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FDA advisers support pediatric studies of three investigational oncology agents
SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.
The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.
Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.
Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.
The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.
Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.
Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.
Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.
To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.
The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.
FDA panelists were cleared of potential conflicts.
SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.
The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.
Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.
Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.
The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.
Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.
Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.
Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.
To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.
The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.
FDA panelists were cleared of potential conflicts.
SILVER SPRING, MD. – Three experimental agents currently being developed as treatments for various cancers in adults – ganetespib, etirinotecan pegol, and a still-unnamed MDM2 (murine double-minute 2) antagonist – should be studied in pediatric patients, according to a Food and Drug Administration advisory panel.
The manufacturers of the three agents presented information on their development and clinical trials for oncology indications in adults, at a meeting of the FDA’s Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee. The meeting was held to allow the manufacturers to provide information about the adult studies and plans for pediatric development and for the expert panelists to discuss the pediatric development of the agents, to help guide the agency’s decisions regarding written requests to companies, which outline the types of pediatric studies, study design, objectives, and age groups that should be studied.
Ganetespib is an inhibitor of heat shock protein 90 (Hsp90), in an injectable formulation, which has been evaluated in phase I, II, and II/III studies of adults with non–small cell lung cancer (NSCLC), breast cancer, ovarian cancer, and acute myeloid leukemia (AML), according to the manufacturer, Synta Pharmaceuticals. It is currently being evaluated in combination with docetaxel, vs. docetaxel alone, as second-line treatment in patients with advanced non–small cell lung adenocarcinoma in an ongoing phase III study (GALAXY-2). To date, several patients have been enrolled in a phase I/II study (SARC023) evaluating ganetespib plus sirolimus for patients with refractory sarcomas, including unresectable or metastatic malignant peripheral nerve sheath tumors, a type of aggressive soft tissue sarcoma, in patients aged 18 years and above. The drug has evidence of antimetastatic effects in clinical studies, and GI toxicity, notably diarrhea, is the most common adverse event.
Panelists agreed that further studies of this agent in pediatric populations should be conducted, evaluating its effect on pediatric malignancies, such as neuroblastoma and sarcomas, and that the age of patients enrolled in the SARC023 study could be lowered to age 12 years. Other recommendations included studies evaluating ganetespib in combination with other agents, because studies to date do not support its use as a single agent; and studies of longterm adverse effects of treatment.
The second drug on the agenda was a prodrug of irinotecan, etirinotecan pegol, a long-acting topoisomerase I inhibitor, which has been studied in more than 1,000 patients, but not in any pediatric patients, according to the manufacturer, Nektar Therapeutics. Efficacy of etirinotecan has been demonstrated against multiple types of tumors, “some of which are pertinent to pediatric oncology,” such as primary brain cancer, and the company has received two proposals from pediatric oncologists to conduct phase I studies in patients with solid tumors, Dr. Alison Hannah, a consultant to the company, said at the meeting.
Etirinotecan has been or is being evaluated in phase I studies of advanced solid tumors, phase II studies of platinum-resistant ovarian cancer, metastatic breast cancer, colorectal cancer with KRAS mutations (as second-line therapy), and in NSCLC (as second- and third-line treatments). The one phase III study is the BEACON study, comparing etirinotecan vs. Treatment of Physicians Choice in 852 women with locally recurrent and metastatic breast cancer. Diarrhea has been the most common toxicity associated with the agent, which has been associated with a low rate of neutropenia (about 5%) and a relatively low rate of alopecia (11%), Dr. Hannah said.
Panelists agreed that etirinotecan was a good candidate for pediatric studies, for treatment of malignancies that included neuroblastoma, Ewing sarcoma and rhabdomyosarcoma, and also recommended that studies evaluate pediatric pharmacokinetics, and treatment with the agent in relapsed patients, as front-line therapy, and as part of combination treatments.
Earlier in the development process is RO5503781 (Hoffmann-La Roche), an orally administered antagonist of murine double minute 2 (MDM2), which binds tumor suppressor protein 53 (p53). Some tumors are thought to “overproduce MDM2 which causes inhibition of p53 activity and promotes tumorigenesis,” according to the FDA.
To date, there is “early evidence of efficacy” of this agent in cancers in adults, particularly AML, and it is being evaluated in phase I studies, according to the manufacturer. Challenges for pediatric studies include identifying the appropriate patients to treat with this agent and developing a formulation suitable for all pediatric age groups, according to the company, which is planning a study evaluating the pharmacokinetics, toxicity, safety, and activity of the agent in children with a solid tumor or acute leukemia.
The panelists expressed interest in pediatric studies, particularly regarding the promising early AML data, and were interested in studies of solid tumors, although which populations of patients to treat, what combinations of treatments, and at what disease stage to study were unclear.
FDA panelists were cleared of potential conflicts.
AT AN FDA ADVISORY COMMITTEE MEETING
Newly approved Gardasil 9 vaccine adds 20% more coverage against cervical cancer
The Food and Drug Administration has approved a new version of the Gardasil vaccine that protects against five more human papillomavirus types that cause about 20% of cervical cancers, the agency announced on Dec. 10.
The new vaccine, which is called Gardasil 9, “has the potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers,” according to the statement.
Gardasil 9 is approved for use in females aged 9 through 26 years and in males aged 9 through 15 years for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. It is administered in three separate intramuscular injections, on a 0, 2-, and 6-month schedule.
HPV types 31, 33, 45, 52 and 58 were not included in the initial Gardasil vaccine approved in 2006. Another HPV vaccine, Cervarix, was approved in 2009 and protects against HPV types 16 and 18.
Approval of Gardasil 9 was based on a randomized, controlled study in about 14,000 females aged 16-26 years, who tested negative for the HPV types in the vaccine and were given the Gardasil or Gardasil 9 vaccine; safety was evaluated in about 13,000 males and females, according to the FDA.
In the study, Gardasil 9 “was determined to be 97% effective in preventing cervical, vulvar, and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58),” the FDA statement said. “In addition, Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.” Injection site pain, swelling, redness, and headaches were among the most common adverse events associated with the vaccine, the statement said.
Studies of about 4,000 males and females aged 9-15 years found that antibody responses to Gardasil 9 were similar to the responses seen in females aged 16-26 years. “The vaccine is expected to have similar effectiveness when used in this younger age group,” according to the FDA.
Adverse events associated with vaccines should be reported to the Vaccine Adverse Event Reporting System.The label for Gardasil 9 is available at the FDA.
The Food and Drug Administration has approved a new version of the Gardasil vaccine that protects against five more human papillomavirus types that cause about 20% of cervical cancers, the agency announced on Dec. 10.
The new vaccine, which is called Gardasil 9, “has the potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers,” according to the statement.
Gardasil 9 is approved for use in females aged 9 through 26 years and in males aged 9 through 15 years for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. It is administered in three separate intramuscular injections, on a 0, 2-, and 6-month schedule.
HPV types 31, 33, 45, 52 and 58 were not included in the initial Gardasil vaccine approved in 2006. Another HPV vaccine, Cervarix, was approved in 2009 and protects against HPV types 16 and 18.
