Industry requests more information from FDA on dosage and administration labeling

Regulatory NewsRegulatory News | 17 March 2023 |  By 

While the US Food and Drug Administration’s (FDA) latest draft guidance on improving the consistency of information in the dosage and administration section of prescription drug labeling is significantly larger than an earlier guidance issued in 2010, industry stakeholders said they wanted more information from the agency on how labeling of specific cases should be handled.
FDA’s draft guidance on improving development of the dosage and administration section of drug labeling is written to inform industry on required and recommended information that is “particularly critical to the safe and effective use of the drug,” such as the dosage range, starting or loading dose, dosage, titration schedule, maximum recommended dosage and duration, effectiveness, and concomitant therapy information, the agency said. (RELATED: FDA issues draft guidance on dosage and administration labeling, Regulatory Focus 13 January 2023)
Other information that should be included in the dosage and administration section include drugs used before, during or after treatment, dosage modifications, dosage in specific patient populations, drug switching and substitution, missed dose information, recommendations for managing vomiting after the administration of an oral drug, drug reduction and discontinuation information where there is a withdrawal risk, and dosage for fixed-combination and co-packaged drug products.
The draft guidance also contains information on situations when industry should include preparation and administration information on the drug labeling, information on how to avoid mishandling the drug or its administration, drug incompatibilities, and storage instructions for reconstituted or diluted product.
Generally, industry stakeholders welcomed the increased detail added to the latest draft guidance but requested more information about specific labeling situations.
Pharmaceutical company Novartis proposed several changes to the draft guidance in their comment to FDA on describing optimal titrating dosages, and clarifying when instructions on the dosage and administration section of the label should reference concentrate for solution for infusion as well as instructions for avoiding discontinuation, considerations for pediatric indications, and restrictions for administration and preparation for parenteral drugs.
Novartis said information in the dosage and administration section should consistently refer to the concentrate for solution for infusion or diluted solution for infusion to reduce the risk of administrative errors. Labels should also contain a recommendation for safety implications if a patient should avoid discontinuing a medication, they noted.
“In the case that there is a paediatric indication, but no adequate pediatric formulation can be developed, Novartis is of the opinion the latter should be stated and provide details regarding extemporaneous preparations in the appropriate section, as it could be an important piece of information for the [healthcare provider],” the company said.
Adding other restrictions to administer and prepare parenteral drugs, such as through a healthcare provider or under aseptic conditions, should also be considered for safety reasons, they said.
Jazz Pharmaceuticals
In their comment, biopharmaceutical company Jazz Pharmaceuticals said they wanted more examples of using algorithms for complex dosage, preparation and administration instructions, and dosage modifications intended to reduce the risk of adverse reactions.
The company also noted that in recent United States Prescribing Information (USPI) approved by FDA, portions of this draft guideline have begun to be implemented, such as including dose interval information in the full prescribing information but said the highlights section of the USPI doesn’t always have interval information. Jazz Pharmaceuticals cited another recent USPI where premedication text for hypersensitivity reactions was included, but the information “was not based on data or normal standard of practice.” In both cases, the company requested more information from FDA on when it is appropriate to include this information.
In a section on dosage modifications, Jazz Pharmaceuticals acknowledged that providing precise dosage instructions works for drugs with a single fixed dosage but proposed allowing use of a percentage for drugs with multiple stable dosages.
PTC Therapeutics
In general, pharmaceutical company PTC Therapeutics explained that it would be useful if the draft guidance had “examples of scenarios where the information required within this section should be omitted if clearly inapplicable.”
They noted that the section on organization and format of the dosage and administration section does not contain information on products administered in a surgical suite. “PTC requests clarification on how or if, for example, information from a surgical manual should be used in this section. Additionally, as the guideline does not contain clear reference to medical devices or ancillary devices co-packages with the product, PTC requests clarification on where these should be mentioned,” they wrote.
PTC Therapeutics also sought clarify on if sponsors should include graphics on a section for drug administration. They also suggested a section on cross-labeled drug-device combination product administration may be useful for products in gene therapy and those with “unique administration methods/techniques.”
In a subsection on content for dosage in patients with renal impairment, PTC Therapeutics asked FDA to detail how dosage recommendations in subpopulations of patients with renal impairment with spare data should be handed. “PTC requests clarification, if there are not clinical data to support all sub-populations, whether is it appropriate to only provide recommendations for those subpopulations with supporting evidence and include a cautionary statement for the other sub-populations,” they said.
The Pharmaceutical Research and Manufacturers of America (PhRMA) told FDA in their comment they believed the 2023 draft guidance offers more detail and direction than the previous 2010 draft guidance on the same topic.
PhRMA noted that there are some situations where “dosing-related information, including pediatric information, may be included, and even required, in other sections of the labeling” even as FDA wrote that “dosing regimens must not be implied or suggested in other sections” apart from the dosing and administration section. PhRMA also explained that situations may arise where a label may need to contain information on a drug “being both prepared and administered in a specific health care setting to ensure safe and effective use.'”
The advocacy group said they appreciated FDA’s flexibility regarding organizational schemes in product labeling but asked them to provide examples on subsection formatting. “To convey complex dosage, in the draft guidance FDA suggests that sponsors consider the use of tables and that the tables be designed through a human factors engineering process. PhRMA believes that the recommended use of a human factors process for table design would be appropriate only for very specific and rare circumstances, for instance, when the dosage is extremely complex,” they wrote. “Thus, PhRMA requests that the Agency clarify the recommendation to conduct human factors engineering processes for tables applies only to narrow and unique circumstances.”
While they agreed the dosage and administration section should identify a concomitant therapy, PhRMA asked about cases when drugs are approved only for use with a concomitant therapy. They also requested FDA provide more information on storage for reconstituted drugs with complex preparations for administration.
PhRMA highlighted several areas where FDA could improve readability of the draft guidance, such as formatting and bringing certain footnotes to the main text of the document. “There may be instances in the current draft guidance where key information can be overlooked because the information is relegated to footnotes rather than placed in the body of the text,” they said.
Draft guidance


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