NORCAL Publications

   Review article

Topical Issues in Translational Pharmacology and Pharmaceuticovigilance: Can Pharmacological Research on Birth Control and Contraception Meet the Requirements of Bioethical Standards?

Kurt Kraetschmer*

Austrian-American Medical Research Institute, Agnesgasse 11, 1090 Vienna, Austria

*Corresponding author: Kurt Kraetschmer, Austrian-American Medical Research Institute, Agnesgasse 11, 1090 Vienna, Austria. E-mail: kurt.kraetschmer@aon.at

Citation: Kraetschmer K (2019) Topical Issues in Translational Pharmacology and Pharmaceuticovigilance: Can Pharmacological Research on Birth Control and Contraception Meet the Requirements of Bioethical Standards? J Pharm Sci Exp Pharmacol 2019: 06-11.

Received Date: 30th August 2019; Accepted Date: 01st October 2019; Published Date: 12th October 2019

Abstract

Aim: On the background of  media reports about serious harm to the health of thousands of women  engaged in birth control and contraception, the research article aims at emphasizing the importance of pharmaceuticovigilance for information on the safe use of contraceptive pills and devices.

Method:

The method consists in an in-depth analysis of those sources of information that are most widely used by women and their healthcare providers, ie, patient information leaflets and packaging labels of manufacturers; statements by governmental  health agencies; publications by the European Medicines Agency (EMA); and infromation by the US Food and Drug Administration (FDA). In addition, findings contained in high-ranked scholarly journals, especially those in pharmacovigilance, are critically surveyed.

Results:

Presently, women are not provided with information suitable for safe contraceptive pursuits. Consumers are not adequately informed about contraceptive products as pharmaceutical companies frequently fail to comply with the principle of informed consent. Clinicians, under the pressure of economic maxims such as cost efficiency, apparently fail to convey salient information to their patients. 

Conclusion:

As it is difficult for women to obtain accurate, complete, comprehensible and reliable  information on the safety of methods of contraception, especially on vital pharmacological parameters, they are advised to intensify autodidactic strategies by using not only print media but also social media via internet.

Intensification of pharmacological education should be pursued not only by individual healthcare providers but also by editors who frequently publish studies obscured by conflicts of interest. To remedy the lack of vital information for the consumer and to avoid detrimental  consequences for women's health research in pharmaceuticovigilance – whose foundation is laid  within this article – should be intensified.

Keywords: Contraception; Emergency and oral hormonal contraception; Long-Acting Reversible Contraception (LARC); Periodic abstinence/fertility awareness; Pharmaceuticovigilance; Pharmacology; Sterilization.

Introduction

Recently, one of the world's leading  pharmaceutical companies became the target of press reports commenting on  complaints lodged by women who had experienced severe adverse events associated with the company's product for permanent contraception.  According to these reports, not only medical problems were at stake but also forensic issues owing to thousands of lawsuits filed against the company. ‘‘The implant has had a troubled history. It has been the subject of an estimated 16,000 lawsuits or claims filed by women who reported severe injuries, including perforation of the uterus and the fallopian tubes. Several deaths, including of a few infants, have also been attributed to the device or to complications from it’’ [1].

From Australia similar reports reached the international readership: ‘‘The device, known as Essure, is a soft, flexible insert placed into each of the patient’s fallopian tubes. Over three months a barrier forms around the inserts, which is intended to block the fallopian tubes and permanently prevent pregnancy. But there have been reports women experienced changes in menstrual bleeding, unintended pregnancy, chronic pain, perforation and migration of the device, allergic reactions and immune-type reactions after being implanted with the device, which is manufactured by the pharmaceutical company Bayer’’ [2].

The medical and legal problems affecting the company's business in a negative fashion originated from a small nickel-titanium coil designed for permanent contraception by way of sterilization. In its instructions for use the company explains the components of the device and defines it as an insert. As such, the consumer envisages it as a foreign object that is inserted into a woman's body similar to a diaphragm or a patch. ‘‘Each insert consists of a Nitinol (nickel-titanium alloy) outer coil, a 316L stainless steel inner coil wrapped in polyethylene terephtalate (PET) fibers, platinum marker bands (2) and a silver-tin solder’’. The Instructions for Use offer information also on the characteristics of the device concerning length and diameter: ‘‘The insert is 4 cm in length and 0.8 mm in diameter in its wound-down configuration’’. As soon as the outer coil is released it expands up to 2.0 mm in diameter ‘‘conforming itself to the varied diameters and shapes of the fallopian tube [3].

As part of their marketing strategy the company  emphasized the unique feature of the device by referring to the FDA. ‘‘Essure is the only FDA-approved non-incisional form of permanent birth control’’ [4]. Concerning the mechanism of action the company specifies that  the ‘‘Essure system’’ is intended  for permanent contraception by means of a ‘‘physical occlusion of the fallopian tubes’’ [3]. Through a transvaginal manoeuvre  the Essure system is placed into the lumen of the  proximal portion of the fallopian tube where it anchors upon release: ‘‘The insert is a dynamic and flexible spring-like device. The outer coil expands upon deployment, conforms to and pushes against the fallopian tube wall, acutely anchoring the insert in the lumen of the fallopian tube’’ [3]. Dynamic anchoring in the fallopian tube, however, does not suffice to effect  contraception; rather it is the occlusion of the fallopian tube through a tissue in-growth that results in sterilization. ‘‘Subsequently, the insert elicits a benign tissue in-growth that permanently occludes the lumen of the fallopian tube, resulting in permanent contraception’’ [3].

