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Update on pregnancy, lactation drug labeling after FDA ruling

A significant change to the labeling of many drug products officially occurred June 30, when a final rule issued by the FDA, the Pregnancy and Lactation Labeling Rule, became effective. This rule applies only to drug products available in the United States by prescription and does not affect the labeling of drug products available over-the-counter.

A drug product’s label is often informally referred to as its package insert, and it contains useful and invaluable information, including indications, dosing, adverse effects, contraindications and use in specific populations such as pregnant women and pediatrics, among other information. This information is vital for the safe and effective use of the drug product.

Edward A. Bell

The FDA does not “approve” a drug product, as is commonly stated, but rather it is the drug product’s labeling that is approved by the FDA. More accurate phrasing would be “This drug is not labeled for this use” as opposed to “This drug is not approved for this use.” How drug products are used for patient care is left to the discretion of the medical community, and quite often drug products are used “off-label,” as pediatric clinicians know all too well.

Novel pregnancy labeling

Descriptions of drug use safety during pregnancy that are most familiar to Infectious Diseases in Children readers include the use of the pregnancy categories ABCDX. Use of these categories began more than 35 years ago, and they are now eliminated with the new Pregnancy and Lactation Labeling Rule (PLLR). Problems with use of these categories have been recognized for many years, however, including a potential for oversimplification of potential risk involved when a drug with a specific risk-letter category is given to a pregnant female.

Use of the current letter system additionally implies a graded level of risk, and risk similarities among drugs within the same letter category, which often is not accurate. The most commonly assigned pregnancy category is C, which states that “animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans ...” or “animal studies have not been conducted and there are no adequate and well-controlled studies in humans.” The current pregnancy classification system, thus, has been criticized as too ambiguous and difficult to apply clinically.

Recognizing these problems, the FDA proposed improvements for drug use safety pregnancy labeling in 2008. Specific drug product labeling — for example, the product’s package insert — will be revised to meet these new requirements, although this may take up to 3 to 5 years to occur for many drug products. Drugs newly labeled, after June 30, will include these new labeling requirements. For example, Daklinza (daclatasvir, Bristol-Myers Squibb) was labeled for use by the FDA in July for treatment of chronic hepatitis C genotype 3 infection in adults. Daclatasvir’s label includes the new pregnancy and lactation labeling (http://packageinserts.bms.com/pi/pi_daklinza.pdf).

More detailed labeling

With application of the PLLR, the type of information included in a drug’s labeling will not largely change. How the information is organized and described in headings, and the amount of information within the label, will improve, however. Use of the subheadings Nursing Mothers and Labor and Delivery in drug labeling will be eliminated. New labeling information will include three sections: 8.1) Pregnancy, 8.2) Lactation and 8.3) Females and Males of Reproductive Potential.

The Pregnancy section will include information organized into three subheadings: Risk Summary, Clinical Considerations, and Data. This information will include potential risks to the developing fetus (including as assessment of risk), known dosing alterations during pregnancy, effects of timing and duration of exposure during pregnancy, maternal adverse reactions, effects of the drug on labor or delivery, and information on pregnancy exposure registry for the drug, if one exists. A pregnancy exposure registry is an observational study with the purpose of collecting health information from women who take prescription drug products while pregnant. Current pregnancy exposure registries can be viewed online at the FDA’s Office of Women’s Health.

Updated breast-feeding, reproductive information

Information described in Risk Summary will include an assessment, characterization and summary of known risks to the developing fetus. The Data subheading will include separate animal and human data, if known. The Lactation section will similarly include three subheadings: Risk Summary, Clinical Considerations, and Data. If human data are available, information may include drug concentrations in milk and relative to plasma concentration, and effects of the drug upon milk production, if known. If data for a drug demonstrate that it does not affect the quantity or quality of human milk and it is likely that the drug is not detectable in human milk (or the amount likely to be consumed will not adversely affect the infant), the label will describe the drug as compatible with breast-feeding.

A new section will be included in drug labeling as required by PLLR, Females and Males of Reproductive Potential. This section will include information describing when pregnancy testing or contraception is required or recommended before, during or after use of the drug product, and relevant animal or human data suggest drug-associated fertility effects. Subheadings will include Pregnancy Testing, Contraception and Infertility.

With implantation of a final rule mandated by the FDA this year affecting drug labeling, additional and improved information on drug use in pregnancy and lactation will become available to health care practitioners. Use of the ABCDX pregnancy risk categories, although familiar to all of us, will be eliminated and replaced by narrative information. This will include standardized, clarified and additional information that can assist clinicians to apply such information to specific clinical scenarios and patients.

