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Even if not included on the package insert, the combination of drugs is not off-label

In short, according to Anvisa, even if not included on the package insert of one of the drugs, the combination is not considered off-label because, when required by one of the registration’s owners and if its use with other drugs was investigated, Anvisa itself evaluates and approves the effectiveness of the drugs.


Contextualization of off-label

Contextualizando o off label.

First of all, we must understand how drugs are approved in Brazil. Their indication is approved by Anvisa, and one or more indications may be included on the package insert, with the support of the agency. However, to grant such registration, the safety, quality, and effectiveness of the drug must be attested, and its effectiveness and safety must be based on clinical trials and evaluations, which test its validity and indications.


When a drug is approved for an indication, it does not mean that it will be used for such purpose. Through studies, other indications may be attested and, therefore, included on the package insert once submitted and approved by Anvisa. Nevertheless, sometimes a doctor chooses to prescribe a drug even before this new indication is approved, either based on clinical knowledge or on an analogy with a similar disease.


The use of the drug in such condition is characterized as off-label. In other words, the doctor takes a chance by choosing said drug. Consequently, off-label, by definition, is the use of a drug that was not authorized by a regulatory agency, not necessarily implying that its use is incorrect, because there are usually supporting evidence and studies.


How does the combined use work?

Mas e quanto ao uso combinado, como funciona?

Basically, when the owner has the registration of combined drugs, the use, indication, and dosage information and data are usually indicated on the package insert of all drugs used in combination. However, keep in mind that the package insert update application must be made by the registration owner.


Nonetheless, when the investigation of the combined use of drugs is not on the hands of their registration owner, no law provision imposes the update of the package inserts of drugs used in said combination, since a third party was the origin of the clinical trials. When it happens, the information related to the combined use will be included only on the package insert of drugs belonging to the party that conducted the clinical trials.


Therefore, one or more drug package inserts may not mention the combined-use indication. Nevertheless, the data were analyzed by Anvisa, and the drug combination effectiveness and safety were approved and authorized.


Meanwhile, it is important to recall that the package inserts follow the dispositions of the Resolution of the Collegiate Board of Directors (RDC) 47/2009, which issues the standards for the elaboration, harmonization, update, publication, and provision of drug package inserts. Its main goal is to improve the package inserts of all drugs registered and commercialized in Brazil, as to their form and content, to make sure that the consumer may safely and properly have access to information, favoring the rational use of drugs.