As noted earlier, prescription drugs are labeled for the healthcare professional, not the patient.
The applicable regulations are somewhat detailed and, in general, require the following information on the commercial label (21 C.F.R. §§ 201.1 201.55 and 201.100):
The name and address of the manufacturer, packer, or distributor
The established name of the drug product
Ingredient information, including the quantity and proportion of each active ingredient
Names of inactive ingredients (with certain exceptions) if not for oral use
A statement of identity (generic and proprietary names)
The quantity in terms of weight or measure (e.g., 100 mg)
The net quantity of the container (e.g., 100 tablets)
A statement of the recommended or usual dosage or reference to the package insert
The symbol "Rx only" or the legend (e.g., "Caution: Federal law prohibits dispensing without prescription")
The route of administration, if it is not for oral use
An identifying lot or control number
A statement directed to the pharmacist specifying the type of container to be used in dispensing the drug (e.g., "Dispense in tight, light-resistant container as defined in the National Formulary")
The expiration date, unless exempted (Note: When an expiration date is stated only in month and year, the expiration date is the last day of the month.)
If the container is too small or unable to accommodate a label with space for all the information and is packaged within an outer container, the recommended dosage, route of administration, inactive ingredients, and statement regarding type of container may be contained in other labeling on or within the package. Moreover, the "Rx only" statement may be placed only on the outer container and the lot number may be printed on the crimp of the dispensing tube.
Unit dose packaging refers to when a single dosage unit of a drug is packaged for direct administration to a patient. Many hospitals, skilled nursing facilities, and other institutions commonly use unit dose systems because they reduce errors and diversion and permit the return of unused sealed doses. It would not be practical to require the label of a unit dose package to contain the same information as a commercial container because of the package size. Thus, the FDA's compliance policy guidance specifies the manufacturer's label on the unit dose container of a solid or liquid oral dosage form prescription drug to include (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cpg-sec-430100-unit-dose-labeling-solid-and-liquid-oral-dosage-forms):
The established name of the drug
The quantity of the active ingredient in each dosage unit
The expiration date
The lot or control number
The name and place of business of the manufacturer, packer, or distributor
Any statements required by a compendia if an official drug, or for unofficial drugs, any pertinent statement regarding special characteristics
The number of dosage units contained, if more than one dosage, and the strength per dosage unit
The statement "Warning: May be habit forming" where applicable
The controlled drug symbol if required by the DEA
The package insert is a pamphlet that must accompany the drug product and contains the essential scientific and medical information needed for safe and effective use of the drug by healthcare professionals. It cannot be promotional in nature, false, or misleading. FDA regulations specify not only the contents and format of the prescription drug's label but also the package insert and other labeling (21 C.F.R. §§ 201.56, 201.57, and 201.100).
Healthcare professionals had not found the package insert very useful and many did not use it as their primary source of drug information. They found that the format and content of the insert made it difficult to read and difficult to distinguish important information and warnings from information clutter and "legalese." In 2000, after evaluating extensive information and feedback from healthcare professionals regarding how the content and format of the package insert could be improved to enhance safer and more effective use of prescription drugs, the FDA proposed a regulation to make major revisions in the package insert and made the regulation final in January 2006 (71 Fed. Reg. 3922-01; 21 C.F.R. parts 201, 314, and 601).
The updated package insert is designed to reduce preventable adverse drug events by making information about the drug more easily accessible, more memorable, and less complex. The insert reorganizes critical information so healthcare professionals can find the information they need quickly. This is accomplished by including a "Highlights" section at the beginning, which summarizes the most important information about the product, including Boxed Warnings, Indications and Usage, and Dosage and Administration. The Highlights section will also refer the reader to the appropriate section of the Full Prescribing Information. To ensure healthcare professionals have the most up-to-date information, manufacturers must include a list of all substantive changes made within the past year.
In order to help healthcare professionals find critical information more quickly, a Table of Contents has been added. The Full Prescribing Information is reorganized to give more prominence to the most important and most commonly referenced information. In addition, a Patient Counseling Information section has been added, designed to facilitate discussion between the healthcare professional and the patient regarding the important uses and limitations of medications. It is also hoped that this section will serve as a guide for discussions about potential risks and how to manage those risks. Any FDA-approved patient information is included immediately after the Patient Counseling section.
The 2006 package insert requirements applied only to drugs whose NDAs were submitted after June 30, 2006, and were phased in gradually for drugs approved 5 years prior to June 30, 2006. The FDA hopes manufacturers of other drug products will comply voluntarily.
Online drug labeling information, including the package insert and labeling history, for most FDA- approved drugs can be accessed at Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). In addition, healthcare professionals and consumers can access the DailyMed website, an information clearinghouse provided through the National Library of Medicine and accessible at http://dailymed.nlm.nih.gov/dailymed/about.cfm; its objective is to provide the most up-to-date drug labeling information.
