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FDA releases draft guidance for drug interaction studies with combined oral contraceptives

Posted 20 November 2020 | By Mary Ellen Schneider  | PDF Link PDF

FDA releases draft guidance for drug interaction studies with combined oral contraceptives

The US Food and Drug Administration (FDA) has issued draft guidance for industry on performing clinical studies to look at the potential interactions between an investigational drug and combined oral contraceptives.
 
Interactions with other therapies can impact the efficacy and safety of combined oral contraceptives by affecting the enzymes involved in metabolizing progestins and estrogens. “For example, decreased progestin concentrations can lead to unintended pregnancy (loss of efficacy), whereas increased estrogen and/or progestin concentrations can increase the risk of venous thromboembolisms (VTEs), a rare but severe adverse event,” the agency wrote in the draft guidance.
 
The agency has issued previous guidance on studies related to cytochrome P450 enzyme- and transporter-mediated drug interactions. The current guidance drills down on recommendations for metabolism-based drug interactions with combined oral contraceptives, which usually contain two synthetic steroid hormones – a progestin and an estrogen. (RELATED: Drug-Drug Interactions: FDA Issues Guidance on Clinical, In Vitro Studies, Regulatory Focus, 23 January 2020,).
 
The FDA advises sponsors to consider conducting a clinical drug-drug interaction study when in vitro studies suggest that the investigational drug is a CYP3A inducer, a moderate or strong CYP3A inhibitor, or has teratogenic potential.
 
Studies can include either premenopausal or postmenopausal women, but sponsors should keep in mind that inclusion of premenopausal subjects allows for the assessment of more pharmacodynamic endpoints. The number of study participants should be sufficient to offer a reliable estimate of the magnitude and variability of the interaction.
 
The agency recommends selecting a contraceptive product that contains the most commonly used progestins in the United States: norethindrone, norgestimate, levonorgestrel or drospirenone (DRSP), combined with ethinyl estradiol. This allows the results to directly inform the “most likely clinical use,” the agency wrote. Including DRSP provides a possible “worst-case scenario” for CYP3A inhibition.
 
DRSP is considered a more sensitive CYP3A substrate, compared with other approved progestins. As a result, the agency advises that if a drug-drug interaction study with a DRSP-containing combined oral contraceptive does not show an interaction, those results can be extrapolated to norethindrone and levonorgestrel. “The specifics of this strategy should be discussed and agreed upon with the Agency prior to initiating the study,” the agency wrote.
 
The FDA recommends studying the investigational drug at the highest proposed therapeutic dose with the combined oral contraceptive dosed as either a single dose or as multiple doses as part of the pharmacokinetic assessment. When conducting pharmacodynamic assessments, multiple doses of the contraceptive are needed. Fixed sequence or randomized crossover studies are preferred, the agency wrote, but parallel study designs are acceptable if the other types of studies are not feasible.
 
The FDA recommends intensive pharmacokinetic sampling of the progestins and estrogens contained in the contraceptive on pharmacokinetic assessment days. Sponsors can also consider assessing some pharmacodynamic parameters – such as luteinizing hormone, follicle stimulating hormone, and progesterone – to provide additional information when pharmacokinetic results are outside of the no-effect boundaries.
 
“Sponsors are encouraged to seek feedback from the appropriate FDA review division when they plan to conduct [pharmacokinetic] assessments using alternative study designs, including [pharmacodynamic] assessments,” the agency wrote.
 
In terms of labeling, the magnitude of the interactions will guide labeling recommendations, the agency wrote. If ethinyl estradiol exposures increase to those observed at a dose of 50 µg or greater, the investigational drug’s labeling might recommend avoiding concomitant use with combined oral contraceptives containing ethinyl estradiol or not using those contraceptives when the ethinyl estradiol exceeds a specific dose. Similarly, if the investigational drug decreases progestin exposure enough to reduce the effectiveness of the contraceptive, the labeling should recommend an alternative or back up form of contraception.
 
Comments can be submitted to www.regulations.gov by 22 February 2021 using docket number FDA-2020-D-1848.
 
Draft Guidance

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