Although the company felt compelled to withdraw its product from the Australian market in 2017 – under the pressure of the  Australian Therapeutic Goods Administration (ATGA)[5] -- and from the US market by the end of 2018, it continued to insist on both efficacy and safety of the device. Thus, in its News Release of 2018 announcing the withdrawal from the US market, the company stressed the research undertaken, which had involved more than 200.000 women. ‘‘The benefit-risk profile of Essure has not changed, and we continue to stand behind the product’s safety and efficacy, which are demonstrated by an extensive body of research, undertaken by Bayer and independent medical researchers, involving more than 200,000 women over the past two decades’’[4].

As its strongest argument for the safety of the device the company can refer to a statement made by the FDA drawing attention to a comparison of benefits and risks. ‘‘The FDA has maintained for several years that the benefits of Essure outweigh its risks’’[4].

Despite  insistence on the  safety of the device, the company felt compelled in 2018 to draw attention to severe adverse events by  providing  important safety information including an explicit warning: ‘‘Some patients implanted with the Essure System for Permanent Birth Control have experienced and/or reported adverse events, including perforation of the uterus and/or fallopian tubes, identification of inserts in the abdominal or pelvic cavity, persistent pain, and suspected allergic or hypersensitivity reactions. If the device needs to be removed to address such an adverse event, a surgical procedure will be required. This information should be shared with patients considering sterilization with the Essure System of Permanent Birth Control during discussion of the benefits and risks of the device’’[4].

As early as 2002, the company issued general warnings regarding perforation, embedment, and expulsion: ‘‘Unsatisfactory device location including perforation, uterine embedment and expulsion may result in pain’’. Warnings about the risk of pregnancy draw attention also to some serious conditions: ‘‘While most pregnancies with Essure in situ have been reported as healthy deliveries at term, pregnancy loss, pre-term labor, pre-term rupture of membranes, pre-term delivery, stillbirth, and neonatal complications have also been reported’’. The hysteroscopist is advised to reduce the risk of hypervolemia and pay attention to the possibility of tubal perforation: “Terminate the procedure if distention fluid deficit exceeds 1500cc, to reduce the risk of hypervolemia’’. As excess fluid deficit can be a sign of  uterine or tubal perforation, the  procedure should be discontinued and the patient evaluated “for possible perforation’’[3].

The “Patient Counseling Information’’ contained in the Instructions for Use warns about  allergies to nickel or other component parts of the insert subsequent to placement. “Typical allergic symptoms reported for this device include hives, urticaria, rash, angioedema, facial edema and pruritis /sic!/’’. The manufacturer requests, therefore, that all patients  be counseled on the materials contained in the insert and on the “potential for allergy/hypersensitivity prior to the Essure procedure’’. Patients are advised to familiarize themselves with the “Patient Information Booklet (PIB)’’[3]. The doctor should review with the patient the ‘‘Patient-Doctor Discussion Checklist,’’ and all of the patients' questions should be answered.

According to the instruction for use of 2002, adverse events resulting from the placement procedure include cramping, pain, nausea/vomiting, dizziness/light headedness, bleeding/spotting, vaso-vagal response, hypervolemia, and band detachment. Among the risks with follow-up procedures allergic reaction is mentioned owing to the use of contrast media for the modified Hysterosalpingography (HSG), and the lethal consequences of an anaphylactic response are described: “Allergic reaction can result in hives or difficulty breathing. In some individuals, an anaphylactic response may occur which may lead to death’’[3].

In a section entitled Directions for Use, attention is drawn to ovulation day calculations and to pretreatment. ‘‘Women with menstrual cycles shorter than 28 days should undergo careful ovulation day calculations. Insert placement should not be performed during menstruation’’. Visualization for the hysteroscopist can be improved through pretreatment for suppression of endometrial proliferation. ‘‘Pretreatment of the patient with medications that suppress endometrial proliferation may enhance visualization and scheduling flexibility’’[3].

As can be seen from the Directions  for Use copyrighted in 2002,  there are numerous warnings and precautions about risks and adverse events. The ‘‘News Release’’ of 2018 contains again warnings  and  draws attention  to  immunosuppressants as well as allergies to metal,  polyester fibers, nickel, titanium, platinum, silver-tin, stainless steel and other components of the Essure system. Moreover,  it explains adverse events that can occur during and subsequent to  the procedure of inserting the device into the fallopian tube. During the procedure, it is possible that the device is  placed incorrectly,  that part of it breaks off, and that perforation through the hysteroscope occurs with ensuing need for surgery.  ‘‘During the Procedure: In the premarketing study, some women experienced mild to moderate pain (9.3%). Your doctor may be unable to place one or both Essure inserts correctly. In rare cases, part of an Essure insert may break off during placement. If breakage occurs, your doctor will remove the piece, if appropriate’’[4]. The complications due to a perforation are appropriately described. ‘‘There is a risk of perforation of the uterus or fallopian tube by the hysteroscope, Essure system or other instruments used during the procedure. In the original premarket studies, perforation due to the Essure insert occurred in 1.8% of women. A perforation may lead to bleeding or injury to bowel or bladder, which may require surgery. Your doctor may recommend a local anesthesia. Ask your doctor about the risks associated with this type of anesthesia’’[4].

Subsequent to the procedure pain, cramping, and vaginal bleeding may occur. ‘‘Immediately Following the Procedure: In the premarketing study, some women experienced mild to moderate pain (12.9%) and/or cramping (29.6%), vaginal bleeding (6.8%), and pelvic or back discomfort for a few days. Some women experienced headaches, nausea and/or vomiting (10.8%), or dizziness and/or fainting. . . In rare instances, an Essure insert may be expelled from the body’’[4].