Approval of Gardasil 9 was based on a randomized, controlled study in about 14,000 females aged 16-26 years, who tested negative for the HPV types in the vaccine and were given the Gardasil or Gardasil 9 vaccine; safety was evaluated in about 13,000 males and females, according to the FDA.
In the study, Gardasil 9 “was determined to be 97% effective in preventing cervical, vulvar, and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58),” the FDA statement said. “In addition, Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.” Injection site pain, swelling, redness, and headaches were among the most common adverse events associated with the vaccine, the statement said.
Studies of about 4,000 males and females aged 9-15 years found that antibody responses to Gardasil 9 were similar to the responses seen in females aged 16-26 years. “The vaccine is expected to have similar effectiveness when used in this younger age group,” according to the FDA.
Adverse events associated with vaccines should be reported to the Vaccine Adverse Event Reporting System.The label for Gardasil 9 is available at the FDA.
The Food and Drug Administration has approved a new version of the Gardasil vaccine that protects against five more human papillomavirus types that cause about 20% of cervical cancers, the agency announced on Dec. 10.
The new vaccine, which is called Gardasil 9, “has the potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers,” according to the statement.
Gardasil 9 is approved for use in females aged 9 through 26 years and in males aged 9 through 15 years for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. It is administered in three separate intramuscular injections, on a 0, 2-, and 6-month schedule.
HPV types 31, 33, 45, 52 and 58 were not included in the initial Gardasil vaccine approved in 2006. Another HPV vaccine, Cervarix, was approved in 2009 and protects against HPV types 16 and 18.
Approval of Gardasil 9 was based on a randomized, controlled study in about 14,000 females aged 16-26 years, who tested negative for the HPV types in the vaccine and were given the Gardasil or Gardasil 9 vaccine; safety was evaluated in about 13,000 males and females, according to the FDA.
In the study, Gardasil 9 “was determined to be 97% effective in preventing cervical, vulvar, and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58),” the FDA statement said. “In addition, Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.” Injection site pain, swelling, redness, and headaches were among the most common adverse events associated with the vaccine, the statement said.
Studies of about 4,000 males and females aged 9-15 years found that antibody responses to Gardasil 9 were similar to the responses seen in females aged 16-26 years. “The vaccine is expected to have similar effectiveness when used in this younger age group,” according to the FDA.
Adverse events associated with vaccines should be reported to the Vaccine Adverse Event Reporting System.The label for Gardasil 9 is available at the FDA.
FROM THE FDA
Pharmacogenetics may help identify drinkers likely to respond to topiramate
AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.
In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.
At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.
Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.
Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.
However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.
Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.
These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.
Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).
Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.
AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.
In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.
At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.
Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.
Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.
However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.
Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.
These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.
Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).
Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.
AVENTURA, FLA.– A single nucleotide polymorphism might help identify heavy drinkers who are most likely to respond to treatment with topiramate, but more studies are needed before testing patients is recommended, Dr. Henry R. Kranzler reported at the annual meeting of the American Academy of Addiction Psychiatry.
In a 12-week placebo-controlled, randomized study of 138 heavy drinkers, the number of days people drank heavily was significantly reduced among those treated with topiramate, compared with those on placebo. But genotyping results indicated that the effect occurred only among those with the polymorphism, according to Dr. Kranzler, the lead author of the study, who is professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania, Philadelphia.
At baseline, the study participants drank about 80% of the days each week. They were randomized to treatment with 200 mg of topiramate a day, in two divided doses, or placebo, with the goal of reducing drinking to safe levels. Brief behavioral counseling was provided at each visit. Over 12 weeks, the number of days participants drank heavily dropped from about 5 days at baseline to about 1.5 days a week among those treated with topiramate, a significant reduction, and to about 3 days a week among those on placebo. In addition, the number of days participants abstained from alcohol increased among those treated with topiramate, from about 1 to almost 3 days per week. Among those on placebo, the number of abstinent days per week increased from about 1 to 1.5 days per week.
Patients were genotyped for the single nucleotide polymorphism (rs2832407) in GRIK1 (glutamate receptor, ionotropic, kainate1), a large gene on chromosome 21, which “encodes the Gluk1 subunit of the kainate (glutamate) receptor” to evaluate its impact as a moderator of topiramate’s effects on drinking and on the adverse effects of the drug. Topiramate affects multiple receptor systems, and the drug’s effects on glutamate (kainate) receptors “are most potent and selective for those containing the GluK1 and GluK2 subunits,” he said.
Genotyping was done in the 122 European Americans in the study to avoid confounding, because the frequency of the allele for the polymorphism varies widely in different populations. In this group, the significant effects over placebo was evident only among the 51 individuals who were “rs2832407 C-allele homozygotes.” They had “a substantially greater response to topiramate, compared to placebo,” and 3 and 6 months after treatment ended, evidence of a beneficial effect of topiramate in this group remained, he added.
However, unlike a small study published in 2009, conducted by different investigators, which found that individuals with this genotype were less likely to experience adverse effects of topiramate therapy, they did not see a pharmacogenetic effect on adverse events associated with topiramate.
Genotyping might help predict which patients may respond to topiramate, testing is not currently recommended, and these results need to be replicated and evaluated in other populations, Dr. Kranzler added.
These findings will also be helpful in identifying targets for more specific medications to treat alcohol abuse, he noted.
Topiramate, marketed as Topamax, also is available in generic formulations; it is not approved for treating alcohol abuse. He referred to a recently published meta-analysis indicating that topiramate had a greater effect than acamprosate or naltrexone in people with alcohol use disorders (Alcohol Clin. Exp. Res. 2014;38:1481-8).
Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He also is a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche. He said that industry had no role in the data he presented.
AT THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF ADDICTION PSYCHIATRY
Key clinical point: Genotyping patients who drink heavily for the single nucleotide polymorphism in a large gene on chromosome 21 might help identify who is likely to respond to treatment with topiramate for alcohol abuse, but results need to be replicated before such testing is recommended.
Major finding: Treatment with topiramate was significantly more effective than was placebo in reducing heavy drinking after 12 weeks; differences were seen only among those with the single nucleotide polymorphism.
Data source: A 12-week placebo-controlled study of 138 heavy drinkers.
Disclosures: Dr. Kranzler disclosed having received honoraria from the Alcohol Clinical Trials Initiative (ACTIVE) of the American Society of Clinical Psychopharmacology, which is supported by AbbVie, Ethypharm, Lilly, Lundbeck, and Pfizer. He is also a consultant to or advisory board member of Alkermes, Lilly, Lundbeck, Otsuka, Pfizer, and Roche.
FDA extends review of panobinostat for combination treatment of multiple myeloma
The Food and Drug Administration’s review of panobinostat, combined with bortezomib and dexamethasone, for the treatment of multiple myeloma has been extended, the manufacturer has announced.
Novartis Pharmaceuticals submitted the new drug application for the pan-deacetylase (pan-DAC) inhibitor in combination with the proteasome inhibitor bortezomib (Velcade) and dexamethasone for the treatment of patients with previously treated multiple myeloma in March 2104; it was given a priority review of 8 months, instead of the standard 12 months. But the agency has extended the review for up to 3 months, the company said in a Nov. 25 statement.
The FDA was expected to make a decision in November.
