Labeling

The FDA guidance recommends the inclusion of both positive and relevant negative findings of the results of the in vivo drug interaction studies in the "Clinical Pharmacology" section under "drug-drug interactions." If the results of the study indicate a potentially clinically significant interaction or the lack of an important interaction that might have been expected, in addition to mentioning it in the "Clinical Pharmacology" section, a more detailed description of the study and its results should be included in the "Precautions" section of the label with advice on how to adjust the dosage in the "Warnings/Precautions," "Dosage and Administration," and "Contraindications" sections of the label. The FDA guidance allows the extrapolation of the results of a drug-drug interaction study with a certain substrate or inhibitor to other substrates or inhibitors/inducers not specifically tested thus allowing for a class label based on the results of the study with a drug that is considered a prototype. For example, if an investigational drug is a potent CYP3A4 inhibitor, not all substrates of this enzymes need to be tested to warn against an interaction with this drug.

The following are examples of appropriate labeling language recommended by the FDA guidance:

Drug-Drug Interactions, Clinical Pharmacology

X In vivo metabolic drug-drug interaction studies indicate little or no pharmacokinetic effect:

Data from a drug-drug interaction study involving (drug) and (probe drug) in_patients/healthy individuals indicate that the PK disposition of

(probe drug) is not altered when the drugs are co-administered. This indicates that (drug) does not inhibit CYP3A4 and will not alter the metabolism of drugs metabolized by this enzyme.

X In vivo metabolic drug-drug interaction studies indicate a clinically significant pharmacokinetic interaction:

The effect of (drug) on the pharmacokinetics of (probe drug) has been studied in____ patients/healthy subjects. The Cmax, AUC, half-life, and clearances of (probe drug) increased/decreased by_% (90% Confidence

Interval: _ to _ %) in the presence of (drug). This indicates that

(drug) can inhibit the metabolism of drugs metabolized by CYP3A4 and can increase blood concentrations of such drugs. (See Precautions, Warnings, Dosage and Administration, or Contraindications sections.)

Precautions and/or Warnings

X An interacting drug causes increased concentrations of the substrate but the administration of both drugs may continue with appropriate dosage adjustment. Results of the studies are described in Clinical Pharmacology, Drug-Drug Interactions, Precautions and/or Warnings and may state:

Drug____/class of drug causes significant increases in concentrations of

_when co-administered, so that dose of__must be adjusted (see

Dosage and Administration). If there is an important interaction, information for patients should point this out also.

X An interacting drug causes increased risk because of increased concentrations of the substrate and the interacting drug should not be used with the substrate. After describing the interaction in the Clinical Pharmacology section, there should be a Contraindications section and possibly a boxed warning if the risk is serious.

Drug /class of drug can cause significant increases in concentrations of drug__when co-administered. The two drugs should not be used together.

Dosage and Administration

X An interacting drug causes increased risk because of increased concentrations of the substrate, but the administration for both drugs may continue with suitable monitoring: Drug____/class of drug leads to significant increases in blood concentrations of_by_%. The dose of

_should be decreased by_% when the patient is also taking_.

Patients should be closely monitored when taking both drugs. Contraindications

X An interacting drug causes increased risk because of increased concentrations of the substrate and should not be co-administered:

Drug /class of drug leads to significant increases in blood concentrations of_, with potentially serious adverse events. Administration of_to patients on drug /class of drug is contraindicated.

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