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NorCal Open Access Publications Journal of Pharmacology and Clinical trials Volume 2019 ; Issue 01 Kraetschmer K

Review article Topical Issues in Translational Pharmacology and Pharmaceuticovigilance: Can Pharmacological Research on 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: [email protected] Received Date: 30th August 2019; Accepted Date: 01st October 2019; Published Date: 12th October 2019

Abstract autodidactic strategies by using not only print media but also social media via internet. Aim: On the background of media reports about serious harm to the health of thousands of women engaged in and contraception, the research article aims pursued not only by individual healthcare providers but at emphasizing the importance of pharmaceuticovigilance alsoIntensification by editors who of frequently pharmacological publish educationstudies obscured should by be for information on the safe use of contraceptive pills and devices. for the consumer and to avoid detrimental consequences for women’sconflicts ofhealth interest. research To remedy in pharmaceuticovigilance the lack of vital information - whose 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 Keywords:foundation is laid within this article - should be intensified. Contraception; Emergency and oral hormonal leaflets and packaging labels of manufacturers; statements contraception; Long-Acting Reversible Contraception by governmental health agencies; publications by the (LARC); Periodic abstinence/fertility awareness; containedEuropean inMedicines high-ranked Agency scholarly (EMA); journals, and infromation especially by those the IntroductionPharmaceuticovigilance; Pharmacology; . inUS pharmacovigilance, Food and Drug Administration are critically (FDA). surveyed. In addition, findings companies became the target of press reports commenting Results: Presently, women are not provided with information on Recently, complaints one lodged of the by world’s women leading who had pharmaceutical experienced suitable for safe contraceptive pursuits. Consumers are severe adverse events associated with the company’s not adequately informed about contraceptive products as product for permanent contraception. According to these pharmaceutical companies frequently fail to comply with the reports, not only medical problems were at stake but also principle of informed consent. Clinicians, under the pressure the company. ‘‘The implant has had a troubled history. It has to convey salient information to their patients. forensic issues owing to thousands of lawsuits filed against of economic maxims such as cost efficiency, apparently fail been the subject of an estimated 16,000 lawsuits or claims Conclusion: complete, comprehensible and reliable information on perforation of the and the fallopian tubes. Several the safety of Asmethods it is difficult of contraception, for women toespecially obtain accurate, on vital deaths,filed by including women of who a few reported infants, severehave also injuries, been attributed including pharmacological parameters, they are advised to intensify to the device or to complications from it’’ [1].

87 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: 87-104.

From Australia similar reports reached the international changed, and we continue to stand behind the product’s insert placed into each of the patient’s fallopian tubes. Over 200.000 women. ‘‘The benefit-risk profile of has not threereadership: months ‘‘The a barrier device, forms known around as Essure, the inserts,is a soft, which flexible is body of research, undertaken by Bayer and independent intended to block the fallopian tubes and permanently medicalsafety and researchers, efficacy, which involving are demonstrated more than 200,000 by an extensive women prevent . But there have been reports women over the past two decades’’[4]. experienced changes in menstrual bleeding, unintended As its strongest argument for the safety of the device the pregnancy, chronic pain, perforation and migration of the company can refer to a statement made by the FDA drawing device, allergic reactions and immune-type reactions after ‘‘The FDA being implanted with the device, which is manufactured by the pharmaceutical company Bayer’’ [2]. outweighattention its to risks’’ a comparison[4]. of benefits and risks. The medical and legal problems affecting the company’s has maintained for several years that the benefits of Essure Despite insistence on the safety of the device, the business in a negative fashion originated from a small nickel- company felt compelled in 2018 to draw attention to titanium coil designed for permanent contraception by severe adverse events by providing important safety way of sterilization. In its instructions for use the company information including an explicit warning: ‘‘Some patients implanted with the Essure System for Permanent Birth insert. As such, the consumer envisages it as a foreign object thatexplains is inserted the components into a woman’s of the body device similar and definesto a diaphragm it as an or a patch. ‘‘Each insert consists of a Nitinol (nickel-titanium Control have experienced and/or reported adverse events, persistentincluding perforationpain, and suspected of the uterus allergic and/or or hypersensitivityfallopian tubes, reactions.identification If the of device inserts needs in the to abdominalbe removed or to pelvicaddress cavity, such bandsalloy) outer(2) and coil, a silver-tina 316L stainless solder’’. steelThe Instructionsinner coil wrapped for Use an adverse event, a surgical procedure will be required. This offerin polyethylene information terephtalate also on the (PET) characteristics fibers, platinum of the marker device information should be shared with patients considering