“We are committed to working with the FDA as they continue to review” the application, Dr. Alessandro Riva, global head of oncology development and medical affairs at Novartis Oncology, said in the statement.
Panobinostat is an epigenetic regulator, which “may help restore cell programming in multiple myeloma,” and if approved, it would be the first pan-DAC inhibitor approved for treating patients with relapsed or relapsed and refractory multiple myeloma, according to the company.
At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with bortezomib and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the proposed indication. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival, and said they hoped the company would continue to study the drug in patients with the disease.
The Food and Drug Administration’s review of panobinostat, combined with bortezomib and dexamethasone, for the treatment of multiple myeloma has been extended, the manufacturer has announced.
Novartis Pharmaceuticals submitted the new drug application for the pan-deacetylase (pan-DAC) inhibitor in combination with the proteasome inhibitor bortezomib (Velcade) and dexamethasone for the treatment of patients with previously treated multiple myeloma in March 2104; it was given a priority review of 8 months, instead of the standard 12 months. But the agency has extended the review for up to 3 months, the company said in a Nov. 25 statement.
The FDA was expected to make a decision in November.
“We are committed to working with the FDA as they continue to review” the application, Dr. Alessandro Riva, global head of oncology development and medical affairs at Novartis Oncology, said in the statement.
Panobinostat is an epigenetic regulator, which “may help restore cell programming in multiple myeloma,” and if approved, it would be the first pan-DAC inhibitor approved for treating patients with relapsed or relapsed and refractory multiple myeloma, according to the company.
At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with bortezomib and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the proposed indication. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival, and said they hoped the company would continue to study the drug in patients with the disease.
The Food and Drug Administration’s review of panobinostat, combined with bortezomib and dexamethasone, for the treatment of multiple myeloma has been extended, the manufacturer has announced.
Novartis Pharmaceuticals submitted the new drug application for the pan-deacetylase (pan-DAC) inhibitor in combination with the proteasome inhibitor bortezomib (Velcade) and dexamethasone for the treatment of patients with previously treated multiple myeloma in March 2104; it was given a priority review of 8 months, instead of the standard 12 months. But the agency has extended the review for up to 3 months, the company said in a Nov. 25 statement.
The FDA was expected to make a decision in November.
“We are committed to working with the FDA as they continue to review” the application, Dr. Alessandro Riva, global head of oncology development and medical affairs at Novartis Oncology, said in the statement.
Panobinostat is an epigenetic regulator, which “may help restore cell programming in multiple myeloma,” and if approved, it would be the first pan-DAC inhibitor approved for treating patients with relapsed or relapsed and refractory multiple myeloma, according to the company.
At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with bortezomib and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the proposed indication. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival, and said they hoped the company would continue to study the drug in patients with the disease.
FDA clears noninvasive method of obtaining FFR measurements
Software that provides an estimate of a patient’s fractional flow reserve using data from a coronary CT scan has been cleared for marketing, the Food and Drug Administration announced Nov. 26.
The software, HeartFlow FFRCT, “is a computer modeling program that provides a functional assessment of blood flow in the coronary arteries from detailed anatomical data,” Dr. William Maisel, deputy director for science and chief scientist in the FDA’s Center for Devices and Radiological Health, said in the FDA statement. He described it as a noninvasive method that “is an additional tool for clinicians who are considering the risks and benefits of invasive coronary procedures.”
The healthcare professional transmits a patient’s coronary CT scan data to the headquarters of the manufacturer, HeartFlow, where an analyst creates 3-D models of the patient’s heart and runs a blood flow simulator program on the models. The clinician is then sent a report with the estimated fractional flow reserve (FFR)-CT values “displayed as color images of the patient’s heart,” according to the FDA statement.
The FDA cleared the device based on data that compared FFR-CT measurements to those obtained with cardiac catheterization in patients with suspected coronary artery disease. The FFR-CT measurements correctly identified 84% of the significant blockages that FFR identified as requiring intervention, and 86% of blockages that FFR identified as not requiring intervention, according to the FDA.
Software that provides an estimate of a patient’s fractional flow reserve using data from a coronary CT scan has been cleared for marketing, the Food and Drug Administration announced Nov. 26.
The software, HeartFlow FFRCT, “is a computer modeling program that provides a functional assessment of blood flow in the coronary arteries from detailed anatomical data,” Dr. William Maisel, deputy director for science and chief scientist in the FDA’s Center for Devices and Radiological Health, said in the FDA statement. He described it as a noninvasive method that “is an additional tool for clinicians who are considering the risks and benefits of invasive coronary procedures.”
The healthcare professional transmits a patient’s coronary CT scan data to the headquarters of the manufacturer, HeartFlow, where an analyst creates 3-D models of the patient’s heart and runs a blood flow simulator program on the models. The clinician is then sent a report with the estimated fractional flow reserve (FFR)-CT values “displayed as color images of the patient’s heart,” according to the FDA statement.
The FDA cleared the device based on data that compared FFR-CT measurements to those obtained with cardiac catheterization in patients with suspected coronary artery disease. The FFR-CT measurements correctly identified 84% of the significant blockages that FFR identified as requiring intervention, and 86% of blockages that FFR identified as not requiring intervention, according to the FDA.
Software that provides an estimate of a patient’s fractional flow reserve using data from a coronary CT scan has been cleared for marketing, the Food and Drug Administration announced Nov. 26.
The software, HeartFlow FFRCT, “is a computer modeling program that provides a functional assessment of blood flow in the coronary arteries from detailed anatomical data,” Dr. William Maisel, deputy director for science and chief scientist in the FDA’s Center for Devices and Radiological Health, said in the FDA statement. He described it as a noninvasive method that “is an additional tool for clinicians who are considering the risks and benefits of invasive coronary procedures.”
The healthcare professional transmits a patient’s coronary CT scan data to the headquarters of the manufacturer, HeartFlow, where an analyst creates 3-D models of the patient’s heart and runs a blood flow simulator program on the models. The clinician is then sent a report with the estimated fractional flow reserve (FFR)-CT values “displayed as color images of the patient’s heart,” according to the FDA statement.
The FDA cleared the device based on data that compared FFR-CT measurements to those obtained with cardiac catheterization in patients with suspected coronary artery disease. The FFR-CT measurements correctly identified 84% of the significant blockages that FFR identified as requiring intervention, and 86% of blockages that FFR identified as not requiring intervention, according to the FDA.
FDA Panel Addresses Neurologic Risks of Epidural Steroid Injections
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
Continued on next page >>
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
Continued on next page >>
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
Continued on next page >>
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
AT AN FDA ADVISORY COMMITTEE MEETING
FDA panel addresses neurologic risks of epidural steroid injections
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
SILVER SPRING, MD. – A Food and Drug Administration advisory panel recommended that a contraindication or warning be added to the labels of injectable corticosteroids, specifically pertaining to transforaminal administration of particulate steroid formulations administered into the cervical spine, at a meeting held to address serious neurologic events associated with epidural steroid injections.
The FDA convened the Nov. 24-25 meeting of its Anesthetic and Analgesic Drug Products Advisory Committee to discuss the available evidence of the benefits of epidural steroid injections (ESIs), widely used off label to treat back pain, and the serious neurologic adverse events associated with ESIs. These events include strokes, paraplegia, quadriplegia, spinal cord infarction, and deaths, and they are the basis of the class warning added to the labels of these products this year.