Adverse events can occur also several weeks after the insertion procedure, during the so-called Essure confirmation test. ‘‘As one of the Essure Confirmation Tests (a modified HSG) requires an x-ray, you may be exposed to very low levels of radiation, as with most x-rays, if this test is used. Some women may experience nausea and/or vomiting, dizziness and/or fainting, cramping, pain or discomfort. In rare instances, women may experience spotting and/or infection’’ [4].

In addition to adverse events during the insertion, after insertion, and during the confirmation test, there are risks that must be considered long-term. The most perilous of these risks is ectopic pregnancy, and, as the manufacturer warns, this can be life-threatening. ‘‘Long-term Risks: Pain (acute or persistent) of varying intensity and length of time may occur and continue following Essure placement. . . . Patients with known hypersensitivity to any of the components of the Essure system may experience an allergic reaction to the insert’’ [4]. Subsequent to placement, the manufacturer specifies, some women may develop an allergy to nickel or other component parts  of the insert. The symptoms reported by users of Essure  may be associated with allergic reactions and include  hives, rash, swelling and itching. Concerning the risk of ectopic pregnancies the manufacturer correctly underscores the seriousness of the condition. ‘‘This can be life-threatening. If insert removal is indicated, surgery will be necessary’’[4]. Concerning special populations, the manufacturer  specifies that neither safety nor efficacy have been established for women under 21 or over 45 years of age. ‘‘The safety and effectiveness of Essure has not been established in women under 21 or over 45 years old’’[4].

As a particular safety measure, the manufacturer  restricted the insertion procedure  of the device to physicians who are competent hysteroscopists: ‘‘Caution: Federal law restricts this device to sale by or on the order of a physician. Device to be used only by physicians who are knowledgeable hysteroscopists; have read and understood the Instructions for Use and Physician Training Manual; and have successfully completed the Essure training program, including preceptoring in placement until competency is established, typically 5 cases’’ [4].

As can be seen from the above citations, the manufacturer (Essure) endeavored to provide comprehensive information on the device and mentions also the life-threatening risks of an anaphylactic reaction and of an ectopic pregnancy. At the same time, however, the consumer notices that the information is not always as comprehensible as required by the bioethical principle of informed consent, which stipulates that the patient be enabled to make ‘‘an intelligent choice’’ [6]. Thus in explaining the mechanism of action the company uses a nomenclature that might be confusing not only to unexperienced consumers but even to educated healthcare providers because it is unclear what kind of  biochemical  process can ‘‘elicit’’ a benign-tissue in-growth, as specified by the manufacturer: ‘‘Subsequently, the insert elicits a benign tissue in-growth that permanently occludes the lumen of the fallopian tube, resulting in permanent contraception’’ [3]. In a different context tubal occlusion and tissue in-growth are explained with reference to PET fibers, ie, ‘‘polyethylene terephthalate (PET) fibers’’. Allegedly, these fibers cause tissue in-growth which facilitates not only retention of the device but also tubal occlusion. ‘‘Tubal occlusion is attributed to the space filling design of the device and the benign occlusive tissue response. PET fiber causes tissue in-growth into and around the insert, facilitating insert retention, resulting in tubal occlusion and contraception’’ [3].

From a physiological viewpoint it  is difficult to understand by what kind of chemical reaction the  device can ‘‘elicit’’ a benign tissue in-growth. It  is not surprising therefore that alternative explanations have been provided which assume an inflammation and ensuing fibrotic growth. ‘‘The small, flexible inserts are made from polyester fibers, nickel-titanium, stainless steel and solder. The insert contains inner polyethylene terephthalate fibers to induce inflammation, causing a benign fibrotic ingrowth’’ [7].

Press reports too avoided the expression ‘‘in-growth’’ and spoke of  ‘‘scar’’ tissue, ie, tissue which results from a wound inflicted to healthy tissue. ‘‘Essure consists of two nickel-titanium coils inserted into the fallopian tubes, where they spur the growth of scar tissue that blocks sperm from fertilizing a woman’s eggs’’[1]. By medical definition, a scar is ‘‘a permanent mark resulting from a wound or disease process in tissue’’[8]. If the insert does in fact cause a wound ethical standards require that the consumer be informed accordingly.

Concerning wounds and ‘‘ingrowth’’ it should be borne in mind that the resemblance between wound healing and tumor growth have been cogently outlined as early as 1986 in a publication focusing on the similarities between wound healing and tumor growth. In describing tumors as wounds that do not heal, the author concludes: ‘‘They have developed the capacity to preempt and subvert the wound-healing response of the host as a means to acquire the stroma they need to grow and expand. They mimic wounds by depositing an extravascular fibrin-fibronectin gel. Such gels, in tumors as at sites of local injury, signal the host to marshal the wound-healing response. This response is stereotyped and similar in both tumors and wounds. In tumors, however, the fibrin-fibronectin matrix signal that evokes the wound-healing response is not selflimited; it continues to operate and new gel is continuously deposited. Thus, tumors appear to the host in the guise of wounds or, more correctly, of an unending series of wounds that continually initiate healing but never heal completely [9].

As can be seen from the foregoing discussion of the Essure implant for permanent contraception, one of the reasons that caused the troubled history of the device is information unsuited  to  enable the patient to make an intelligent choice. The problem of inadequate information is not a specificity of the insert for permanent contraception discussed above; it is a crux also in other descriptions of products for birth control and contraception. It seems appropriate  therefore to investigate as to whether or not pharmaceutical  companies manufacturing pills and devices for birth control and contraception can stand up to the ethical standards of the principle of informed consent which requires comprehensive and comprehensible information for the patient [6].

The subsequent sections are devoted to such an investigation and aim at bringing to light deficits and shortcomings in information provided by pharmaceutical companies.  Given that Long-Acting Reversible Contraception (LARC), oral hormonal contraceptives, and pills for  Emergency Contraception are the most widely used forms of contraception, the pharmaceutical companies producing these pills and devices are the focal points.