concerning length and diameter: ‘‘The insert is 4 cm in length sterilization with the Essure System of Permanent Birth As soon as the outer coil is released it expands up to 2.0 mm and 0.8 mm in diameter in its wound-down configuration’’. device’’[4]. in diameter ‘‘conforming itself to the varied diameters and Control during discussion of the benefits and risks of the shapes of the [3]. As early as 2002, the company issued general warnings regarding perforation, embedment, and expulsion: As part of their marketing strategy the company ‘‘Unsatisfactory device location including perforation, emphasized the unique feature of the device by referring to uterine embedment and expulsion may result in pain’’. the FDA. ‘‘Essure is the only FDA-approved non-incisional Warnings about the risk of pregnancy draw attention also form of permanent birth control’’ [4]. Concerning the to some serious conditions: ‘‘While most with Essure in situ have been reported as healthy deliveries at system’’ is intended for permanent contraception by means term, pregnancy loss, pre-term labor, pre-term rupture mechanism of action the company specifies that the ‘‘Essure of a ‘‘physical occlusion of the fallopian tubes’’ [3]. Through of membranes, pre-term delivery, , and neonatal a transvaginal manoeuvre the Essure system is placed into complications have also been reported’’. The hysteroscopist the lumen of the proximal portion of the fallopian tube is advised to reduce the risk of hypervolemia and pay where it anchors upon release: ‘‘The insert is a dynamic attention to the possibility of tubal perforation: “Terminate deployment, conforms to and pushes against the fallopian reduce the risk of hypervolemia’’. and flexible spring-like device. The outer coil expands upon tube wall, acutely anchoring the insert in the lumen of the bethe aprocedure sign of uterine if distention or tubal fluid perforation, deficit exceeds the 1500cc,procedure to fallopian tube’’ [3]. Dynamic anchoring in the fallopian tube, should be discontinued and theAs patient excess fluidevaluated deficit “forcan possible perforation’’[3]. it is the occlusion of the fallopian tube through a tissue in- growthhowever, that does results not in suffice sterilization. to effect ‘‘Subsequently, contraception; the ratherinsert The “Patient Counseling Information’’ contained in the elicits a benign tissue in-growth that permanently occludes Instructions for Use warns about allergies to nickel or other the lumen of the fallopian tube, resulting in permanent component parts of the insert subsequent to placement. contraception’’ [3]. “Typical allergic symptoms reported for this device include hives, urticaria, rash, angioedema, facial and pruritis Although the company felt compelled to withdraw its product from the Australian market in 2017 - under patients be counseled on the materials contained in the the pressure of the Australian Therapeutic Goods /sic!/’’. The manufacturer requests, therefore, that all Administration (ATGA)[5] -- and from the US market by the prior to the Essure procedure’’. Patients are advised to familiarizeinsert and onthemselves the “potential with forthe allergy/hypersensitivity “Patient Information Booklet (PIB)’’[3]. The doctor should review with the patient theend withdrawalof 2018, it continued from the toUS insist market, on both the companyefficacy and stressed safety the ‘‘Patient-Doctor Discussion Checklist,’’ and all of the theof the research device. Thus,undertaken, in its News which Release had involved of 2018 announcingmore than patients’ questions should be answered.

J Pharm Sci Exp Pharmacol 2019: 87-104. 88 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: 87-104.

According to the instruction for use of 2002, adverse events rare instances, an Essure insert may be expelled from the resulting from the placement procedure include cramping, body’’[4]. Adverse events can occur also several weeks after the insertion procedure, during the so-called Essure andpain, band /, detachment. Among dizziness/light the risks with headedness, follow-up proceduresbleeding/spotting, allergic reaction vaso-vagal is mentioned response, owing hypervolemia, to the use veryconfirmation low levels test. of radiation, ‘‘As one of as the with Essure most Confirmationx-rays, if this testTests is (a modified HSG) requires an x-ray, you may be exposed to responseof contrast are media described: for the “Allergic modified reaction Hysterosalpingography can result in hives (HSG), and the lethal consequences of an anaphylactic used. Some women may experience nausea and/or vomiting, response may occur which may lead to death’’[3]. dizziness and/or fainting, cramping, pain or discomfort. In or difficulty breathing. In some individuals, an anaphylactic infection’’ [4]. In a section entitled Directions for Use, attention is drawn rare instances, women may experience spotting and/or In addition to adverse events during the insertion, to day calculations and to pretreatment. ‘‘Women with menstrual cycles shorter than 28 days should undergo are risks that must be considered long-term. The most careful ovulation day calculations. Insert placement should perilousafter insertion, of these and risks during is ectopic the confirmationpregnancy, and, test, as there the not be performed during ’’. Visualization for the hysteroscopist can be improved through pretreatment for suppression of endometrial proliferation. ‘‘Pretreatment andmanufacturer length of time warns, may thisoccur can and be continue life-threatening. following ‘‘Long-Essure of the patient with medications that suppress endometrial placement.term Risks: . Pain. . Patients (acute with or persistent) known hypersensitivity of varying intensity to any proliferation may enhance visualization and scheduling of the components of