In April 2014, the FDA issued a safety communication about these reports, warning that “injection of corticosteroids into the epidural space of the spine may result in rare but serious adverse events, including loss of vision, stroke, paralysis, and death.” An estimated 9 million ESIs are administered each year in the United States.
The panel voted 15-7, with one abstention, in favor of a contraindication, while those voting no supported a warning as more appropriate. The original voting question on the agenda was whether all epidural steroid injections should be contraindicated, but the FDA reworded the question because the panelists felt it was too broad.
Dr. Michael Weisman, director of the division of rheumatology at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, said that, considering the wide variety of conditions treated with ESIs and the complicated anatomy of the spine, the benefits of depot formulations, particularly in the cervical spine, do not outweigh the significant risks. The risk is small, “but when it happens, it is very significant,” he said.
Dr. Jeffrey Kirsch, professor and chair of the department of anesthesiology and perioperative medicine at Oregon Health and Science University, Portland, supported the contraindication because “it’s too risky to administer the particulate medication in the cervical region, because of the risk of intravascular and intraarterial injection.”
In the medical literature, corticosteroids are classified as particulate or nonparticulate formulations, but the FDA uses the terms suspension or solution to classify steroids. Some studies have suggested that the risks and benefits of the two formulations may be different, and the agency has been criticized for not distinguishing between particulate and nonparticulate products in the warning statement.
Based on the available data, which had substantial limitations, the panelists were most concerned with the risks of epidural injections of particulate steroid products administered into the cervical spine with a transforaminal (TFA) approach because of a greater risk of accidental injection into the vasculature. They also noted that the risks were not limited to TFA cervical administration or to particulate products. As one panelist put it, “Why would anybody want sludge injected into their artery that goes to the brain?”
Based on the available evidence, the panel generally agreed that ESIs can have moderate beneficial effects in treating back pain, with substantial variations between patients, and that these benefits should be considered in the context of the risks and benefits of alternative therapies. They also said that there was not enough evidence to support a particular injection method or location or steroid formulation as superior. As one panelist pointed out, depot formulations may be more effective than nondepot formulations, but the differences are marginal and the risks are greater. One panelist supported a contraindication for all particulate injections for epidural use.
The FDA has been evaluating serious neurologic events associated with ESIs since 2009, after being contacted by an anesthesiologist about the risk of catastrophic neurologic injuries associated with TFA epidural injections of depot steroid formulations.
A review of events reported to the FDA’s Adverse Event Reporting System (FAERS) between November 1997 and April 2014 identified 90 cases of serious neurologic events associated with ESIs, including quadriplegia in a 53-year-old man who developed weakness in the left arm and both legs shortly after a triamcinolone injection – an MRI showed a diffuse vascular infarct to the cervical cord. As of April 2014, the FDA also received 41 reports of arachnoiditis in patients being treated for a variety of indications, most often unspecified back pain.
As with the FAERS data, cases identified in a medical literature review of studies between August 2012 and August 2014, also presented by the FDA at the meeting, were diverse. Cases were reported with cervical and lumbar TFA and interlaminar injections. No catastrophic cases associated with nonparticulate (solution) formulations were reported, but it is unclear whether that is related to the safety profile or lower use of nonparticulate formulations, according to the agency.
One of the panelists, Dr. Michael Sprintz, chief medical officer of the Sprintz Center for Pain and Dependency, The Woodlands, Tex., cautioned that the consequences of not having ESIs available should be considered. “By limiting patient access to these procedures, most pain docs are left with very little” to help these patients, which could result in a “massive increase” in opioid prescriptions, he said.
There are five injectable corticosteroids marketed in the United States: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, and triamcinolone. In 2011, a statement was added to the labeling of injectable triamcinolone (Kenalog-10 and -40), manufactured by Bristol-Myers Squibb, that it was “not for epidural or intrathecal use.”
In 2013, about 420,000 people aged 65 years and older received ESIs, based on Medicare data, and about 604,000 people younger than 65 years in a national database of commercially insured patients also received ESIs. Both figures represent increases since 2009, according to the FDA. In both groups, almost half were TFA injections, most steroids used were suspensions, and more than one-third of the ESIs used were steroid suspensions administered by the TFA route.
The panelists had no conflicts to disclose. The FDA usually follows the recommendations of its advisory panels.
Serious adverse events associated with the use of epidural steroid injections should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/ or 800-332-1088.
AT AN FDA ADVISORY COMMITTEE MEETING
FDA approves extended-release hydrocodone with abuse-deterrent features
An extended-release formulation of hydrocodone with properties that are “expected to reduce, but not totally prevent” abuse has been approved, the Food and Drug Administration announced on Nov. 20.
The hydrocodone-only product is indicated for treating pain “severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate,” according to the FDA statement. It is not approved for as-needed pain relief, and because of its risks for abuse, misuse, and addiction, “should only be prescribed to people for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient pain management,” the FDA statement said.
The product will be marketed as Hysingla ER, by Purdue Pharma, the manufacturer of extended-release oxycodone marketed as OxyContin.
Hysingla ER comes in 20-mg, 30-mg, 40-mg, 60-mg , 100-mg, and 120-mg strengths, taken once a day; daily doses of 80 mg or more should not be prescribed to people who have not previously been treated with an opioid. These amounts are higher than immediate-release hydrocodone combination products, but the range is “comparable” to currently available extended-release opioids, the statement points out.
The tablet has properties that make it difficult to crush, break, or dissolve. It also forms a thick gel when put in liquid, which “resists passage through a hypodermic needle,” according to the prescribing information. While the product’s physical and chemical properties are expected to make abuse by these routes difficult, abuse by these routes is still possible, the FDA statement said.
As part of the FDA’s Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, Purdue is required to provide health care professionals with information on how to safely prescribe the drug and to provide documents to patients, including a medication guide with each prescription, about how to safely use, store, and dispose of these products.
The company is also required to conduct postmarketing studies to evaluate the impact of the abuse-deterrent properties on the risk of abuse and the impact of that abuse in the community, according to the statement.
“While the science of abuse deterrence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the U.S.,” Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said in the statement. “Encouraging the development of opioids with abuse-deterrent properties is just one component of a broader approach to reducing abuse and misuse and will better enable the agency to balance addressing this problem with ensuring that patients have access to appropriate treatments for pain,” she added.
In October, hydrocodone was switched from a schedule III to the stricter schedule II category.
Hysingla ER is expected to be available in early 2015, according to a statement by Purdue.
In August 2014, hydrocodone was switched from a schedule III to a schedule II controlled substance.
The prescribing information is available at http://www.purduepharma.com/wp-content/uploads/hysinglaerpi.pdf.
An extended-release formulation of hydrocodone with properties that are “expected to reduce, but not totally prevent” abuse has been approved, the Food and Drug Administration announced on Nov. 20.
The hydrocodone-only product is indicated for treating pain “severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate,” according to the FDA statement. It is not approved for as-needed pain relief, and because of its risks for abuse, misuse, and addiction, “should only be prescribed to people for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient pain management,” the FDA statement said.