LARC – the most effective form of contraception

LARC comprise implants and intrauterine devices and are considered the most effective form of contraception owing  to estimates of 0.05% for implants, 0.2% for levonorgestrel containing intrauterine devices, such as Mirena, [10] and 0.6 (perfect use/0.8 typical use) for copper containing such as ParaGard.

The Etonogestrel implants (Nexplanon and Implanon):

Information on the etonogestrel-containing implants furnished by the manufacturer is available as a 52-page ‘‘Patient Information Leaflet’’ containing  various headings, namely a Highlights of Prescribing Information, a Full Prescribing Information for Nexplanon [I] (comprising 14 pages), a FDA-Approved Patient Labeling for Nexplanon[II](comprising 5 pages), a Highlights of Prescribing Information and a Full Prescribing Information for the etonogestrel implant Implanon, and   a FDA-Approved ‘‘Patient Labeling IMPLANON® (etonogestrel implant), Subdermal Use’’ [III], comprising 11 pages [11].

The Full Prescribing Information specifies that  Nexplanon is a progestin-only, flexible and soft  radiopaque implant. Destined for subdermal use, it is  preloaded in a disposable sterile applicator. The length of  the white/off-white, non-biodegradable implant is 4 cm, and its  diameter is 2 mm. Its ethylene vinyl acetate (EVA) copolymer core contains 68 mg etonogestrel (a synthetic progestin), barium sulfate (radiopaque ingredient), but may contain also  magnesium stearate, surrounded by an EVA copolymer skin.  ‘‘Once inserted subdermally, the release rate is 60-70 mcg/day in week 5-6’’. Thereafter it decreases to about 35-45 mcg per day by the end of the first year; by the end of the second year it decreases to about  30-40 mcg per day, and by the end of the third year to approximately 25-30 mcg per day. As Nexplanon is a progestin-only implant it  does not contain estrogen; it neither contains latex [11].

Etonogestrel [13-Ethyl-17-hydroxy-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-3-one], is structurally derived from 19-nortestosterone, which is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula [11] (Figure 1).

 

Figure 1: Etonogestrel.

 

Concerning clinical pharmacology, the mechanism of action consists in suppressing ovulation, in increasing the viscosity of the cervical mucus, and in altering the endometrium.

Regarding pharmacodynamics, it has been admitted that exposure-response relationships of the etonogestrel implants  are unknown.  With respect to pharmacokinetics it is assumed that absorption takes place subsequent to subdermal insertion of the etonogestrel implant. Etonogestrel is released into the circulation and is approximately 100% bioavailable.  The serum concentration for Nexplanon was established on the basis of a three-year clinical trial. The mean (plus-minus SD) maximum serum etonogestrel concentrations were 1200 (plus-minus 604) pg/mL; they were reached within the first two weeks following implantation (n=50). The mean (plus-minus SD) serum etonogestrel concentration decreased gradually over time, reaching 202 (plus-minus  55) pg/mL by the end of the first year (n=41),  reached 164 (plus-minus  58) pg/mL by the end of the second year (n=37), and reached 138 (plus-minus  43) pg/mL by the end of the third year. (n=32). In the case of the non-radiopaque implant Implanon, a  precursor of Nexplanon, the mean (plus-minus SD) maximum concentration of etonogestrel were 1145 (plus-minus 577) pg/ml attained within two weeks after implantation [11].

Concerning distribution the manufacturer states that the apparent volume of distribution averages about 201 L. Approximately 66% of etonogestrel is bound to albumin in blood and 32% is bound to sex hormone binding globulin (SHBG).  As regards metabolism, in vitro data indicate that etonogestrel is metabolized in microsomes of the liver by the cytochrome P450 3A4 isoenzyme. Regarding the biological activity of etonogestrel metabolites no data are available. Concerning excretion, according to the manufacturer, the elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites -- as free steroid or as conjugates -- is primarily in urine and to a minor extent in feces [11].

Besides details of clinical pharmacology the  ‘‘Full Prescribing Information’’ furnished by the manufacturer contains important information also on contraindications, warnings and precautions, adverse reactions,  drug interactions and use in specific populations [11]. As regards contraindications several conditions are enumerated, namely known or suspected pregnancy, current or past history of thrombosis or thromboembolic disorders, liver tumors, benign or malignant (or active liver disease), undiagnosed abnormal genital bleeding, known or suspected breast cancer (personal history of breast cancer, or other progestin-sensitive cancer, presently or in the past), allergic reaction to any of the components of Nexplanon [11].

Complications pertaining to insertion and removal procedures include pain, paresthesias, bleeding, hematoma, scarring or infection. The manufacturer warns about incorrectly inserted implants and describes potential complications of removal. ‘‘Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm’’ and should therefore be performed by a physician knowledgeable in the anatomy of the upper extremity. If the implant is not removed the effects of etonogestrel will continue and result in ‘‘compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event’’[11].

Regarding Changes in Menstrual Bleeding Patterns, the manufacturer specifies that  subsequent to initiating contraception with Nexplanon, patients will most likely experience a change of their normal menstrual bleeding pattern. ‘‘These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration’’ [11]. Pertaining to ectopic pregnancy, which is possible with  all progestin-only contraceptive products, caution should be exercised in case of pregnancy or lower abdominal pain. ‘‘Although ectopic pregnancies are uncommon among women using NEXPLANON, a pregnancy that occurs in a woman using NEXPLANON may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception’’ [11].

As regards thrombotic and other vascular events, the manufacturer calls to mind that combination hormonal contraceptives containing both progestin and estrogen increase the risk of arterial events such as stroke and myocardial infarction as well as deep venous thrombotic events, such as venous thromboembolism, deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis. As Nexplanon is a progestin-only contraceptive, it is not known whether these increased risks are relevant for etonogestrel alone.  ‘‘It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed’’ [11].