the Essure system may experience an [3]. allergic reaction to the insert’’ [4]. Subsequent to placement, flexibility’’As can be seen from the Directions for Use copyrighted in 2002, there are numerous warnings and precautions allergy to nickel or other component parts of the insert. The symptomsthe manufacturer reported specifies, by users some of Essure women may may be developassociated an 2018 contains again warnings and draws attention to with allergic reactions and include hives, rash, swelling immunosuppressantsabout risks and adverse as well events. as allergies The ‘‘News to metal, Release’’ polyester of and itching. Concerning the risk of ectopic pregnancies the manufacturer correctly underscores the seriousness of the and other components of the Essure system. Moreover, condition. ‘‘This can be life-threatening. If insert removal is itfibers, explains nickel, adverse titanium, events platinum, that silver-tin,can occur stainless during steeland indicated, surgery will be necessary’’[4]. Concerning special 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, overpopulations, 45 years the of age.manufacturer ‘‘The safety specifies and effectiveness that neither of Essure safety and that perforation through the hysteroscope occurs hasnor efficacynot been have established been established in women for under women 21 under or over 21 45or with ensuing need for surgery. ‘‘During the Procedure: In years old’’[4]. the premarketing study, some women experienced mild As a particular safety measure, the manufacturer to moderate pain (9.3%). Your doctor may be unable to restricted the insertion procedure of the device to place one or both Essure inserts correctly. In rare cases, physicians who are competent hysteroscopists: ‘‘Caution: part of an Essure insert may break off during placement. Federal law restricts this device to sale by or on the order If breakage occurs, your doctor will remove the piece, if of a physician. Device to be used only by physicians who are 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 haveknowledgeable successfully hysteroscopists; completed the have Essure read training and understood program, system or other instruments used during the procedure. In includingthe Instructions preceptoring for Use andin placement Physician Traininguntil competency Manual; and is the original premarket studies, perforation due to the Essure established, typically 5 cases’’ [4]. insert occurred in 1.8% of women. A perforation may lead to bleeding or injury to bowel or bladder, which may require As can be seen from the above citations, the manufacturer surgery. Your doctor may recommend a local anesthesia. (Essure) endeavored to provide comprehensive information Ask your doctor about the risks associated with this type of on the device and mentions also the life-threatening risks anesthesia’’[4]. of an anaphylactic reaction and of an ectopic pregnancy. At the same time, however, the consumer notices that the Subsequent to the procedure pain, cramping, and vaginal information is not always as comprehensible as required bleeding may occur. ‘‘Immediately Following the Procedure: by the bioethical principle of informed consent, which In the premarketing study, some women experienced stipulates that the patient be enabled to make ‘‘an intelligent choice’’ [6]. Thus in explaining the mechanism of action the (6.8%), and pelvic or back discomfort for company uses a nomenclature that might be confusing not amild few to days. moderate Some painwomen (12.9%) experienced and/or crampingheadaches, (29.6%), nausea only to unexperienced consumers but even to educated healthcare providers because it is unclear what kind of and/orJ Pharm Scivomiting Exp Pharmacol (10.8%), 2019: or 87-104. dizziness and/or fainting. . . In 89 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: 87-104. biochemical process can ‘‘elicit’’ a benign-tissue in-growth, intelligent choice. The problem of inadequate information is elicits a benign tissue in-growth that permanently occludes theas specified lumen ofby thethe manufacturer:fallopian tube, ‘‘Subsequently,resulting in permanent the insert productsnot a specificity for birth of thecontrol insert andfor permanentcontraception. contraception It seems contraception’’ [3]. In a different context tubal occlusion and appropriatediscussed above; therefore it is ato crux investigate also in otheras to whether descriptions or not of pharmaceutical companies manufacturing pills and devices for birth control and contraception can stand up to the tissue in-growth are explained with reference to PET fibers, ethical standards of the principle of informed consent which onlyie, ‘‘polyethylene retention of terephthalatethe device but (PET) also fibers’’. tubal occlusion. Allegedly, requires comprehensive and comprehensible information these fibers cause tissue in-growth which facilitates not for the patient [6]. the device and the benign occlusive tissue response. PET ‘‘Tubal occlusion is attributed to the space filling design of The subsequent sections are devoted to such an facilitating insert retention, resulting in tubal occlusion and contraception’’fiber causes tissue [3]. in-growth into and around the insert, shortcomings in information provided by pharmaceutical investigation and aim at bringing to light deficits and understand by what kind of chemical reaction the device Emergencycompanies. GivenContraception that Long-Acting are the Reversiblemost widely Contraception used forms canFrom ‘‘elicit’’ a a physiologicalbenign tissue viewpointin-growth. It it is isnot difficult surprising to of(LARC), contraception, oral hormonal the pharmaceutical contraceptives, companies and producing pills for therefore that alternative explanations have been provided these pills and devices are the focal points.