Disclosure: Bell reports no relevant financial disclosures.

A significant change to the labeling of many drug products officially occurred June 30, when a final rule issued by the FDA, the Pregnancy and Lactation Labeling Rule, became effective. This rule applies only to drug products available in the United States by prescription and does not affect the labeling of drug products available over-the-counter.

A drug product’s label is often informally referred to as its package insert, and it contains useful and invaluable information, including indications, dosing, adverse effects, contraindications and use in specific populations such as pregnant women and pediatrics, among other information. This information is vital for the safe and effective use of the drug product.

Edward A. Bell

The FDA does not “approve” a drug product, as is commonly stated, but rather it is the drug product’s labeling that is approved by the FDA. More accurate phrasing would be “This drug is not labeled for this use” as opposed to “This drug is not approved for this use.” How drug products are used for patient care is left to the discretion of the medical community, and quite often drug products are used “off-label,” as pediatric clinicians know all too well.

Novel pregnancy labeling

Descriptions of drug use safety during pregnancy that are most familiar to Infectious Diseases in Children readers include the use of the pregnancy categories ABCDX. Use of these categories began more than 35 years ago, and they are now eliminated with the new Pregnancy and Lactation Labeling Rule (PLLR). Problems with use of these categories have been recognized for many years, however, including a potential for oversimplification of potential risk involved when a drug with a specific risk-letter category is given to a pregnant female.

Use of the current letter system additionally implies a graded level of risk, and risk similarities among drugs within the same letter category, which often is not accurate. The most commonly assigned pregnancy category is C, which states that “animal studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans ...” or “animal studies have not been conducted and there are no adequate and well-controlled studies in humans.” The current pregnancy classification system, thus, has been criticized as too ambiguous and difficult to apply clinically.

Recognizing these problems, the FDA proposed improvements for drug use safety pregnancy labeling in 2008. Specific drug product labeling — for example, the product’s package insert — will be revised to meet these new requirements, although this may take up to 3 to 5 years to occur for many drug products. Drugs newly labeled, after June 30, will include these new labeling requirements. For example, Daklinza (daclatasvir, Bristol-Myers Squibb) was labeled for use by the FDA in July for treatment of chronic hepatitis C genotype 3 infection in adults. Daclatasvir’s label includes the new pregnancy and lactation labeling (http://packageinserts.bms.com/pi/pi_daklinza.pdf).

More detailed labeling

With application of the PLLR, the type of information included in a drug’s labeling will not largely change. How the information is organized and described in headings, and the amount of information within the label, will improve, however. Use of the subheadings Nursing Mothers and Labor and Delivery in drug labeling will be eliminated. New labeling information will include three sections: 8.1) Pregnancy, 8.2) Lactation and 8.3) Females and Males of Reproductive Potential.

The Pregnancy section will include information organized into three subheadings: Risk Summary, Clinical Considerations, and Data. This information will include potential risks to the developing fetus (including as assessment of risk), known dosing alterations during pregnancy, effects of timing and duration of exposure during pregnancy, maternal adverse reactions, effects of the drug on labor or delivery, and information on pregnancy exposure registry for the drug, if one exists. A pregnancy exposure registry is an observational study with the purpose of collecting health information from women who take prescription drug products while pregnant. Current pregnancy exposure registries can be viewed online at the FDA’s Office of Women’s Health.

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Updated breast-feeding, reproductive information

Information described in Risk Summary will include an assessment, characterization and summary of known risks to the developing fetus. The Data subheading will include separate animal and human data, if known. The Lactation section will similarly include three subheadings: Risk Summary, Clinical Considerations, and Data. If human data are available, information may include drug concentrations in milk and relative to plasma concentration, and effects of the drug upon milk production, if known. If data for a drug demonstrate that it does not affect the quantity or quality of human milk and it is likely that the drug is not detectable in human milk (or the amount likely to be consumed will not adversely affect the infant), the label will describe the drug as compatible with breast-feeding.

A new section will be included in drug labeling as required by PLLR, Females and Males of Reproductive Potential. This section will include information describing when pregnancy testing or contraception is required or recommended before, during or after use of the drug product, and relevant animal or human data suggest drug-associated fertility effects. Subheadings will include Pregnancy Testing, Contraception and Infertility.

With implantation of a final rule mandated by the FDA this year affecting drug labeling, additional and improved information on drug use in pregnancy and lactation will become available to health care practitioners. Use of the ABCDX pregnancy risk categories, although familiar to all of us, will be eliminated and replaced by narrative information. This will include standardized, clarified and additional information that can assist clinicians to apply such information to specific clinical scenarios and patients.

Disclosure: Bell reports no relevant financial disclosures.