Regarding ovarian cysts, the manufacturer explains that atresia of the follicle is  sometimes delayed in case of follicular development ‘‘and the follicle may continue to grow beyond the size it would attain in a normal cycle’[11]. With respect to carcinomas of the breast and reproductive organs, the manufacturer recommends that women with current or past breast cancer ‘‘should not use hormonal contraception because breast cancer may be hormonally sensitive’’. Attention is drawn also to studies suggesting an association between the use of combination hormonal contraceptives and an increased risk of intraepithelial neoplasias or cervical cancer. ‘‘Women with a family history of breast cancer or who develop breast nodules should be carefully monitored’’ [11].

Concerning liver disease the manufacturer recommends removal of Nexplanon if there is a development of jaundice and draws attention to the association between  hepatic adenomas and combination hormonal contraceptives (estimate of the attributable risk is 3.3 cases per 100.000 users). Whether a similar risk can be assumed for progestin-only contraceptives, such as Nexplanon, is unknown [11]. Weight gain occurred during use of the non-radiopaque etonogestrel implant Implanon and was 2.8 pounds after one year and 3.7 pounds after two years. Concerning elevated blood pressure, the manufacturer recommends that women with a history of hypertension-related diseases or renal diseases abstain from using hormonal contraception. As regards gallbladder disease, the manufacturer mentions  studies  suggesting a slight increase in the relative risk of developing gallbladder disease among users of combination hormonal contraceptives. Whether this holds true also for progestin-only contraception is unknown.

Pertaining to carbohydrate and lipid metabolic effects the manufacturer mentions the possibility of a mild insulin resistance and slight changes in glucose concentrations due to Nexplanon. ‘‘Women who are being treated for hyperlipidemia should be followed closely if they elect to use NEXPLANON. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult’’ [11]. With regard to depressed mood the manufacturer recommends careful observation  of  women with a history of such a condition and advises removal of Nexplanon ‘‘in patients who become significantly depressed’’ [11].

Regarding return to ovulation the manufacturer specifies that in clinical trials with Implanon, pregnancies occurred as early as seven to fourteen  days after removal. ‘‘Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired’’ [11]. Fluid retention,  according to the manufacturer, can be caused by hormonal contraceptives so that caution should be exercised in prescribing them for patients ‘‘with conditions which might be aggravated by fluid retention’’ [11]. Whether Nexplanon causes fluid retention is not known. Concerning contact lenses the manufacturer advises that in case of visual changes or changes in lens tolerance assessment  by an ophthalmologist be sought.

 In response to reports of broken or bent implants in the patient’s arm, the manufacturer specifies that the release rate of etonogestrel may be slightly increased. Women implanted with Nexplanon should be monitored and have the possibility of ‘‘a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care’’ [11].  Concerning drug-laboratory test interactions the manufacturer draws attention to sex hormone-binding globulin and thyroxine. ‘‘Sex hormone-binding globulin concentrations may be decreased for the first six months after NEXPLANON insertion followed by gradual recovery. Thyroxine concentrations may initially be slightly decreased followed by gradual recovery to baseline’’ [11]. 

In discussing adverse reactions associated with the use of hormonal contraception, the manufacturer draws attention again to changes in menstrual bleeding patters, ectopic pregnancies, thrombotic and other vascular events, and liver disease. In presenting  statistical  data  pertaining to adverse reactions the manufacturer focuses on  the non-radiopaque implant Implanon and not on Nexplanon. Those adverse reactions which result in a rate of discontinuation of  Implanon greater or equal to 1% include: bleeding irregularities, emotional lability, weight increase, headache, acne, and depression. Adverse reactions reported by 5% (or more) in trials with Implanon include headache (24.9%), vaginitis (14.5%), weight increase(13.7%), acne (13.5%), breast pain (12.8%), pharyngitis (10.5%), leukorrhea (9.6%), influenza-like symptoms(7.6%), dizziness (7.2%), dysmenorrhea (7.2%), back pain (6.8%), emotional lability (6.5%), nausea (6.4%), pain (5.6%), nervousness (5.6%), depression (5.5%), hypersensitivity (5.4%), and insertion site pain (5.2%) [11].

Concerning implant site, the manufacturer mentions a clinical trial which examined this location subsequent to insertion of Nexplanon and found that 8.6% of women reported reactions. ‘‘Erythema was the most frequent implant site complication, reported during and/or shortly after insertion, occurring in 3.3% of subjects. Additionally, hematoma (3.0%), bruising (2.0%), pain (1.0%), and swelling (0.7%) were reported’’[11]. Additional adverse reactions to Implanon were brought to light by postmarketing experience, identified during post-approval use and reported voluntarily from a population of uncertain size. The adverse reactions reported  include: gastrointestinal disorders (constipation, diarrhea, flatulence, vomiting); general disorders and conditions of administration site  (edema, fatigue, implant site reaction, pyrexia); immune system disorders (anaphylactic reactions); infections and infestations (rhinitis, urinary tract infection); investigations (clinically relevant rise in blood pressure, weight decreased); metabolism and nutrition disorders (increase in appetite); musculoskeletal and connective tissue disorders (arthralgia, musculoskeletal pain, myalgia); [11] nervous system disorders (convulsions, migraine, somnolence); pregnancy, puerperium and perinatal conditions (ectopic pregnancy); psychiatric disorders (anxiety, insomnia, decrease of libido); renal and urinary disorders (dysuria); reproductive system and breast disorders (breast discharge, breast enlargement, ovarian cyst, pruritus genitalis, vulvovaginal discomfort); skin and subcutaneous tissue disorders (angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, rash,  pruritus, urticaria, seborrhea); vascular disorders (hot flush). Among the complications related to the insertion or removal procedures of  Implanon were ‘‘bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess’’[11].