The product will be marketed as Hysingla ER, by Purdue Pharma, the manufacturer of extended-release oxycodone marketed as OxyContin.
Hysingla ER comes in 20-mg, 30-mg, 40-mg, 60-mg , 100-mg, and 120-mg strengths, taken once a day; daily doses of 80 mg or more should not be prescribed to people who have not previously been treated with an opioid. These amounts are higher than immediate-release hydrocodone combination products, but the range is “comparable” to currently available extended-release opioids, the statement points out.
The tablet has properties that make it difficult to crush, break, or dissolve. It also forms a thick gel when put in liquid, which “resists passage through a hypodermic needle,” according to the prescribing information. While the product’s physical and chemical properties are expected to make abuse by these routes difficult, abuse by these routes is still possible, the FDA statement said.
As part of the FDA’s Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, Purdue is required to provide health care professionals with information on how to safely prescribe the drug and to provide documents to patients, including a medication guide with each prescription, about how to safely use, store, and dispose of these products.
The company is also required to conduct postmarketing studies to evaluate the impact of the abuse-deterrent properties on the risk of abuse and the impact of that abuse in the community, according to the statement.
“While the science of abuse deterrence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the U.S.,” Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said in the statement. “Encouraging the development of opioids with abuse-deterrent properties is just one component of a broader approach to reducing abuse and misuse and will better enable the agency to balance addressing this problem with ensuring that patients have access to appropriate treatments for pain,” she added.
In October, hydrocodone was switched from a schedule III to the stricter schedule II category.
Hysingla ER is expected to be available in early 2015, according to a statement by Purdue.
In August 2014, hydrocodone was switched from a schedule III to a schedule II controlled substance.
The prescribing information is available at http://www.purduepharma.com/wp-content/uploads/hysinglaerpi.pdf.
An extended-release formulation of hydrocodone with properties that are “expected to reduce, but not totally prevent” abuse has been approved, the Food and Drug Administration announced on Nov. 20.
The hydrocodone-only product is indicated for treating pain “severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate,” according to the FDA statement. It is not approved for as-needed pain relief, and because of its risks for abuse, misuse, and addiction, “should only be prescribed to people for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient pain management,” the FDA statement said.
The product will be marketed as Hysingla ER, by Purdue Pharma, the manufacturer of extended-release oxycodone marketed as OxyContin.
Hysingla ER comes in 20-mg, 30-mg, 40-mg, 60-mg , 100-mg, and 120-mg strengths, taken once a day; daily doses of 80 mg or more should not be prescribed to people who have not previously been treated with an opioid. These amounts are higher than immediate-release hydrocodone combination products, but the range is “comparable” to currently available extended-release opioids, the statement points out.
The tablet has properties that make it difficult to crush, break, or dissolve. It also forms a thick gel when put in liquid, which “resists passage through a hypodermic needle,” according to the prescribing information. While the product’s physical and chemical properties are expected to make abuse by these routes difficult, abuse by these routes is still possible, the FDA statement said.
As part of the FDA’s Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, Purdue is required to provide health care professionals with information on how to safely prescribe the drug and to provide documents to patients, including a medication guide with each prescription, about how to safely use, store, and dispose of these products.
The company is also required to conduct postmarketing studies to evaluate the impact of the abuse-deterrent properties on the risk of abuse and the impact of that abuse in the community, according to the statement.
“While the science of abuse deterrence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the U.S.,” Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said in the statement. “Encouraging the development of opioids with abuse-deterrent properties is just one component of a broader approach to reducing abuse and misuse and will better enable the agency to balance addressing this problem with ensuring that patients have access to appropriate treatments for pain,” she added.
In October, hydrocodone was switched from a schedule III to the stricter schedule II category.
Hysingla ER is expected to be available in early 2015, according to a statement by Purdue.
In August 2014, hydrocodone was switched from a schedule III to a schedule II controlled substance.
The prescribing information is available at http://www.purduepharma.com/wp-content/uploads/hysinglaerpi.pdf.
FROM THE FDA
Mastectomies, reconstruction, on the rise for women with early stage disease
Significant increases in the mastectomy rate among women with early breast cancer who were candidates for breast conservation surgery during a recent 14-year period in the United States were accompanied by increases in breast reconstruction and bilateral mastectomies, in a retrospective cohort study that tracked national trends in this group of women.
The results, based on outcomes of about 1.2 million women with early breast cancer in a national oncology outcomes database, “are generally consistent with trends noted in other state, regional, and national studies,” reported Dr. Kristy Kummerow of the division of surgical oncology and endocrine surgery, Vanderbilt University, Nashville, Tenn., and her associates. While they speculated on some of the reasons behind these findings, “further research is needed to understand patient, provider, policy, and social factors associated with these trends,” they concluded in the study, which was published online Nov. 19 in JAMA Surgery (doi:10.1001/jamasurg.2014.2895).
While the use of breast conservation surgery (BCS) as an alternative to mastectomy for early-stage breast cancer increased steadily after studies showed the two approaches had equal outcomes, and after endorsement by a National Institutes of Health Consensus Conference in 1990, the authors noted that there has been evidence that the trend is reversing.
Using data from the National Cancer Data Base, which collects outcomes data on about 70% of the patients diagnosed with cancer in the United States, they evaluated trends in mastectomies among adult women newly diagnosed with early (unilateral) breast cancer from January 1998 through December 2011. Women were included if TNM stage information was available, tumors were 5 cm or less with nine or fewer involved axillary lymph nodes based on clinical staging, and they underwent BCS (lumpectomy, segmental mastectomy, or re-excision of the biopsy site) or mastectomy (subcutaneous, total, modified radical or radical).
Over the 14-year period, among the approximately 1.2 million women who met the criteria, 64.5% had BCS and 35.5% had a mastectomy. The women who had a mastectomy were slightly younger (mean age 59.6 years vs. 61.6 years), and the proportion of racial and ethnic minorities was lower in this group.
The proportion of women eligible for BCS who underwent a mastectomy increased from 34.3% in 1998 to 37.8% in 2011, a statistically significant increase, “with steeper increases” seen in women who had node-negative and noninvasive disease, the authors reported. For the most recent 8-year period – 2003 to 2011 – the rate increased by 34%, “with the most notable rise in mastectomy rates occurring after 2006,” and the highest increases seen among women with clinically node-negative disease. Age and tumor size were “the most influential covariates,” with younger women “more likely to undergo mastectomy irrespective of tumor size, while in older women mastectomy was strongly associated with tumor size greater than 2 cm.”
During the period studied, there were significant increases in breast reconstruction and bilateral mastectomies among women who had mastectomies, which were secondary outcome measures. The proportion of women who underwent breast reconstruction increased from 11.6% in 1998 to 36.4% in 2011, and the proportion of women who had a bilateral mastectomy for unilateral disease increased from 1.9% to 11.2% during this period. The trend toward more reconstruction surgery could be due to 1998 legislation mandating insurance coverage of reconstructive surgery after mastectomy, the authors wrote.
Study limitations included missing clinical staging information for a large proportion of the women, no information on BRCA status or triple-negative tumors, and an inability to determine why the mastectomy was performed in individual cases, they noted.
