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Nexplanon: The new implant for long-term contraception. A comprehensive descriptive review Article in Gynecological Endocrinology · February 2012 DOI: 10.3109/09513590.2011.652247 · Source: PubMed
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Gynecological Endocrinology
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Nexplanon®: the new implant for long-term contraception. A comprehensive descriptive review
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Journal:
Manuscript ID:
Date Submitted by the Author:
07-Aug-2011
Palomba, Stefano; University, Obstetrics and Gynecology Falbo, Angela; University of Catanzaro, Obstetrics and Gynecology Di Cello, Annalisa; University of Catanzaro, Obstetrics and Gynecology Materazzo, Caterina; University of Catanzaro, Obstetrics and Gynecology Zullo, Fulvio; University of Catanzaro, Obstetrics and Gynecology
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Keywords:
Review
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Complete List of Authors:
DGYE-2011-0222
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Manuscript Type:
Gynecological Endocrinology
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long-acting contraceptive, etonogestrel, nexplanon, implanon, contraceptive efficacy
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On URL: http://mc.manuscriptcentral.com/dgye Email:
[email protected]
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Nexplanon®: the new implant for long-term contraception. A comprehensive descriptive review.
Stefano Palomba, MD; Angela Falbo, MD; Annalisa Di Cello, MD; Caterina Materazzo, MD; Fulvio Zullo, MD
Department of Obstetrics & Gynaecology, University “Magna Graecia” of Catanzaro, Viale Europa - 88100 Catanzaro; Italy.
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Author responsible for correspondence and for reprint request: Stefano Palomba, MD – Department of Gynecology & Obstetrics – “Magna Graecia” University - Catanzaro - Via T. Campanella 182/1 – 88100
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Catanzaro – Italy – email:
[email protected]
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Running title: Long-acting etonogestrel implant: Nexplanon®
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Keywords: Long-acting contraceptive, etonogestrel, Nexplanon, Implanon, contraceptive efficacy.
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Gynecological Endocrinology
1 URL: http://mc.manuscriptcentral.com/dgye Email:
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Gynecological Endocrinology
Abstract Nexplanon® is a new long-term reversible contraception method. The current review is aimed to analyze the published data concerning the contraceptive effectiveness of Nexplanon® and its effects on reproductive function. Pharmacological properties and technical procedures of insertion and removal, as well as the efficacy and safety data available, were discussed. Possible strategies for treating Nexplanon®-related bleeding were also described. With regard to the future research and the future scientific developments of contraceptive implants,
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the possible use of Nexplanon® wide-ranging for the symptomatic treatment of endometriosis and premenstrual syndrome (PMS) were considered. Finally, it was defined in which women the use of Nexplanon® is indicated and in which it is contra-indicated.
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2 URL: http://mc.manuscriptcentral.com/dgye Email:
[email protected]
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Introduction Nexplanon® [Schering-Plough Limited/Merck Sharp & Dohme Limited (MSD), US] is a subcutaneous implant releasing etonogestrel (ENG) consisting in a new long acting contraceptive device. It was born in the United Kingdom and it has been entered the European market since June 2010. The new device is intended to totally replace the Implanon®, which is the most widely used implantation system in the world. From a pharmacological point of view, the Nexplanon® is equivalent to Implanon®. In
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fact, both contain 68 mg of ENG and, once placed at the sub-dermal level, provide contraceptive coverage to women of at least 3 years.
Significant differences exist, however, between the two devices both in the implant structure and in the procedures required for its insertion.
The need to introduce a new system borns from the concern about the high inefficacy rate related to
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Implanon®. In particular, a post-marketing analysis [1] showed that 50% of unwanted pregnancies was
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determined by a “missing insertion” of the releasing ENG implant. Arguably, the inefficacy given by the “missing insertion” may be the result either of an incorrect insertion technique [2] or of expulsion / removal of the implant [3].
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Less frequently, the failure of the insertion is determined by a too deep positioning of the device [4], a
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complication reported approximately in 1 of 1000 users of Implanon® [4]. These problems are completely overcome by the new applicator.
