FDA’s new labeling rule: clinical implications

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at obnews@frontlinemedcom.com. Scan this QR code or go to obgynnews.com to view similar columns.

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at obnews@frontlinemedcom.com. Scan this QR code or go to obgynnews.com to view similar columns.

As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.

Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.

Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.

Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.

The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.

But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.

Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.

As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.

Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.

Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information about reproductive mental health. He has been a consultant to manufacturers of antidepressant medications and is the principal investigator of the National Pregnancy Registry for Atypical Antipsychotics, which receives support from the manufacturers of those drugs. To comment, e-mail him at obnews@frontlinemedcom.com. Scan this QR code or go to obgynnews.com to view similar columns.