None of the authors had disclosures to report. The study is based on work supported by the Office of Academic Affiliations, Department of Veterans Affairs, the VA National Quality Scholars Program, and with the use of facilities at the VA Tennessee Valley Healthcare System, Nashville.
In an accompanying editorial, Dr. Bonnie Sun and Dr. Michael Zenilman wrote that the “surprising rise” in the mastectomy rate for women with early stage breast cancers in this study raises various questions, including whether all the patients were candidates for BCS, which is difficult to determine “without accounting for findings on magnetic resonance imaging, family history, clinical stage, and tumor to breast ratio.” Another question is why the women chose a mastectomy and whether the reasons for that choice were valid. “While the choice to pursue mastectomy over BCS is never wrong, it must be made for the right reasons,” they said, adding, “when presenting these surgical options, we must ensure that decisions are not based on misconceptions.” This study “ should at least serve as a wake-up call that as we fulfill that responsibility, and use every modality of care to give patients the best quality of life and survival advantage, the guidelines may need to change again,” they wrote (JAMA Surgery 2014 Nov. 19 [doi:10.1001/jamasurg.2014.2902)].
Dr. Bonnie Sun and Dr. Michael E. Zenilman are in the department of surgery, Johns Hopkins Medicine, Bethesda, Md. Dr. Zenilman is a consultant for Champions in Oncology; Dr. Sun had no disclosures to report.
In an accompanying editorial, Dr. Bonnie Sun and Dr. Michael Zenilman wrote that the “surprising rise” in the mastectomy rate for women with early stage breast cancers in this study raises various questions, including whether all the patients were candidates for BCS, which is difficult to determine “without accounting for findings on magnetic resonance imaging, family history, clinical stage, and tumor to breast ratio.” Another question is why the women chose a mastectomy and whether the reasons for that choice were valid. “While the choice to pursue mastectomy over BCS is never wrong, it must be made for the right reasons,” they said, adding, “when presenting these surgical options, we must ensure that decisions are not based on misconceptions.” This study “ should at least serve as a wake-up call that as we fulfill that responsibility, and use every modality of care to give patients the best quality of life and survival advantage, the guidelines may need to change again,” they wrote (JAMA Surgery 2014 Nov. 19 [doi:10.1001/jamasurg.2014.2902)].
Dr. Bonnie Sun and Dr. Michael E. Zenilman are in the department of surgery, Johns Hopkins Medicine, Bethesda, Md. Dr. Zenilman is a consultant for Champions in Oncology; Dr. Sun had no disclosures to report.
In an accompanying editorial, Dr. Bonnie Sun and Dr. Michael Zenilman wrote that the “surprising rise” in the mastectomy rate for women with early stage breast cancers in this study raises various questions, including whether all the patients were candidates for BCS, which is difficult to determine “without accounting for findings on magnetic resonance imaging, family history, clinical stage, and tumor to breast ratio.” Another question is why the women chose a mastectomy and whether the reasons for that choice were valid. “While the choice to pursue mastectomy over BCS is never wrong, it must be made for the right reasons,” they said, adding, “when presenting these surgical options, we must ensure that decisions are not based on misconceptions.” This study “ should at least serve as a wake-up call that as we fulfill that responsibility, and use every modality of care to give patients the best quality of life and survival advantage, the guidelines may need to change again,” they wrote (JAMA Surgery 2014 Nov. 19 [doi:10.1001/jamasurg.2014.2902)].
Dr. Bonnie Sun and Dr. Michael E. Zenilman are in the department of surgery, Johns Hopkins Medicine, Bethesda, Md. Dr. Zenilman is a consultant for Champions in Oncology; Dr. Sun had no disclosures to report.
Significant increases in the mastectomy rate among women with early breast cancer who were candidates for breast conservation surgery during a recent 14-year period in the United States were accompanied by increases in breast reconstruction and bilateral mastectomies, in a retrospective cohort study that tracked national trends in this group of women.
The results, based on outcomes of about 1.2 million women with early breast cancer in a national oncology outcomes database, “are generally consistent with trends noted in other state, regional, and national studies,” reported Dr. Kristy Kummerow of the division of surgical oncology and endocrine surgery, Vanderbilt University, Nashville, Tenn., and her associates. While they speculated on some of the reasons behind these findings, “further research is needed to understand patient, provider, policy, and social factors associated with these trends,” they concluded in the study, which was published online Nov. 19 in JAMA Surgery (doi:10.1001/jamasurg.2014.2895).
While the use of breast conservation surgery (BCS) as an alternative to mastectomy for early-stage breast cancer increased steadily after studies showed the two approaches had equal outcomes, and after endorsement by a National Institutes of Health Consensus Conference in 1990, the authors noted that there has been evidence that the trend is reversing.
Using data from the National Cancer Data Base, which collects outcomes data on about 70% of the patients diagnosed with cancer in the United States, they evaluated trends in mastectomies among adult women newly diagnosed with early (unilateral) breast cancer from January 1998 through December 2011. Women were included if TNM stage information was available, tumors were 5 cm or less with nine or fewer involved axillary lymph nodes based on clinical staging, and they underwent BCS (lumpectomy, segmental mastectomy, or re-excision of the biopsy site) or mastectomy (subcutaneous, total, modified radical or radical).
Over the 14-year period, among the approximately 1.2 million women who met the criteria, 64.5% had BCS and 35.5% had a mastectomy. The women who had a mastectomy were slightly younger (mean age 59.6 years vs. 61.6 years), and the proportion of racial and ethnic minorities was lower in this group.
The proportion of women eligible for BCS who underwent a mastectomy increased from 34.3% in 1998 to 37.8% in 2011, a statistically significant increase, “with steeper increases” seen in women who had node-negative and noninvasive disease, the authors reported. For the most recent 8-year period – 2003 to 2011 – the rate increased by 34%, “with the most notable rise in mastectomy rates occurring after 2006,” and the highest increases seen among women with clinically node-negative disease. Age and tumor size were “the most influential covariates,” with younger women “more likely to undergo mastectomy irrespective of tumor size, while in older women mastectomy was strongly associated with tumor size greater than 2 cm.”
During the period studied, there were significant increases in breast reconstruction and bilateral mastectomies among women who had mastectomies, which were secondary outcome measures. The proportion of women who underwent breast reconstruction increased from 11.6% in 1998 to 36.4% in 2011, and the proportion of women who had a bilateral mastectomy for unilateral disease increased from 1.9% to 11.2% during this period. The trend toward more reconstruction surgery could be due to 1998 legislation mandating insurance coverage of reconstructive surgery after mastectomy, the authors wrote.
Study limitations included missing clinical staging information for a large proportion of the women, no information on BRCA status or triple-negative tumors, and an inability to determine why the mastectomy was performed in individual cases, they noted.
None of the authors had disclosures to report. The study is based on work supported by the Office of Academic Affiliations, Department of Veterans Affairs, the VA National Quality Scholars Program, and with the use of facilities at the VA Tennessee Valley Healthcare System, Nashville.
Significant increases in the mastectomy rate among women with early breast cancer who were candidates for breast conservation surgery during a recent 14-year period in the United States were accompanied by increases in breast reconstruction and bilateral mastectomies, in a retrospective cohort study that tracked national trends in this group of women.