polyester LARC - the most effective form of contraception whichnickel- assumetitanium an, stainlessinflammation steel and and ensuing solder fibrotic. The growth. insert ‘‘The small, flexible inserts are made from fibers, considered the most effective form of contraception owing [7]. to estimatesLARC comprise of 0.05% implants for implants, and intrauterine 0.2% for devices levonorgestrel and are contains inner polyethylene terephthalate fibers to induce containing intrauterine devices, such as Mirena, [10] and 0.6 inflammation,Press reports causing too aavoided benign thefibrotic expression ingrowth’’ ‘‘in-growth’’ and spoke of ‘‘’’ tissue, ie, tissue which results from a ParaGard. nickel-titanium coils inserted into the fallopian tubes, where (perfect use/0.8 typical use) for copper containing such as wound inflicted to healthy tissue. ‘‘Essure consists of two The Etonogestrel implants (Nexplanon and they spur the growth of scar tissue that blocks sperm from Implanon): fertilizing a woman’s eggs’’[1]. is ‘‘a permanent mark resulting from a wound or disease Information on the etonogestrel-containing implants process in tissue’’[8]. If the insert By does medical in fact definition, cause a wound a scar furnished by the manufacturer is available as a 52-page ethical standards require that the consumer be informed accordingly. Prescribing‘‘Patient Information Information Leaflet’’ for Nexplanon containing [I] various (comprising headings, 14 Concerning wounds and ‘‘ingrowth’’ it should be borne namely a Highlights of Prescribing Information, a Full in mind that the resemblance between wound healing and tumor growth have been cogently outlined as early as 1986 andpages), a Fulla FDA-Approved Prescribing PatientInformation Labeling for forthe Nexplanon[II] etonogestrel in a publication focusing on the similarities between wound (comprising 5 pages), a Highlights of Prescribing Information healing and tumor growth. In describing tumors as wounds that do not heal, the author concludes: ‘‘They have developed comprisingimplant Implanon, 11 pages and [11]. a FDA-Approved ‘‘Patient Labeling the capacity to preempt and subvert the wound-healing IMPLANON® (etonogestrel implant), Subdermal Use’’ [III], response of the host as a means to acquire the stroma they need to grow and expand. They mimic wounds by depositing DestinedThe Full for Prescribing subdermal Information use, it is preloaded specifies thatin a Nexplanondisposable as at sites of local injury, signal the host to marshal the is a progestin-only, flexible and soft radiopaque implant. wound-healingan extravascular response. fibrin-fibronectin This response gel. Such is stereotyped gels, in tumors and biodegradable implant is 4 cm, and its diameter is 2 mm. similar in both tumors and wounds. In tumors, however, Itssterile ethylene applicator. vinyl Theacetate length (EVA) of thecopolymer white/off-white, core contains non- 68 mg etonogestrel (a synthetic progestin), barium sulfate (radiopaque ingredient), but may contain also magnesium the fibrin-fibronectin matrix signal that evokes the wound- and new gel is continuously deposited. Thus, tumors appear stearate, surrounded by an EVA copolymer skin. ‘‘Once tohealing the host response in the isguise not ofselflimited; wounds or, it morecontinues correctly, to operate of an unending series of wounds that continually initiate healing week 5-6’’. Thereafter it decreases to about 35-45 mcg per but never heal completely [9]. inserted subdermally, the release rate is 60-70 mcg/day in As can be seen from the foregoing discussion of the year it decreases to about 30-40 mcg per day, and by the Essure implant for permanent contraception, one of the endday byof the the third end ofyear the to first approximately year; by the 25-30 end ofmcg the per second day. reasons that caused the troubled history of the device is As Nexplanon is a progestin-only implant it does not contain information unsuited to enable the patient to make an

J Pharm Sci Exp Pharmacol 2019: 87-104. estrogen; it neither contains latex [11]. 90 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: 87-104.

