FDA drafts guidance on drug interaction labeling

The US Food and Drug Administration (FDA) has released a new draft guidance describing what should and should not be included in the Drug Interactions (DIs) section for human prescription drug and biological product labeling as well as how drug interaction information should appear in other areas of the product’s labeling.

FDA said the goal of the guidance is offer recommendations to applicants on how to write drug interaction content for labeling on these products and “to enhance communication of clinically significant drug interactions and facilitate the safe and effective use of prescription drugs by healthcare practitioners.”

“Prescription drug labeling must contain a summary of the essential information necessary for safe and effective use of the drug and is a primary tool for FDA to communicate drug interaction information to healthcare practitioners,” the agency wrote in a accompanying Federal Register notice. “Effective communication of drug interaction information informs the optimal use of the drug and the healthcare practitioner’s clinical decision-making.”

According to the draft guidance, the applicant must document clinically significant observed or predicted drug interactions in the Drug Interactions section, including interactions with over-the-counter drugs, prescription drugs, drug classes, and foods as well as interference with laboratory tests. It also must contain “specific practical instructions” for the prevention and management of drug interactions that are clinically significant, descriptions of any known mechanisms of the drug interaction, and the potential clinical effects of the drug interaction.

If a drug interaction is in the Contraindications or Warnings and Precautions section, it should also be included and elaborated on in the Drug Interactions section, FDA explained. “Cross-references should be used to reduce redundancy of information if pertinent DI information is presented in more than one section of labeling,” they noted.

Human prescription drugs and biological products without clinically significant drug interactions should be removed from the labeling if it is not applicable, the agency said.

When describing clinically significant drug interactions, applicants should use language that is “understandable and clinically informative” for healthcare practitioners and written to be understood by practitioners with little-to-no pharmacology expertise. The description of a drug interaction should follow a specific order, starting with instructions on the prevention or management, known mechanisms, and any clinical effects of the drug interactions. For situations that involve communicating the absence of a clinically significant drug interaction, FDA recommends the applicant use a justification for its inclusion, such as if a drug has a clinically significant drug interaction with all but one drug in a particular drug class.

The agency noted that when a drug interferes with a laboratory result, the Drug Interaction section should detail the interference and any steps to prevent or manage it “when an erroneous test result would negatively affect clinical decision-making.” Drugs that interfere with more than one laboratory test should be documented under a subsection describing the drug’s interference with the specific laboratory tests.

“Information in the DRUG INTERACTIONS section should generally be placed into subsections to enhance the organization, presentation, and accessibility of information. Subsections should be ordered to reflect the content’s importance and relative public health significance,” FDA wrote.

Types of information that does not go into the Drug Interactions section include most non-clinically significant drug interactions, in vitro and animal data, repeated details of pharmacokinetic studies from the clinical pharmacology section, recommendations to modify dosage or administration, reduction of immunological response to a vaccine by an immunosuppressive drug, and drug incompatibilities such as a physical or chemical reaction.

Drug interaction content in other sections

Other areas in the product prescribing information where drug interaction information may appear include the Boxed Warning, Dosage and Administration, Contraindications, Warnings and Precautions, Clinical Pharmacology, and Patient Counseling Information.

Drug interaction information will also appear in the highlights of the prescribing information, FDA said, and “must include a concise summary of the information required” such as the clinically significant drug interactions and practical instructions for prevention or management.

“To minimize redundancy and fragmentation of DI information between the Dosage and Administration and the Drug Interactions headings in Highlights, dosage modifications due to DIs should be included under the Drug Interactions heading instead of the Dosage and Administration heading in Highlights,” FDA said.

Sometimes the drug may have a number of clinically significant drug interactions that cannot be summarized, the agency noted. In these situations, applicants should include the most critical drug interactions and provide a statement so healthcare providers know there is additional information in the Drug Interactions section.

FDA noted in its Federal Register notice announcing the draft guidance that it is seeking input on how to document complex drug interactions, and is asking for feedback on the usefulness of a website as a resource where healthcare practitioners can look up clinical substrates, inhibitors, and inducers of Cytochrome P–450 (CYP) enzymes and substrates and inhibitors of transporters.

Draft guidance

FDA drafts guidance on drug interaction labeling

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