With respect to changes in contraceptive efficacy due to coadministration of other products the manufacturer draws attention to the induction of enzymes, including CYP3A4, that metabolize progestins. They  may cause a reduction in the plasma concentrations of progestins and may therefore decrease the effectiveness of Nexplanon. ‘‘In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug’’[11]. Among the drugs or herbal products inducing enzymes, including CYP3A4, the following are listed:  barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John’s wort, and topiramate.  In this context, the manufacturer draws attention also to HIV antiretrovirals, since significant changes (decrease or increase) in the progestin plasma levels  have been noted ‘‘in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors’’[11].

In discussing the use of Nexplanon in specific populations the manufacturer addresses problems of  pregnant women, nursing mothers, pediatric use, geriatric use, hepatic impairment, renal impairment, and overweight women.  Concerning pregnancy, the manufacturer states that the implant is not for use during pregnancy and refers to teratology studies which did not produce any evidence of fetal harm due to etonogestrel exposure. ‘‘Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives’’ [11].

Concerning nursing mothers, the manufacturer admits that only limited clinical data are available: ‘‘NEXPLANON may be used during breastfeeding after the fourth postpartum week. Use of NEXPLANON before the fourth postpartum week has not been studied’’ [11].  Available data indicate that etonogestrel is excreted in breast milk so that 100 ng might be ingested by the child during the first month, and the daily infant etonogestrel dose one month after insertion of the device is approximately 2.2% of the weight-adjusted maternal dose. ‘‘Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of NEXPLANON, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of the non-radiopaque etonogestrel implant (IMPLANON) is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose’’ [11]. In discussing issues pertaining to nursing mothers, attention is drawn also to non-hormonal contraceptives which might be an alternative option:  ‘‘Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients’’[11].

Concerning pediatric use the manufacturer claims that safety as well as  efficacy of Nexplanon have been established for women of reproductive age. ‘‘Safety and efficacy of NEXPLANON are expected to be the same for postpubertal adolescents’’ [11]. Unfortunately, no data are provided to substantiate this precarious claim, and the assumption concerning postpubertal adolescents is no more than speculative.  For users less than 18 years no studies have been undertaken. ‘‘However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated’’ [11].

Concerning  specific populations with hepatic impairment the manufacturer admits that no studies are available  ‘‘to evaluate the effect of hepatic disease on the disposition of  NEXPLANON’’ [11]. The same holds true for women suffering from renal impairment: ‘‘No studies were conducted to evaluate the effect of renal disease on the disposition of NEXPLANON’’ [11]. As regards overweight women the manufacturer calls to mind the inverse relationship between etonogestrel serum concentrations and body weight. Consequently, the possibility exists ‘‘that NEXPLANON may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers’’ [11].

 Besides the Full Prescribing Information discussed above, the manufacturer offers also a FDA-Approved Patient Labeling. In this piece of information users are advised that  NEXPLANON implant must be removed after 3 years.  As regards the mechanism of action, thickening of the cervical mucus to prevent contact between ovum and sperm is underlined, as well as changes in the lining of the uterus.

Concerning the efficacy of Nexplanon, a chart is presented which, alas, reflects no more than a rudimentary notion of ranking contraceptive methods, and which cannot stand up to the standards of the most widely recognized ratings and rankings developed by Contraceptive Technology,[12] the World Health Organization (WHO),[13] the US Food and Drug Administration (FDA),[14] and research on the safety of contraceptive methods [15]. In contrast to the latter research which ranks contraceptive methods according to safety, the chart presented by the manufacturer of Nexplanon does not contain any information on this parameter which, in the opinion of this author, is of utmost importance to most women. In addition, only 12 methods are mentioned, ie, 50 per cent of the methods  contained in the Contraceptive Failure Table of Contraceptive Technology [12], [Table 3-2] and less than 50% contained in the WHO chart [13]. 

Concerning allergies, the manufacturer correctly warns  prospective users about allergies to numbing medicines, ie, anesthetics and those used to  clean the skin, ie, antiseptics. ‘‘These medicines  will be used when the implant is placed into or removed from your arm’’. Concerning side effects reference is made to studies showing that ‘‘one out of ten women stopped using the implant because of an unfavorable change in their bleeding pattern’’ [11]

Regarding  problems with insertion  and removal it is specified that  infection and ‘‘scarring, including a thick scar called a keloid around the insertion site’’  might  occur. The possibility of expulsion is explained in terms of  ‘‘coming out’’: ‘‘The implant may come out by itself. You may become pregnant if the implant comes out by itself’’. In explaining the risk of an ectopic pregnancy, the manufacturer appropriately mentions the possibility of a lethal outcome. ‘‘Ectopic pregnancy is a medical emergency that often requires surgery. Ectopic pregnancies can cause serious internal bleeding, infertility, and even death’’ [11].

In the same vein, the death-bearing sequelae of serious blood clots are mentioned  ‘‘It is possible to die from a problem caused by a blood clot, such as a heart attack or a stroke’’[11]. And in this context examples of serious blood clots are cited, such as deep vein thrombosis located in the legs, pulmonary embolism located in the lungs, stroke located in the brain, heart attack, and total or partial blindness afflicting  the eyes [11]. Additionally, the recommendable advice is given to quit smoking.