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

contraindications several conditions are enumerated, namelyinteractions known and oruse suspected in specific pregnancy,populations current[11]. As regardsor past history of thrombosis or thromboembolic disorders, liver tumors, benign or malignant (or active liver disease), undiagnosed abnormal genital bleeding, known or suspected Figure 1: Etonogestrel. breast cancer (personal history of breast cancer, or other progestin-sensitive cancer, presently or in the past), allergic Etonogestrel [13-Ethyl-17-hydroxy-11-methylene-18,19 reaction to any of the components of Nexplanon [11]. from 19-nortestosterone, which is the synthetic biologically Complications pertaining to insertion and removal active- dinor-17α-pregn-4-en-20-yn-3-one], metabolite of the synthetic progestin is structurally . derived It procedures include pain, paresthesias, bleeding, hematoma, has a molecular weight of 324.46 and the following structural scarring or infection. The manufacturer warns about formula [11] (Figure 1). incorrectly inserted implants and describes potential Concerning clinical pharmacology, the mechanism of action consists in suppressing ovulation, in increasing implants should be conducted with caution in order to complications of removal. ‘‘Removal of deeply inserted the viscosity of the cervical , and in altering the prevent injury to deeper neural or vascular structures in endometrium. 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 that exposure-response relationships of the etonogestrel will continue and result in ‘‘compromised fertility, ectopic implantsRegarding are unknown. pharmacodynamics, With respect it to has pharmacokinetics been admitted pregnancy, or persistence or occurrence of a drug-related it is assumed that absorption takes place subsequent adverse event’’[11]. 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 contraceptionRegarding Changeswith Nexplanon, in Menstrual patients Bleeding will most Patterns, likely clinical trial. The mean (plus-minus SD) maximum serum experiencethe manufacturer a change specifies of their that normal subsequent menstrual to initiatingbleeding etonogestrel concentrations were 1200 (plus-minus 604) pattern. ‘‘These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity following implantation (n=50). The mean (plus-minus SD) (reduced or increased) or duration’’ [11]. Pertaining to serumpg/mL; etonogestrel they were concentration reached within decreased the first gradually two weeks over ectopic pregnancy, which is possible with all progestin- only contraceptive products, caution should be exercised in case of pregnancy or lower . ‘‘Although thetime, end reaching of the 202second (plus-minus year (n=37), 55) pg/mLand reached by the 138 end (plus-of the ectopic pregnancies are uncommon among women using first year (n=41), reached 164 (plus-minus 58) pg/mL by case of the non-radiopaque implant Implanon, a precursor ofminus Nexplanon, 43) pg/mL the by themean end of(plus-minus the third year. SD) (n=32). maximum In the pregnancyNEXPLANON, occurring a pregnancy in a woman that using occurs no contraception’’ in a woman using [11]. concentration of etonogestrel were 1145 (plus-minus 577) NEXPLANON may be more likely to be ectopic than a As regards thrombotic and other vascular events, the manufacturer calls to mind that combination hormonal pg/mlConcerning attained withindistribution two weeks the manufacturerafter implantation states [11]. that contraceptives containing both progestin and estrogen increase the risk of arterial events such as stroke and Approximately 66% of etonogestrel is bound to albumin in myocardial infarction as well as deep venous thrombotic bloodthe apparent and 32% volume is bound of distribution to sex hormone averages binding about globulin 201 L. events, such as venous thromboembolism, deep venous thrombosis, pulmonary , and retinal vein etonogestrel is metabolized in microsomes of the liver by the thrombosis. As Nexplanon is a progestin-only contraceptive, (SHBG). As regards metabolism, in vitro data indicate that it is not known whether these increased risks are relevant activity of etonogestrel metabolites no data are available. for etonogestrel alone. ‘‘It is recommended, however, that Concerningcytochrome excretion,P450 3A4 accordingisoenzyme. to Regarding the manufacturer, the biological the women with risk factors known to increase the risk of venous elimination half-life of etonogestrel is approximately 25 and arterial thromboembolism be carefully assessed’’ [11].

J Pharm Sci Exp Pharmacol 2019: 87-104. 91 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: 87-104.

