UK Recommends Double Emergency Contraceptive Dose To Counter Enzyme Inducers
This article was originally published in The Pink Sheet
Executive Summary
Women taking CYP3A4 enzyme inducers or St. John's wort should use double the standard dose of levonorgestrel, if using it as an emergency contraceptive, to compensate for reduced plasma levels of the ingredient, UK agency says.
Drug interaction effects of products containing enzyme inducers and St. John's wort herbal supplements have prompted the UK health authority to advise women using levonorgestrel emergency contraceptives to increase their dosage if they also use those products.
The Medicines and Healthcare products Regulatory Agency on Sept. 19 published a notification for consumers and health care providers stating that women who are taking cytochrome P450 3A4 enzyme inducers and also need an emergency contraceptive (EC) should double the standard dose of levonorgestrel – up from 1.5mg to 3 mg – to compensate for reduced plasma levels of the ingredient.
Officials at FDA's Center for Drug Evaluation and Research said they are aware of the MHRA announcement and are monitoring post-marketing data relating to the safety and efficacy of levonorgestrel ECs and other drug products.
Levonorgestrel-containing emergency contraceptives are available nonprescription and Rx in the UK as a single 1.5mg tablet and by prescription as two 0.75mg tablets taken as a single dose. They are indicated to prevent pregnancy when taken within 72 hours of unprotected intercourse or failure of a contraceptive method. Brand names in the UK include Emerres, Ezinelle, Isteranda, Levonelle, Melkine, Toomee and Upostelle.
Cytochrome P450 3A4 (CYP3A4) enzyme inducers that reduce plasma levonorgestrel levels include products indicated to treat epilepsy, tuberculosis, HIV and fungal infections. Herbal remedies that contain St John’s wort also reduce levonorgestrel levels.
Concomitant use of liver enzyme inducers – mainly inducers of CYP3A4 enzymes – increases the metabolism of levonorgestrel and elevated levels can persist for up to four weeks after cessation of the enzyme-inducing medicine.
The agency explained that concomitant administration of the antiretroviral efavirenz to treat HIV reduces plasma levels of levonorgestrel by around 50%. While data are not available for all CYP3A4 enzyme inducers, studies of levonorgestrel-containing combined hormonal contraceptives show other hepatic enzyme-inducing medicines or herbal medicines may produce similar reductions in plasma levels.
According to the notice, MHRA recommends that women using drugs that contain enzyme inducers or St. John's wort use a copper intrauterine device as a contraceptive. However, no increased risk of side effects is expected from using a double dose of levonorgestrel to compensate for reduced plasma levonorgestrel levels.
In the US, 1.5mg Plan B One-Step is available OTC. FDA approved Teva Pharmaceutical Industries Ltd.'s supplemental new drug application in 2009 as a follow-on to the original two-.75mg Plan B approved in 2006; Teva no longer markets Plan B.
FDA also has approved abbreviated NDAs from multiple firms for OTC single- or two-pill for levonorgestrel ECs. Teva's three-year OTC market exclusivity for Plan B One-Step's OTC indication for consumers 15 and older expired in April, allowing other levonorgestrel ECs to expand their label indications.
FDA's latest regulatory mention of levonorgestrel ECs came earlier in 2016 with documents posted to its Postmarket Drug Safety Information website stating that it reviewed available scientific data concerning effectiveness of 1.5mg levonorgestrel in women weighing more than 165 pounds or with a body-mass index of more than 25 kg/m. The data are "conflicting and too limited to make a definitive conclusion" and FDA "does not believe that a change in the labeling for [the] products is warranted at this time," according to the documents. (Also see "Weight Of Emergency Contraceptive Data Does Not Support Label Change" - Pink Sheet, 1 Jun, 2016.)
From the editors of the Tan Sheet