Consultation of the physician is recommended in case of the following conditions: pain in the lower leg that persists, severe or sharp chest pain or heaviness felt  in the chest; sudden shortness of breath or coughing blood;  symptoms of a severe allergic reaction such as swelling of face, tongue or throat; trouble breathing or swallowing; sudden severe headache which is different from  usual headaches; weakness or numbness in the arm or leg, or trouble speaking; sudden partial or complete blindness (indicative of a cerebrovascular event); yellowing of  skin or whites of the eyes, especially in conjunction with fever, tiredness, loss of appetite, dark colored urine, or light colored bowel movements (indicative of a liver disease); severe pain, swelling, or tenderness in the lower stomach or abdomen; lump in the breast;  problems sleeping, lack of energy, tiredness,  feeling of  sadness (indicative of depressed mood); and intense menstrual bleeding.

Concerning breast feeding, the manufacturer explicates that  ‘‘A small amount of the hormone contained in NEXPLANON passes into your breast milk. The health of breast-fed children whose mothers were using the implant has been studied up to 3 years of age in a small number of children. No effects on the growth and development of the children were seen’’ [11].

As can be seen from the FDA-Approved Patient Labeling discussed above  lacunae still exist and this might be the reason the manufacturer recommends repeated consultation of the physician or contact with the company itself.  Despite the manufacturer's offer to provide assistance, users should not rely solely on such offers because in some instances,  health agencies such as the WHO have to intervene to warn the consumer about potential complications and risks. Thus, the WHO has issued rare reports of complications regarding Nexplanon, in particular  migration from insertion site: ‘‘The MHRA has issued a warning about rare reports of complications with etonogestrel (Nexplanon) contraceptive implants. In rare cases, such implants have moved from the insertion site and reached the lung via the pulmonary artery. An implant that cannot be palpated at its insertion site in the arm should be located as soon as possible and removed at the [16] earliest opportunity. If an implant cannot be located within the arm, chest imaging should be performed. Correct subdermal insertion reduces the risk of these events’’[16].

As can be seen, the WHO had to intervene to inform the consumer about risks not mentioned  by the manufacturer of the implants Nexplanon and Implanon. Incompleteness of the manufacturer's Patient Information Leaflet  must therefore be assumed by the consumer despite numerous precautions and  warnings appropriately discussed. Pertaining to risks  the manufacturers mentions correctly the possibility of death in the case of ectopic pregnancy and in association with  blood clots. There are, of course,  areas in which important information is missing due to a lack of pertinent studies, as for example in special populations with  hepatic disease  or renal impairment. In addition, the consumer might be irritated by the speculative assumption in case of the most important issues of  contraception, namely safety and efficacy.  If safety and efficacy is in fact established for women of child-bearing age -- the manufacturer provides no reliable  data -- it seems ethically unjustified to warrant safety and efficacy  also for younger women. Equally disturbing for the reader is the use of an euphemistic nomenclature  which uses the terminology ‘‘insert’’  and ‘‘insert-site’’ when in fact the procedure is an implantation, ie, substantially  more  risk-ful than an insertion of a diaphragm into the   vagina.  Vagueness of terminology is a weakness also of the FDA-Approved Patient Labeling where the size of the device is compared to a matchstick: ‘‘The implant is a flexible plastic rod about the size of a matchstick that contains a progestin hormone called etonogestrel’’ [11]. As matchsticks come in different sizes  the consumer might prefer measurements in terms of international units. On a general note, the question must  be raised as to whether or not each consumer reading the Patient Information Leaflet will pay sufficient  attention to some important risks and potential complications, which are not always sufficiently underscored.

According to the manufacturer low doses of levonorgestrel can be administered into the uterine cavity with the Mirena intrauterine delivery system. Initially, levonorgestrel is released at a rate of approximately 20 μg/day. This rate decreases progressively to half that value after 5 years.

Additional methods of contraception

Despite undeniable advantages of LARCs, of oral hormonal contraception, and of Emergency Contraception, adverse events, risks and complications can be serious so that some women might be willing to embark on birth control only under the condition that risks can be precluded. Prevention of harm seems possible owing to the existence of non-hormonal methods. While condom and coitus interruptus have a long history, non-hormonal methods known under the designation fertility awareness-based (natural family planning, periodic abstinence) methods came into existence only during the last century. Some of these methods -- whose greatest drawback is irregularity of menstrual cycles -- deserve attention because they might be the solution for the increasing  number of women who do not tolerate hormones and devices [31] or women with certain cultural and religious backgrounds who are determined  to use only natural, non-hormonal methods.

Non-hormonal (fertility awareness-based, periodic abstinence, natural family planning) methods:

Under the designation ‘‘natural family planning’’ some non-hormonal methods have been known since the last century, especially in Western Europe where the first investigations took place.[25,pp.61-64]  Van de Velde from the Netherlands described the Basal Body Temperature method als early as 1927. The Japanese Ogino (1932) and the Austrian Knaus (1933) were instrumental in developing the Calendar  method (also  designated as ‘‘rhythm’’), and in 1964 the Australian John Billings delineated the Ovulation or Cervical Mucus method as a result of extensive research on fertility. The latter was then combined with other methods and defined as symptothermal method by the Austrian Rötzer. Extensive discussion of these methods and their assessments have been presented recently in a scholarly investigation [32].

Additional methods are available on the international market. They are included in a table entitled ‘‘Safety – Efficacy – Convenience – Cost Ranking,’’ which differs from all other tables presented hitherto in the literature as it prioritizes safety and contains additional clinically important parameters such as convenience  and cost.  In a ranking which prioritizes safety, non-hormonal methods would be ranked highest, as can be seen from (Table  1) (Safety – Efficacy – Convenience – Cost Ranking, 2019) in the Appendix.

