix for Hib vaccination at the next meeting, when Hib recommendations will be on the agenda.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
Infants at increased risk for meningococcal disease should receive four doses of the Hib-MenCY-TT vaccine at ages 2, 4, 6 months and between 12-15 months, according to the majority of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
At a meeting on Oct. 24, the committee voted 13-1, with one abstention, to support this proposal by ACIP’s meningococcal vaccines work group. Children at risk include those with recognized persistent complement pathway deficiencies and those with anatomic or functional asplenia including sickle cell disease. The vaccine also can be used in infants aged 2-18 months who live in communities with outbreaks of serogroup C and Y meningococcal disease, according to the proposal.
ACIP is not recommending routine meningococcal vaccination for infants.
The meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (MenHibrix) was approved in June 2012 to prevent invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b in children aged 6 weeks through 18 months.
Current ACIP recommendations for routine meningococcal vaccination recommend vaccination at ages 11-12 years with a booster dose at age 16 years. For younger children, the schedule recommends one of the quadrivalent meningococcal conjugate vaccines for children at high risk including those with persistent complement component deficiency; the minimum age for Menactra (MenACWY-D) is 9 months and is 2 years for Menveo (MenACWY-CRM).
The work group considered two options: a recommendation for all infants or vaccination only or for those at increased risk for meningococcal disease, said Dr. Amanda Cohn, a medical officer in the CDC’s National Center for Immunization and Respiratory Diseases. The work group concluded that the data do not currently support routine infant meningococcal vaccination.
But the group recommended vaccination for high-risk infants, a small group (about 5,000 infants a year), who are a "feasible target for vaccination," she said, adding that this approach was consistent with current recommendations for other age groups.
N. meningitidis is the third most common cause of sepsis in people with asplenia, and Hib-MenCY-TT provides an alternative to using MenACWY-D with PCV13 during the second year of life, providing protection for children with sickle cell disease detected on newborn screening before they develop functional asplenia, she said.
In a community outbreak, the need for multiple doses of Hib-MenCY-TT would limit the benefit of the vaccine, but having the vaccine available for infants would be useful if infants are targeted for vaccination in an outbreak. N. meningitidis is also the primary pathogen with late component complement deficiency, she said.
The work group noted that the amount of preventable meningococcal disease cases in children under age 5 years is low, because currently rates are low, and under age 1, most cases are caused by serogroup B, which is not covered by the new vaccine, she said. Most meningococcal disease in this age group is caused by serogroup B, and the incidence declines after 6- 8 months.
About 50%-60% of meningococcal disease in children under 5 years is due to serogroup B. The proportion caused by serogroups C, Y and w135 increases with age. Between 2007 to 2009 (considered "low incidence years"), there were 77 cases of serogroup Y and C meningococcal cases among children under age 5 in the United States and 4-8 deaths, considerably lower than the rates in the late 1990s, she said. Of these cases, 44 cases and 2-4 deaths were potentially preventable.
Meningococcal disease is cyclical, but because it last peaked in the late 1990s, the incidence has declined to historically low levels, and there is no indication that rates are starting to increase. Rates have declined in all age groups, Dr. Cohn said.
So far this year, meningococcal disease appears to be lower that last year, with 407 cases under age 5 years reported by week 41 this year, compared with 541 at the same time last year. So far this year, there have been seven cases and two deaths from serogroup C and Y in children aged 6-59 months, and the working group believes that there is no evidence that this will increase in the near future, she said.
ACIP will review the use of MenHibrix for Hib vaccination at the next meeting, when Hib recommendations will be on the agenda.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
FROM A MEETING OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION'S ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES
CDC Panel Backs Tdap Vaccination During Every Pregnancy
All pregnant women should receive a dose of the Tdap vaccine, whether she has received the vaccine previously, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended.