In response to reports of broken or bent implants in the that atresia of the follicle is sometimes delayed in case of follicularRegarding development ovarian ‘‘and cysts, the the follicle manufacturer may continue explains to rate of etonogestrel may be slightly increased. Women grow beyond the size it would attain in a normal cycle’[11]. implantedpatient’s arm, with the Nexplanon manufacturer should specifies be monitored that the and release have With respect to carcinomas of the breast and reproductive the possibility of ‘‘a yearly visit with her healthcare provider organs, the manufacturer recommends that women with for a pressure check and for other indicated health current or past breast cancer ‘‘should not use hormonal care’’ [11]. Concerning drug-laboratory test interactions contraception because breast cancer may be hormonally the manufacturer draws attention to sex hormone-binding sensitive’’. Attention is drawn also to studies suggesting globulin and thyroxine. ‘‘Sex hormone-binding globulin an association between the use of combination hormonal contraceptives and an increased risk of intraepithelial neoplasias or cervical cancer. ‘‘Women with a family history Thyroxineconcentrations concentrations may be decreased may initially for be the slightly first six decreased months of breast cancer or who develop breast nodules should be followedafter NEXPLANON by gradual insertion recovery followedto baseline’’ by gradual[11]. recovery. carefully monitored’’ [11]. In discussing adverse reactions associated with the Concerning liver disease the manufacturer recommends use of hormonal contraception, the manufacturer draws removal of Nexplanon if there is a development of jaundice attention again to changes in menstrual bleeding patters, and draws attention to the association between hepatic ectopic pregnancies, thrombotic and other vascular events, adenomas and combination hormonal contraceptives and liver disease. In presenting statistical data pertaining (estimate of the attributable risk is 3.3 cases per 100.000 to adverse reactions the manufacturer focuses on the non- users). Whether a similar risk can be assumed for progestin- radiopaque implant Implanon and not on Nexplanon. Those only contraceptives, such as Nexplanon, is unknown [11]. adverse reactions which result in a rate of discontinuation Weight gain occurred during use of the non-radiopaque of Implanon greater or equal to 1% include: bleeding etonogestrel implant Implanon and was 2.8 pounds after one irregularities, emotional lability, weight increase, headache, year and 3.7 pounds after two years. Concerning elevated acne, and depression. Adverse reactions reported by 5% (or blood pressure, the manufacturer recommends that women more) in trials with Implanon include headache (24.9%), with a history of hypertension-related diseases or renal vaginitis (14.5%), weight increase(13.7%), acne (13.5%), diseases abstain from using hormonal contraception. As breast pain (12.8%), pharyngitis (10.5%), leukorrhea regards gallbladder disease, the manufacturer mentions studies suggesting a slight increase in the relative risk of (7.2%), back pain (6.8%), emotional lability developing gallbladder disease among users of combination (6.5%),(9.6%), nausea influenza-like (6.4%), symptoms(7.6%), pain (5.6%), nervousness dizziness (7.2%),(5.6%), hormonal contraceptives. Whether this holds true also for depression (5.5%), hypersensitivity (5.4%), and insertion progestin-only contraception is unknown. site pain (5.2%) [11]. Pertaining to carbohydrate and lipid metabolic effects Concerning implant site, the manufacturer mentions the manufacturer mentions the possibility of a mild insulin a clinical trial which examined this location subsequent resistance and slight changes in glucose concentrations to insertion of Nexplanon and found that 8.6% of women due to Nexplanon. ‘‘Women who are being treated for reported reactions. ‘‘Erythema was the most frequent hyperlipidemia should be followed closely if they elect to use after insertion, occurring in 3.3% of subjects. Additionally, hematomaimplant site (3.0%), , bruising (2.0%), reported pain during (1.0%), and/or and swelling shortly [11].NEXPLANON. With regard Some toprogestins depressed may mood elevate the LDL manufacturer levels and (0.7%) were reported’’[11]. Additional adverse reactions recommendsmay render thecareful control observation of hyperlipidemia of women more with a difficult’’ history to Implanon were brought to light by postmarketing of such a condition and advises removal of Nexplanon ‘‘in reported voluntarily from a population of uncertain size. Theexperience, adverse identifiedreactions reported during post-approvalinclude: gastrointestinal use and patients who become significantly depressed’’ [11]. that in clinical trials with Implanon, pregnancies occurred as general disorders and conditions of administration site earlyRegarding as seven return to fourteen to ovulation days theafter manufacturer removal. ‘‘Therefore, specifies disorders (constipation, , flatulence, vomiting); a woman should re-start contraception immediately after removal of the implant if continued contraceptive (edema, fatigue, implant site reaction, pyrexia); immune protection is desired’’ [11]. Fluid retention, according to the system disorders (anaphylactic reactions); infections and manufacturer, can be caused by hormonal contraceptives infestations (rhinitis, ); investigations so that caution should be exercised in prescribing them for musculoskeletal(clinically relevant and rise connective in blood pressure, tissue disorders weight decreased);(arthralgia, metabolism and nutrition disorders (increase in appetite); ispatients not known. ‘‘with conditionsConcerning which contact might lenses be aggravated the manufacturer by fluid musculoskeletal