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In this review we shell describe the new device showing the mechanism of action, and the
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pharmacodynamic and pharmacokinetic properties. The technique of insertion and removal, as well as the possible complications arising from an incorrect insertion or removal, will be carefully described. Moreover, the current international clinical experience regarding the efficacy and safety of Nexplanon®
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Gynecological Endocrinology
will be shown. Concerning the safety of the device, the problem of changes in menstrual pattern, which causes the main early implant removal request, will be treated. Possible strategies for treatment of bleeding will also be described. Wide space will be dedicated to non-contraceptive uses of the device and implant contraceptive use in specific groups of women i.e. adolescents, obese women and women in post-partum and breastfeeding. In addition, the costs related to the use of Nexplanon ® and the cost / effectiveness will be evaluated. With regard to the future research and future scientific developments in the field of contraceptive implant, the possible use of Nexplanon® wide-ranging for the symptomatic treatment of endometriosis and premenstrual 3 URL: http://mc.manuscriptcentral.com/dgye Email:
[email protected]
Gynecological Endocrinology
syndrome (PMS) will be considered. In addition, the need for a pre-insertion counseling during which the woman is carefully informed about the risks and benefits in order to reduce discontinuation rates will be discussed. Finally, on the basis of current data available in literature, we will try to define clearly in which women the use of Nexplanon® is indicated and in which it is contra-indicated.
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Search strategy
Through the use of several search systems (PubMed, the Institute for Scientific Information Web of Science, the National Health Institute Registry, Department of Health Archives, National Institute for Health and Clinical Excellence website), a search of articles and abstracts related to long acting contraception implants releasing ENG was carried out. The research was conducted by combining keywords such as: “long-acting contraceptive”,
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“etonogestrel implant”, “Nexplanon®”, “Implanon®”, “efficacy”, “safety”. No limits concerning languages and
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dates were used. Through an initial evaluation of the title and a subsequent reading of the abstracts only studies on Nexplanon® and Implanon® inherent the pharmacological properties of administration of 68mg ENG were selected.
What is Nexplanon®?
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Nexplanon® is a device made of biodegradable material with a single road through which ENG. This new
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device has the shape of a cylindrical rod 4 cm long and 2 mm thick. It contains 68 mg of ENG and a central core
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consisting of ethylene vinyl acetate (EVA) at 37%. In addition, its core was enriched with 15 mg of barium sulfate (3%), a material that makes the implant radio-opaque without changing its pharmacological properties. The radio-opacity allows to locate, through ray or ultrasound, the device even when it has been inserted deeply
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and it is, thus, not palpable [5]. In fact, it is recommended to identify non-palpable systems sonographically before proceeding to their removal. In addition, further modifications made to Nexplanon® applicator seem to simplify the procedure inserting for example the device with one hand and reduce the rate of complications related to incorrect insertion (see below).
1. Pharmacokinetics and pharmacodynamics 4 URL: http://mc.manuscriptcentral.com/dgye Email:
[email protected]
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a. Pharmacokinetic properties Nexplanon® works by releasing continuously subcutaneous ENG, a synthetic progestin molecule. Specifically, the ENG is the biologically active metabolite of desogestrel (DSG), a third-generation progestin derived from 19-nortestosterone norethisterone (NET), already widely used at the aim of contraception both in oral contraceptives and in vaginal rings [6,7]. The efficacy and safety of DSG have been widely tested [6]. In this sense, the contraceptive efficacy and
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safety data, with particular attention to the cardiovascular and metabolic disease, could probably be shifted to Nexplanon® [6,7]. In addition, administration of the drug already in form of active metabolite avoids the hepatic first-pass effect, otherwise needed for the activation of the prodrug by hepatic microsomal enzymes. The prodrug and its active metabolite are characterized by an intense anti-gonadotrophic and progestin action [6,7]. Conversely, they have a rather low affinity for the androgen receptor. The circulating metabolite,
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partially linked to sex hormone-binding proteins (SHBG), doesn’t present significant adverse effects on liver
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function and doesn’t change the lipid profile in women using the drug [6,7]. After Nexplanon® implantation, serum ENG levels increase rapidly reaching mean levels of 265.9 ± 80.9 pg/mL after 8 hours [8]. Serum levels reach maximum values after about 4 days from the insertion of the device
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reaching a stady-state (200 pg/ml) after 4-6 months. Wenzl et al. [9] have examined the bioavailability and
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accumulation of the drug in 8 healthy women aged between 18 and 40 years and with a body mass index (BMI) range of 19.6-27.5 kg/m2 showing that the rate of ENG absorption is approximately 60 mg/day after 3 months, and it drops to 30 mg/day after 2 years [9].
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Concentrations of ENG, however, remain stable over the 3 years on sufficient levels to inhibit ovulation [10]. The levels of ENG are undetectable (