At a meeting on Oct. 24, the committee voted 14-0, with one abstention, to support the recommendation proposed by the ACIP pertussis vaccine work group that providers of prenatal care implement a Tdap immunization program for all pregnant women and that health care personnel "should administer a dose of Tdap during each pregnancy, irrespective of the patient’s prior history of receiving Tdap." If not administered, during pregnancy, "Tdap should be administered immediately post partum," according to the recommendation.
The recommendation is a change from the previous recommendation made by ACIP in June 2011, which says that that Tdap should be administered during pregnancy "only to women who have not previously received Tdap." The current recommendation also states that women who do not receive the vaccine during pregnancy should be vaccinated immediately post partum.
Optimally, women should receive Tdap between 27 and 36 weeks’ gestation, to maximize the maternal antibody response and passive transfer of antibodies to the infant, said Dr. Jennifer Liang, the lead CDC member of the ACIP pertussis vaccine work group. Based on work group’s review, the evidence is "reassuring" – that two doses of Tdap are safe, she said.
Dr. Liang said that only about 2.6% of pregnant women are vaccinated with Tdap during pregnancy and that the work group is attempting to remove barriers to improve the uptake of the vaccine.
The work group concluded that Tdap maternal pertussis antibodies would wane greatly between subsequent pregnancies, and that a single Tdap dose during one pregnancy was not sufficient to provide adequate protection for subsequent pregnancies. Considering that the number of children born per woman in the United States is about two, a "very small proportion of women – about 5% – would receive four or more Tdap doses, she said.
The number of expected pertussis cases in the United States this year is expected to be the highest since 1959, with more than 32,000 cases reported to date.* There have been 16 deaths so far, and most were in infants, who also have the highest rates of hospitalization, according to the CDC.
In the United States, the rate overall is 10.6 cases/100,000 population, but the rate varies considerably by state. In infants under age 1 year, the rate ranges from 20-100 cases/100,000.
The work group has requested that the CDC conduct safety studies to address the potential increase in severe adverse events when Tdap is given in subsequent pregnancies, she said.
"This is a great opportunity for obstetricians to help their patients protect their newborns and themselves. I urge all obstetricians to recommend and give Tdap vaccine to their pregnant patients," Dr. Richard Beigi, a member of the American College of Obstetricians and Gynecologists immunization work group and the ACIP pertussis vaccines work group said after the vote. Dr. Beigi was not at the meeting.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
* This story was updated on 10/26/2012.
All pregnant women should receive a dose of the Tdap vaccine, whether she has received the vaccine previously, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended.
At a meeting on Oct. 24, the committee voted 14-0, with one abstention, to support the recommendation proposed by the ACIP pertussis vaccine work group that providers of prenatal care implement a Tdap immunization program for all pregnant women and that health care personnel "should administer a dose of Tdap during each pregnancy, irrespective of the patient’s prior history of receiving Tdap." If not administered, during pregnancy, "Tdap should be administered immediately post partum," according to the recommendation.
The recommendation is a change from the previous recommendation made by ACIP in June 2011, which says that that Tdap should be administered during pregnancy "only to women who have not previously received Tdap." The current recommendation also states that women who do not receive the vaccine during pregnancy should be vaccinated immediately post partum.
Optimally, women should receive Tdap between 27 and 36 weeks’ gestation, to maximize the maternal antibody response and passive transfer of antibodies to the infant, said Dr. Jennifer Liang, the lead CDC member of the ACIP pertussis vaccine work group. Based on work group’s review, the evidence is "reassuring" – that two doses of Tdap are safe, she said.
Dr. Liang said that only about 2.6% of pregnant women are vaccinated with Tdap during pregnancy and that the work group is attempting to remove barriers to improve the uptake of the vaccine.
The work group concluded that Tdap maternal pertussis antibodies would wane greatly between subsequent pregnancies, and that a single Tdap dose during one pregnancy was not sufficient to provide adequate protection for subsequent pregnancies. Considering that the number of children born per woman in the United States is about two, a "very small proportion of women – about 5% – would receive four or more Tdap doses, she said.