 

Method Safety (no harm in the sense of “nil nocere“) Efficacy Perfect-Typical use Convenience % of women continuing use after one year of use Cost & Specifications Symptothermal                                High 0.4-24 High No cost. Body temperature must be measured,  cervical mucus must  be observed (clear texture), cervix must be palpated (soft consistency and open). Ovulation     (based on cervical mucus) High 3-24 High No cost. Cervical mucus must be observed (“spinnbarkeit“) TwoDay (based on cervical mucus) High 4-24 High No cost. Coitus must be avoided during fertile days. Fertile days determined  by presence of  cervical mucus (color and consistency). Coitus may be resumed after 2 consecutive dry days (or absence of secretion). Standard Days Method (SDM) – based on calendar High   5-24 High No cost. Fertile period is tracked and coitus avoided (usually days 8-19 of each  26-32  day cycle). Basal Body Temperature (BBT) High 1-25 High No cost. Fertile phase has passed when body temperature has risen (0.2-0.5° C) and remained such for 3 days. Conception  is unlikely from 4th day following rise of temperature until next menstruation. Calendar (rhythm) method High 9-25 High No cost. Menstrual cycle is monitored for at least 6 months. 18 is subtracted from shortest cycle (this is the estimated first fertile day). 11 is subtracted from the longest cycle (this is the estimated last  fertile day). Caution when drugs are used (NSAID, certain antibiotics, anxiolytics, anti-depressants, etc.). Coitus interruptus   4-22 Moderate/26% Sperms must not enter the vagina. Male condoms     Moderate   2-18 . High/ 43% Low cost. Protects against sexually transmitted diseases (STD) including HIV. Female condom Moderate 5-21 Moderate/ 41% Moderate cost. Prevents contact between sperm and egg. Protects against sexually transmitted diseases (STD) including HIV (according to WHO). Diaphragms                                Moderate 6-12 Low/57% High cost. Must be used for each coitus. Implant (Small, flexible rod or capsule placed under the skin of the upper arm; contains progestogen hormone only). Moderate 0.05-0.05 High/84% High cost. Implanted  by clinician. Irregular vaginal bleeding common. Mirena (LNG) Intrauterine device (IUD) (T-shaped plastic device inserted into the uterus that  releases continuously small amounts of levonorgestrel). Moderate 0.2-0.2 Moderate/80% High cost. Prevenis contact between sperm and egg by thickening cervical mucus. Amenorrhea.     ParaGard (copper IUD) Moderate 0.6-0.8 Moderate/78% High cost. Copper component damages sperms. Depo-Provera   Moderate 0.2-6 Moderate/56% High cost.   Combined oral contraceptive (COCs)= “the pill“ Moderate 0.3-9 Moderate/67% Moderate cost. Contains estrogen and progestogen.. Progestogen-only        pill (POP) or “minipill“ Moderate 1-3 (10) Moderate/67% Moderate cost. Thickens cervical mucus and prevents ovulation. Evra patch Moderate 0.3-9 Moderate/67% High cost. NuvaRing Moderate 0.3-9 Moderate/67% High cost. Combined contraceptive patch and combined  contraceptive vaginal ring    (CVR) Moderate 1-8(?) (Research on efficacy limited). Low High cost. Continuously releases a progestin and an estrogen directly through the skin (patch) or from the ring. Prevents ovulation, copper component damages sperms. Pharmaco-kinetic profile comparable to COCs. Monthly injectables or combined injectable contraceptives (CIC) Moderate       1-3       Low High cost. Irregular vaginal bleeding. Injected monthly into muscle. Progestogen-only injectables Moderate   1-3 Low High cost. Injected into the muscle or under the skin every 2 or 3 months, depending on product. Irregular vaginal bleeding; delayed return to fertility after use. Emergency Contraception Moderate - Low 15-15 Moderate Moderate cost. Pills (ulipristal acetate 30 mg or levonorgestrel 1.5 mg) must taken twice to prevent pregnancy up to 5 days after coitus. Alternatively IUD (copper or levonorgestrel) to be inserted. Lactational Amenorrhea (LAM) High     1-2 Moderate No cost. Effective in preventing ovulation as long as monthly  bleeding has not yet returned. Requires exclusive breastfeeding day and night of infant less than 6 months old. Male sterilization (vasectomy)                                   Moderate <1 (after 3-months  semen evaluation). 2-3 (without semen evaluation). High/100% High cost. Surgical intervention. Permanent contraception by cutting vas deferens tubes which transport sperm from the testicles. Female sterilization (tubal ligation )   Low 0.5-0.5 Moderate-Low/100% High cost. Surgical intervention. Permanent contraception by blocking or cutting the fallopian tubes. Sponge Moderate 20-24 - parous women 9-12-nulliparous women Moderate/36% Moderate cost. To be used for each coitus. Spermicides Moderate 18-28 High/42% Moderate cost. Table 1: Safety – Efficacy - Convenience Rating, 2019

 

Conclusions and consequences

The foregoing investigation proves that  pharmacological research does not always stand up to the expectations of the consumer who looks for  accurate, complete, and comprehensible information on contraceptive products. Especially with regard to the requirements of medical ethics and the principle of informed consent severe deficits are conspicuous because the instances where the consumer is enabled to make an intelligent choice are rather an exception.

It must stipulated therefore that  translational pharmacology assists pharmaceutical companies in increasing sensibility for the needs of the consumer by presenting information in such a way that there is no room for misunderstandings or misinterpretations. Besides pharmacovigilance, which  investigates the safety of substances, research in pharmaceuticovigilance is called upon to assess the quality of information provided by manufacturers for the consumer. This information should avoid euphemistic nomenclature that misleads the reader into believing that a high-risk procedure is an uncomplicated intervention involving no harm.  Unadulterated information phrased in understandable language will contribute not only to upholding ethical standards but also to averting  forensic proceedings including costly lawsuits. 

 

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