The results, based on outcomes of about 1.2 million women with early breast cancer in a national oncology outcomes database, “are generally consistent with trends noted in other state, regional, and national studies,” reported Dr. Kristy Kummerow of the division of surgical oncology and endocrine surgery, Vanderbilt University, Nashville, Tenn., and her associates. While they speculated on some of the reasons behind these findings, “further research is needed to understand patient, provider, policy, and social factors associated with these trends,” they concluded in the study, which was published online Nov. 19 in JAMA Surgery (doi:10.1001/jamasurg.2014.2895).
While the use of breast conservation surgery (BCS) as an alternative to mastectomy for early-stage breast cancer increased steadily after studies showed the two approaches had equal outcomes, and after endorsement by a National Institutes of Health Consensus Conference in 1990, the authors noted that there has been evidence that the trend is reversing.
Using data from the National Cancer Data Base, which collects outcomes data on about 70% of the patients diagnosed with cancer in the United States, they evaluated trends in mastectomies among adult women newly diagnosed with early (unilateral) breast cancer from January 1998 through December 2011. Women were included if TNM stage information was available, tumors were 5 cm or less with nine or fewer involved axillary lymph nodes based on clinical staging, and they underwent BCS (lumpectomy, segmental mastectomy, or re-excision of the biopsy site) or mastectomy (subcutaneous, total, modified radical or radical).
Over the 14-year period, among the approximately 1.2 million women who met the criteria, 64.5% had BCS and 35.5% had a mastectomy. The women who had a mastectomy were slightly younger (mean age 59.6 years vs. 61.6 years), and the proportion of racial and ethnic minorities was lower in this group.
The proportion of women eligible for BCS who underwent a mastectomy increased from 34.3% in 1998 to 37.8% in 2011, a statistically significant increase, “with steeper increases” seen in women who had node-negative and noninvasive disease, the authors reported. For the most recent 8-year period – 2003 to 2011 – the rate increased by 34%, “with the most notable rise in mastectomy rates occurring after 2006,” and the highest increases seen among women with clinically node-negative disease. Age and tumor size were “the most influential covariates,” with younger women “more likely to undergo mastectomy irrespective of tumor size, while in older women mastectomy was strongly associated with tumor size greater than 2 cm.”
During the period studied, there were significant increases in breast reconstruction and bilateral mastectomies among women who had mastectomies, which were secondary outcome measures. The proportion of women who underwent breast reconstruction increased from 11.6% in 1998 to 36.4% in 2011, and the proportion of women who had a bilateral mastectomy for unilateral disease increased from 1.9% to 11.2% during this period. The trend toward more reconstruction surgery could be due to 1998 legislation mandating insurance coverage of reconstructive surgery after mastectomy, the authors wrote.
Study limitations included missing clinical staging information for a large proportion of the women, no information on BRCA status or triple-negative tumors, and an inability to determine why the mastectomy was performed in individual cases, they noted.
None of the authors had disclosures to report. The study is based on work supported by the Office of Academic Affiliations, Department of Veterans Affairs, the VA National Quality Scholars Program, and with the use of facilities at the VA Tennessee Valley Healthcare System, Nashville.
FROM JAMA SURGERY
Key clinical point: Significantly more women with early breast cancer are undergoing mastectomy, despite being eligible for breast conservation surgery.
Major finding: The proportion of women with early breast cancer eligible for BCS who had a mastectomy increased from 34.3% in 1998 to 37.8% in 2011, a statistically significant increase.
Data source: A retrospective cohort study of trends during 1998-2011 in mastectomies among 1.2 million women with early breast cancer who were eligible for BCS and enrolled in the National Cancer Data Base.
Disclosures:None of the authors had disclosures to report. The study is based on work supported by the Office of Academic Affiliations, Department of Veterans Affairs , the VA National Quality Scholars Program, and with the use of facilities at the VA Tennessee Valley Healthcare System, Nashville.
Alemtuzumab, two-course infusion, approved for relapsing MS
Alemtuzumab, administered in two intravenous infusions over several days 1 year apart, has been approved by the Food and Drug Administration for patients with relapsing forms of multiple sclerosis, the manufacturer, Genzyme, announced on Nov. 14.
Alemtuzumab, a monoclonal antibody that targets CD52, a cell surface antigen present at high levels on T and B lymphocytes, will be marketed as Lemtrada. (Alemtuzumab was first approved in the United States in 2001 for treatment of B-cell chronic lymphocytic leukemia, and is marketed as Campath for that indication.)
“Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS,” according to the Genzyme statement. This wording is included in the approved indication in the prescribing information.
Exactly how alemtuzumab works in MS is unknown. After each treatment course, alemtuzumab “depletes circulating T and B lymphocytes,” which are “thought to be responsible for the damaging inflammatory process in MS,” according to Genzyme’s statement. “Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes.”
Approval is based on two phase III, open-label studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing-remitting MS. The CARE-MS I trial enrolled patients who had not been treated previously, whereas the CARE-MS II trial involved patients who had relapsed while on treatment.
In the CARE-MS I study of about 550 patients, the annualized relapse rate (ARR) over 2 years was significantly lower among those on alemtuzumab, compared with those on interferon beta-1a (0.18 vs. 0.39, a relative risk reduction of 55%). There were no significant differences in the time to confirmed disability progression or on the primary MRI endpoint of change in T2 lesion volume. After 2 years, 78% of those on alemtuzumab were relapse free vs. 59% of those on interferon beta-1a, a significant difference, according to the prescribing information.
In the CARE-MS II study of about 600 patients treated previously, the ARR over 2 years was significantly lower among those on alemtuzumab (0.26 vs. 0.52, a relative risk reduction of 49%) and the time to onset of 6-month confirmed disability progression was also significantly delayed. At year 2, 13% of those on alemtuzumab has disability progression, compared with 21% of those on interferon, a 42% relative risk reduction. At year 2, 65% of those on alemtuzumab were relapse free vs. 47% of those on interferon, which was statistically significant. There was no significant difference in T2 lesion volume changes between the two treatment groups.
The most common adverse events, affecting at least 10% of those treated and that were more common than in those treated with interferon beta-1a, were rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infections, diarrhea, and fatigue.
Because of its serious risks, alemtuzumab will be available through a restricted distribution program, as part of its Risk Evaluation and Mitigation Strategy. The label includes a boxed warning about the risks, which include serious, “sometimes fatal autoimmune conditions,” such as immune thrombocytopenia and antiglomerular basement membrane disease, “serious and life-threatening infusion reactions,” and an increased risk of malignancies.
The approval process for alemtuzumab for MS has been long. In December 2013, Genzyme announced that the FDA had declined to approve alemtuzumab for the treatment of MS because of a lack of well-controlled data from clinical studies indicating that the benefits outweighed the risks. That announcement followed a November 2013 meeting of an FDA advisory committee, which voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.
Among the company’s postmarketing requirements for the drug is a U.S. pregnancy registry study that will compare the maternal, fetal, and infant outcomes in women with MS exposed to Lemtrada during pregnancy and in control groups of women with and without MS who did not take the drug, according to the FDA’s approval letter.