The number of expected pertussis cases in the United States this year is expected to be the highest since 1959, with more than 32,000 cases reported to date.* There have been 16 deaths so far, and most were in infants, who also have the highest rates of hospitalization, according to the CDC.
In the United States, the rate overall is 10.6 cases/100,000 population, but the rate varies considerably by state. In infants under age 1 year, the rate ranges from 20-100 cases/100,000.
The work group has requested that the CDC conduct safety studies to address the potential increase in severe adverse events when Tdap is given in subsequent pregnancies, she said.
"This is a great opportunity for obstetricians to help their patients protect their newborns and themselves. I urge all obstetricians to recommend and give Tdap vaccine to their pregnant patients," Dr. Richard Beigi, a member of the American College of Obstetricians and Gynecologists immunization work group and the ACIP pertussis vaccines work group said after the vote. Dr. Beigi was not at the meeting.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
* This story was updated on 10/26/2012.
All pregnant women should receive a dose of the Tdap vaccine, whether she has received the vaccine previously, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended.
At a meeting on Oct. 24, the committee voted 14-0, with one abstention, to support the recommendation proposed by the ACIP pertussis vaccine work group that providers of prenatal care implement a Tdap immunization program for all pregnant women and that health care personnel "should administer a dose of Tdap during each pregnancy, irrespective of the patient’s prior history of receiving Tdap." If not administered, during pregnancy, "Tdap should be administered immediately post partum," according to the recommendation.
The recommendation is a change from the previous recommendation made by ACIP in June 2011, which says that that Tdap should be administered during pregnancy "only to women who have not previously received Tdap." The current recommendation also states that women who do not receive the vaccine during pregnancy should be vaccinated immediately post partum.
Optimally, women should receive Tdap between 27 and 36 weeks’ gestation, to maximize the maternal antibody response and passive transfer of antibodies to the infant, said Dr. Jennifer Liang, the lead CDC member of the ACIP pertussis vaccine work group. Based on work group’s review, the evidence is "reassuring" – that two doses of Tdap are safe, she said.
Dr. Liang said that only about 2.6% of pregnant women are vaccinated with Tdap during pregnancy and that the work group is attempting to remove barriers to improve the uptake of the vaccine.
The work group concluded that Tdap maternal pertussis antibodies would wane greatly between subsequent pregnancies, and that a single Tdap dose during one pregnancy was not sufficient to provide adequate protection for subsequent pregnancies. Considering that the number of children born per woman in the United States is about two, a "very small proportion of women – about 5% – would receive four or more Tdap doses, she said.
The number of expected pertussis cases in the United States this year is expected to be the highest since 1959, with more than 32,000 cases reported to date.* There have been 16 deaths so far, and most were in infants, who also have the highest rates of hospitalization, according to the CDC.
In the United States, the rate overall is 10.6 cases/100,000 population, but the rate varies considerably by state. In infants under age 1 year, the rate ranges from 20-100 cases/100,000.
The work group has requested that the CDC conduct safety studies to address the potential increase in severe adverse events when Tdap is given in subsequent pregnancies, she said.
"This is a great opportunity for obstetricians to help their patients protect their newborns and themselves. I urge all obstetricians to recommend and give Tdap vaccine to their pregnant patients," Dr. Richard Beigi, a member of the American College of Obstetricians and Gynecologists immunization work group and the ACIP pertussis vaccines work group said after the vote. Dr. Beigi was not at the meeting.
There are 15 experts in immunization-related fields on the ACIP committee, which develops written recommendations for the routine administration of vaccines to children and adults in the civilian population.
* This story was updated on 10/26/2012.
FROM A MEETING OF THE CENTERS FOR DISEASE CONTROL AND PREVENTION'S ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES
Second TNF Blocker Approved for Refractory UC
Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.
The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.
Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.
Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.
In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.
At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.
Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.
In the studies, no new side effects were identified, the agency said.
The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."
The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.
"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.
Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.