pain, myalgia); [11] advisesretention’’ that [11]. in caseWhether of visual Nexplanon changes causes or changes fluid retention in lens disorders (convulsions, migraine, somnolence); pregnancy, tolerance assessment by an ophthalmologist be sought. puerperium and perinatal conditions (ectopic pregnancy); psychiatric disorders (anxiety, insomnia, decrease of libido); J Pharm Sci Exp Pharmacol 2019: 87-104. renal and urinary disorders (dysuria); reproductive system92 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: 87-104. and breast disorders (breast discharge, breast enlargement, be ingested by the child per day based on an average daily skin and subcutaneous tissue disorders (angioedema, ovarian cyst, pruritus genitalis, vulvovaginal discomfort); monthmilk ingestion after insertion of 658 mL.of the Based non-radiopaque on daily milk etonogestrelingestion of hereditary angioedema, alopecia, chloasma, hypertrichosis, 150 mL/kg, the mean daily infant etonogestrel dose one aggravation of angioedema and/or aggravation of maternal daily dose, or about 0.2% of the estimated absolute maternalimplant (IMPLANON) daily dose’’ [11]. is about In discussing 2.2% of theissues weight-adjusted pertaining to orrash, removal pruritus, procedures urticaria, of seborrhea); Implanon vascular were ‘‘bruising, disorders slight (hot nursing mothers, attention is drawn also to non-hormonal flush). Among the complications related to the insertion contraceptives which might be an alternative option: site, paresthesia or paresthesia-like events, scarring and abscess’’[11].local irritation, pain or itching, fibrosis at the implant non-hormonal contraceptive options, as steroids may not be the‘‘Healthcare initial choice providers for these should patients’’[11]. discuss both hormonal and coadministration of other products the manufacturer draws Concerning pediatric use the manufacturer claims attentionWith respect to the toinduction changes ofin enzymes,contraceptive including efficacy CYP3A4, due to that metabolize progestins. They may cause a reduction in established for women of reproductive age. ‘‘Safety and the plasma concentrations of progestins and may therefore that safety as well as efficacy of Nexplanon have been decrease the effectiveness of Nexplanon. ‘‘In women postpubertal adolescents’’ [11]. Unfortunately, no data on long-term treatment with hepatic enzyme inducing areefficacy provided of NEXPLANON to substantiate are this expected precarious to be claim, the same and the for drugs, it is recommended to remove the implant and to assumption concerning postpubertal adolescents is no more advise a contraceptive method that is unaffected by the than speculative. For users less than 18 years no studies interacting drug’’[11]. Among the drugs or herbal products inducing enzymes, including CYP3A4, the following are been conducted in women less than 18 years of age. Use of listed: barbiturates, bosentan, carbamazepine, felbamate, thishave product been undertaken. before menarche ‘‘However, is not noindicated’’ clinical studies[11]. have griseofulvin, oxcarbazepine, phenytoin, rifampin, St. John’s wort, and topiramate. In this context, the manufacturer the manufacturer admits that no studies are available ‘‘to evaluateConcerning the effect specific of hepatic populations disease with on hepatic the disposition impairment of changes (decrease or increase) in the progestin plasma draws attention also to HIV antiretrovirals, since significant levels have been noted ‘‘in some cases of co-administration from renal impairment: ‘‘No studies were conducted to evaluateNEXPLANON’’ the effect [11]. Theof renal same holdsdisease true on for the women disposition suffering of transcriptase inhibitors’’[11]. with HIV protease inhibitors or with non-nucleoside reverse manufacturer calls to mind the inverse relationship between NEXPLANON’’ [11]. As regards overweight women the the manufacturer addresses problems of pregnant women, etonogestrel serum concentrations and body weight. nursingIn discussing mothers, the pediatricuse of Nexplanon use, geriatric in specific use, populations hepatic impairment, renal impairment, and overweight women. be less effective in overweight women, especially in the Consequently, the possibility exists ‘‘that NEXPLANON may Concerning pregnancy, the manufacturer states that the presence of other factors that decrease serum etonogestrel implant is not for use during pregnancy and refers to concentrations such as concomitant use of hepatic enzyme teratology studies which did not produce any evidence of inducers’’ [11]. fetal harm due to etonogestrel exposure. ‘‘Studies have Besides the Full Prescribing Information discussed revealed no increased risk of birth defects in women above, the manufacturer offers also a FDA-Approved Patient 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 regardsLabeling. the In mechanismthis piece of of information action, thickening users are of advisedthe cervical that that of combination oral contraceptives’’ [11]. mucusNEXPLANON to prevent implant contact must bebetween removed ovum after and 3 years.sperm Asis underlined, as well as changes in the lining of the uterus. Concerning nursing mothers, the manufacturer admits may be used during breastfeeding after the fourth that only limited clinical data are available: ‘‘NEXPLANON rankingConcerning contraceptive the efficacy methods, of Nexplanon, and which a chart cannot is presented stand up postpartum week has not been studied’’ [11]. Available data towhich, the standardsalas, reflects of the no mostmore widelythan a recognizedrudimentary ratings notion and of indicatepostpartum that week.etonogestrel Use of is NEXPLANON excreted in breast before milk the so fourth that rankings developed by Contraceptive Technology,[12] the and the daily infant etonogestrel dose one month after Drug Administration (FDA),[14] and research on the safety insertion100 ng might of the be device ingested is approximatelyby the child during 2.2% the of firstthe weight- month, ofWorld contraceptive Health Organization methods [15]. (WHO),[13] In contrast the USto the Food latter and adjusted maternal dose. ‘‘Small amounts of etonogestrel 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, etonogestrelare excreted are in breasthighest, milk. about During 100 ng the of firstetonogestrel months aftermay in the opinion of this author, is of utmost importance to most insertion of NEXPLANON, when maternal blood levels of J Pharm Sci Exp Pharmacol 2019: 87-104. 