After having considered this issue for several years, in December of 2014, the FDA issued a proposed rule that, if finalized, would require that manufacturers replace paper distribution of the package insert with electronic distribution (https://www.federalregister.gov/articles/2014/12/18/2014-29522/electronic-distribution-of-prescribing-information-for-human-prescription-drugs-including-biological). There would be no change to the substantive content of the insert. The FDA believes the change to electronic form is necessary because prescribers often do not receive the paper package insert and pharmacists often complain about the paper form having small font size, thin paper, and multiple folds, making it difficult to read. The agency is also concerned that changes in prescribing information do not appear in the printed package insert until several months later.
The proposed rule would require manufacturers to submit updated labeling information to the FDA's website (https://labels.fda.gov) within 2 days of a labeling change. It also requires manufacturers to verify that their labeling information is accurate and current and to notify the FDA if this is not true. Manufacturers would be required to revise the label and outside packaging of a product to include the FDA's labeling website and a toll-free number to obtain prescribing information if the Internet is unavailable. The toll-free number must be staffed 24 hours a day, 7 days a week. The FDA proposes to exempt companies from the rule where compliance would adversely affect the safety, efficacy, purity, or potency of the drug, or if it is not technologically feasible or is not appropriate.
When the use of a drug may lead to death or serious injury, the FDA may require the warning of the special problem in the package insert to be placed within a prominently displayed box, also known as a black box warning (21 C.F.R. § 201.57(c)(1)). The FDA first implemented black box warnings in 1979 and considers a decision to require a boxed warning to be a dramatic step. Originally, it required the warning for relatively few drugs. In the last decade, however, an increasing percentage of new drug approvals are required to contain black box warnings. Despite the prominence of the boxed warning in the insert and the seriousness of the warning, many critics argue that they are usually ineffective. Reports indicate that many prescribers are either unaware of the warnings or simply do not heed them. Many drugs (e.g., Propulsid, Duract) may not have needed to be withdrawn from the market if healthcare professionals simply observed and managed the risks contained in the boxed warning. The FDA is hoping that the new revisions to the package insert will improve the effectiveness of the boxed warnings. If not, the FDA will likely require other risk management strategies for high-risk drugs. When appropriate, pharmacists should include black box warnings in their patient counseling.
Labeling regulations require that the package insert contain information about the risks of using the drug or biological during pregnancy and lactation (21 C.F.R. § 201.57(c)(9)). In December of 2014, the FDA issued a final regulation replacing the prior labeling system that required most drug and biological products be placed into one of five letter categories (79 Fed. Reg. 72063; https://federalregister.gov/a/2014-28241). The more recent labeling regulations became effective on June 30, 2015, and apply to products approved on or after that date. The labeling standards will be gradually phased in for products approved prior to that date. Thus, healthcare professionals should be familiar with both labeling standards for the near future.
Under the prior risk warning requirements, a drug or biological, unless not absorbed systemically and presenting no known harm to the fetus, was placed into one of five letter categories briefly summarized as:
Category A: Adequate and well-controlled studies in pregnant women have not demonstrated a risk to the fetus. The labeling for drugs in this category also must contain a notice that because studies cannot rule out the possibility of harm, however, the drug should be used during pregnancy "only if clearly needed."
Category B: Animal studies have failed to demonstrate a risk to the fetus and there are no adequate well-controlled studies in pregnant women. As with Category A, a statement must be included providing that the drug should be used during pregnancy "only if clearly needed."
Category C: Either animal studies have shown an adverse effect on the fetus or there are no animal reproductive studies, and there are no adequate well-controlled studies in pregnant women. A statement must be included that the drug should be used during pregnancy "only if the potential benefit justifies the potential risk to the fetus."
Category D: Positive evidence of fetal risk exists based upon data from investigational or marketing experience or studies in humans; however, potential benefits from the drug may be acceptable despite potential risks (e.g., in life-threatening or serious disease situations for which a safer drug cannot be used). A statement must be included in the Warnings and Precautions section that the drug can cause fetal harm and that the patient should be apprised of the risk if pregnant.
Category X: Studies in animals or humans have demonstrated fetal risk, and that risk in pregnant women clearly outweighs any benefit. The contraindications section must state that the drug "may cause fetal harm when administered to a pregnant woman." A statement must also be included that the patient should be apprised of the potential hazard to the fetus if used while pregnant. Accutane and Thalidomide are examples of drugs that fall into this category.
The 2014 regulation replaces this classification system (regarded by the FDA as overly simplistic and subject to misinterpretation as a grading system), with three detailed subsections that the labeling must include to describe the risks. The three subsections are "Pregnancy" "Lactation" and "Females and Males of Reproductive Potential." The "Pregnancy" subsection must provide information relevant to the use of the drug in pregnant women, including dosing and potential risks to the fetus. It must also include information about whether a registry exists that collects and maintains data on the product's use in pregnancy. The "Lactation" subsection will provide information about using the drug during breastfeeding, including the amount of drug in breast milk and potential effects on the child. The "Females and Males of Reproductive Potential" subsection must include information about pregnancy testing, contraception, and infertility as related to the drug. Both the "Pregnancy" and "Lactation" subsections will include subheadings of "risk summary" "clinical considerations" and "data."