It is good news for patients who have ulcerative colitis and the health care providers who take care of them that a second anti-TNF agent is now available. The FDA’s approval of Humira (adalimumab) for moderate to severe ulcer-ative colitis provides us with an additional option that we definitely need because there are many patients who suffer from ulcerative colitis and fail to respond to the "conventional" treatments with aminosalicylates or steroids and thiopurines, or lose response to infliximab. Adalimumab is an option for many of these types of patients and may be the first choice anti–tumor necrosis factor agent for some patients or providers, due to the injectable delivery method for this therapy.
Despite this good news, however, we need to acknowledge that 8-week remission rates of 18.5% and 16.5% leave a lot of room for improvement. Future studies with adalimumab in ulcerative colitis will focus on how to optimize this therapy and will explore adjustable dosing schedules, combination therapies, and other important longer-term outcomes such as sustained remission and mucosal healing.
David T. Rubin, M.D., AGAF, is a professor of medicine and co-director of the Inflammatory Bowel Disease Center at the University of Chicago. He has served as a consultant for Janssen and for Abbott.
It is good news for patients who have ulcerative colitis and the health care providers who take care of them that a second anti-TNF agent is now available. The FDA’s approval of Humira (adalimumab) for moderate to severe ulcer-ative colitis provides us with an additional option that we definitely need because there are many patients who suffer from ulcerative colitis and fail to respond to the "conventional" treatments with aminosalicylates or steroids and thiopurines, or lose response to infliximab. Adalimumab is an option for many of these types of patients and may be the first choice anti–tumor necrosis factor agent for some patients or providers, due to the injectable delivery method for this therapy.
Despite this good news, however, we need to acknowledge that 8-week remission rates of 18.5% and 16.5% leave a lot of room for improvement. Future studies with adalimumab in ulcerative colitis will focus on how to optimize this therapy and will explore adjustable dosing schedules, combination therapies, and other important longer-term outcomes such as sustained remission and mucosal healing.
David T. Rubin, M.D., AGAF, is a professor of medicine and co-director of the Inflammatory Bowel Disease Center at the University of Chicago. He has served as a consultant for Janssen and for Abbott.
It is good news for patients who have ulcerative colitis and the health care providers who take care of them that a second anti-TNF agent is now available. The FDA’s approval of Humira (adalimumab) for moderate to severe ulcer-ative colitis provides us with an additional option that we definitely need because there are many patients who suffer from ulcerative colitis and fail to respond to the "conventional" treatments with aminosalicylates or steroids and thiopurines, or lose response to infliximab. Adalimumab is an option for many of these types of patients and may be the first choice anti–tumor necrosis factor agent for some patients or providers, due to the injectable delivery method for this therapy.
Despite this good news, however, we need to acknowledge that 8-week remission rates of 18.5% and 16.5% leave a lot of room for improvement. Future studies with adalimumab in ulcerative colitis will focus on how to optimize this therapy and will explore adjustable dosing schedules, combination therapies, and other important longer-term outcomes such as sustained remission and mucosal healing.
David T. Rubin, M.D., AGAF, is a professor of medicine and co-director of the Inflammatory Bowel Disease Center at the University of Chicago. He has served as a consultant for Janssen and for Abbott.
Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.
The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.
Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.
Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.
In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.
At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.
Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.
In the studies, no new side effects were identified, the agency said.
The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."
The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.
"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.
Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.
Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.
The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).
Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.
Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.
Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.
In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.
At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.
Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.
In the studies, no new side effects were identified, the agency said.
The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."
The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.
"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.
Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.
Panel Advises Approving Short Bowel Syndrome Drug
SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.
At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.
While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.
Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.
In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.
While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.
There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.
NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.
The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.
"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.
"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.
If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.
The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.
At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.
While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.
Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.
In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.
While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.
There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.
NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.
The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.
"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.
"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.
If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.
The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.
At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.
While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.
Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.
In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.
While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.
There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.
NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.
The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.
"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.
"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.
If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.
The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.
The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