The drug was approved for MS in September 2013 in the European Union and is approved in more than 40 countries, according to Genzyme, a Sanofi company.
This story was updated 11/18/2014.
Alemtuzumab, administered in two intravenous infusions over several days 1 year apart, has been approved by the Food and Drug Administration for patients with relapsing forms of multiple sclerosis, the manufacturer, Genzyme, announced on Nov. 14.
Alemtuzumab, a monoclonal antibody that targets CD52, a cell surface antigen present at high levels on T and B lymphocytes, will be marketed as Lemtrada. (Alemtuzumab was first approved in the United States in 2001 for treatment of B-cell chronic lymphocytic leukemia, and is marketed as Campath for that indication.)
“Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS,” according to the Genzyme statement. This wording is included in the approved indication in the prescribing information.
Exactly how alemtuzumab works in MS is unknown. After each treatment course, alemtuzumab “depletes circulating T and B lymphocytes,” which are “thought to be responsible for the damaging inflammatory process in MS,” according to Genzyme’s statement. “Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes.”
Approval is based on two phase III, open-label studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing-remitting MS. The CARE-MS I trial enrolled patients who had not been treated previously, whereas the CARE-MS II trial involved patients who had relapsed while on treatment.
In the CARE-MS I study of about 550 patients, the annualized relapse rate (ARR) over 2 years was significantly lower among those on alemtuzumab, compared with those on interferon beta-1a (0.18 vs. 0.39, a relative risk reduction of 55%). There were no significant differences in the time to confirmed disability progression or on the primary MRI endpoint of change in T2 lesion volume. After 2 years, 78% of those on alemtuzumab were relapse free vs. 59% of those on interferon beta-1a, a significant difference, according to the prescribing information.
In the CARE-MS II study of about 600 patients treated previously, the ARR over 2 years was significantly lower among those on alemtuzumab (0.26 vs. 0.52, a relative risk reduction of 49%) and the time to onset of 6-month confirmed disability progression was also significantly delayed. At year 2, 13% of those on alemtuzumab has disability progression, compared with 21% of those on interferon, a 42% relative risk reduction. At year 2, 65% of those on alemtuzumab were relapse free vs. 47% of those on interferon, which was statistically significant. There was no significant difference in T2 lesion volume changes between the two treatment groups.
The most common adverse events, affecting at least 10% of those treated and that were more common than in those treated with interferon beta-1a, were rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infections, diarrhea, and fatigue.
Because of its serious risks, alemtuzumab will be available through a restricted distribution program, as part of its Risk Evaluation and Mitigation Strategy. The label includes a boxed warning about the risks, which include serious, “sometimes fatal autoimmune conditions,” such as immune thrombocytopenia and antiglomerular basement membrane disease, “serious and life-threatening infusion reactions,” and an increased risk of malignancies.
The approval process for alemtuzumab for MS has been long. In December 2013, Genzyme announced that the FDA had declined to approve alemtuzumab for the treatment of MS because of a lack of well-controlled data from clinical studies indicating that the benefits outweighed the risks. That announcement followed a November 2013 meeting of an FDA advisory committee, which voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.
Among the company’s postmarketing requirements for the drug is a U.S. pregnancy registry study that will compare the maternal, fetal, and infant outcomes in women with MS exposed to Lemtrada during pregnancy and in control groups of women with and without MS who did not take the drug, according to the FDA’s approval letter.
The drug was approved for MS in September 2013 in the European Union and is approved in more than 40 countries, according to Genzyme, a Sanofi company.
This story was updated 11/18/2014.
Alemtuzumab, administered in two intravenous infusions over several days 1 year apart, has been approved by the Food and Drug Administration for patients with relapsing forms of multiple sclerosis, the manufacturer, Genzyme, announced on Nov. 14.
Alemtuzumab, a monoclonal antibody that targets CD52, a cell surface antigen present at high levels on T and B lymphocytes, will be marketed as Lemtrada. (Alemtuzumab was first approved in the United States in 2001 for treatment of B-cell chronic lymphocytic leukemia, and is marketed as Campath for that indication.)
“Because of its safety profile, the use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS,” according to the Genzyme statement. This wording is included in the approved indication in the prescribing information.
Exactly how alemtuzumab works in MS is unknown. After each treatment course, alemtuzumab “depletes circulating T and B lymphocytes,” which are “thought to be responsible for the damaging inflammatory process in MS,” according to Genzyme’s statement. “Lymphocyte counts then increase over time with a reconstitution of the lymphocyte population that varies for the different lymphocyte subtypes.”
Approval is based on two phase III, open-label studies comparing treatment with alemtuzumab to high-dose subcutaneous interferon beta-1a (Rebif) in patients with relapsing-remitting MS. The CARE-MS I trial enrolled patients who had not been treated previously, whereas the CARE-MS II trial involved patients who had relapsed while on treatment.
In the CARE-MS I study of about 550 patients, the annualized relapse rate (ARR) over 2 years was significantly lower among those on alemtuzumab, compared with those on interferon beta-1a (0.18 vs. 0.39, a relative risk reduction of 55%). There were no significant differences in the time to confirmed disability progression or on the primary MRI endpoint of change in T2 lesion volume. After 2 years, 78% of those on alemtuzumab were relapse free vs. 59% of those on interferon beta-1a, a significant difference, according to the prescribing information.
In the CARE-MS II study of about 600 patients treated previously, the ARR over 2 years was significantly lower among those on alemtuzumab (0.26 vs. 0.52, a relative risk reduction of 49%) and the time to onset of 6-month confirmed disability progression was also significantly delayed. At year 2, 13% of those on alemtuzumab has disability progression, compared with 21% of those on interferon, a 42% relative risk reduction. At year 2, 65% of those on alemtuzumab were relapse free vs. 47% of those on interferon, which was statistically significant. There was no significant difference in T2 lesion volume changes between the two treatment groups.
The most common adverse events, affecting at least 10% of those treated and that were more common than in those treated with interferon beta-1a, were rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infections, diarrhea, and fatigue.
Because of its serious risks, alemtuzumab will be available through a restricted distribution program, as part of its Risk Evaluation and Mitigation Strategy. The label includes a boxed warning about the risks, which include serious, “sometimes fatal autoimmune conditions,” such as immune thrombocytopenia and antiglomerular basement membrane disease, “serious and life-threatening infusion reactions,” and an increased risk of malignancies.
The approval process for alemtuzumab for MS has been long. In December 2013, Genzyme announced that the FDA had declined to approve alemtuzumab for the treatment of MS because of a lack of well-controlled data from clinical studies indicating that the benefits outweighed the risks. That announcement followed a November 2013 meeting of an FDA advisory committee, which voted 12-6 that the manufacturer had provided substantial evidence that the drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.
Among the company’s postmarketing requirements for the drug is a U.S. pregnancy registry study that will compare the maternal, fetal, and infant outcomes in women with MS exposed to Lemtrada during pregnancy and in control groups of women with and without MS who did not take the drug, according to the FDA’s approval letter.
The drug was approved for MS in September 2013 in the European Union and is approved in more than 40 countries, according to Genzyme, a Sanofi company.
This story was updated 11/18/2014.