93 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: 87-104. women. In addition, only 12 methods are mentioned, ie, 50 per cent of the methods contained in the Contraceptive discussed above lacunae still exist and this might be the Failure Table of Contraceptive Technology [12], [Table 3-2] reasonAs can the bemanufacturer seen from the recommends FDA-Approved repeated Patient consultation Labeling of the physician or contact with the company itself. Despite the manufacturer’s offer to provide assistance, users should andConcerning less than 50% allergies, contained the inmanufacturer the WHO chart correctly [13]. warns prospective users about allergies to numbing medicines, ie, not rely solely on such offers because in some instances, anesthetics and those used to clean the skin, ie, antiseptics. ‘‘These medicines will be used when the implant is placed the consumer about potential complications and risks. Thus, health agencies such as the WHO have to intervene to warn into or removed from your arm’’. Concerning side effects reference is made to studies showing that ‘‘one out of ten Nexplanon, in particular migration from insertion site: the WHO has issued rare reports of complications regarding women stopped using the implant because of an unfavorable change in their bleeding pattern’’ [11] complications with etonogestrel (Nexplanon) contraceptive implants.‘‘The MHRA In rare has cases, issued such a warning implants about have moved rare reports from the of insertion site and reached the lung via the pulmonary artery. An implant that cannot be palpated at its insertion site in the calledRegarding a keloid around problems the with insertion insertion site’’ andmight removal occur. itThe is arm should be located as soon as possible and removed at specified that infection and ‘‘scarring, including a thick scar possibility of expulsion is explained in terms of ‘‘coming the [16] earliest opportunity. If an implant cannot be located out’’: ‘‘The implant may come out by itself. You may become within the arm, chest imaging should be performed. Correct pregnant if the implant comes out by itself’’. In explaining subdermal insertion reduces the risk of these events’’[16]. the risk of an ectopic pregnancy, the manufacturer appropriately mentions the possibility of a lethal outcome. ‘‘Ectopic pregnancy is a medical emergency that often consumer about risks not mentioned by the manufacturer of requires surgery. Ectopic pregnancies can cause serious the Asimplants can be Nexplanon seen, the WHO and Implanon. had to intervene Incompleteness to inform of the , , and even death’’ [11]. be assumed by the consumer despite numerous precautions In the same vein, the death-bearing sequelae of serious andmanufacturer’s warnings appropriatelyPatient Information discussed. Leaflet Pertaining must therefore to risks blood clots are mentioned ‘‘It is possible to die from a the manufacturers mentions correctly the possibility of problem caused by a blood clot, such as a heart attack or a death in the case of ectopic pregnancy and in association stroke’’[11]. And in this context examples of serious blood with blood clots. There are, of course, areas in which clots are cited, such as deep vein thrombosis located in the important information is missing due to a lack of pertinent legs, pulmonary embolism located in the lungs, stroke located studies, as for example in special populations with hepatic in the brain, heart attack, and total or partial blindness disease or renal impairment. In addition, the consumer might be irritated by the speculative assumption in case of advice is given to quit . afflicting the eyes [11]. Additionally, the recommendable the most important issues of contraception, namely safety Consultation of the physician is recommended in case of the following conditions: pain in the lower leg that persists, women of child-bearing age -- the manufacturer provides no and efficacy. If safety and efficacy is in fact established for ofsevere a severe or sharp allergic chest reaction pain such or heaviness as swelling felt of inface, the tongue chest; thereliable reader data is --the it seemsuse of anethically euphemistic unjustified nomenclature to warrant whichsafety sudden shortness of breath or coughing blood; symptoms usesand efficacy the terminology also for younger ‘‘insert’’ women. and ‘‘insert-site’’ Equally disturbing when in fact for the procedure is an implantation, ie, substantially more or throat; trouble breathing or swallowing; sudden severe risk-ful than an insertion of a diaphragm into the vagina. partialheadache or complete which is different blindness from (indicative usual headaches; of a cerebrovascular weakness Vagueness of terminology is a weakness also of the FDA- or numbness in the arm or leg, or trouble speaking; sudden in conjunction with fever, tiredness, loss of appetite, dark event); yellowing of skin or whites of the eyes, especially colored urine, or light colored bowel movements (indicative rodApproved about the Patient size Labelingof a matchstick where that the sizecontains of the a progestin device is hormonecompared called to a matchstick: etonogestrel’’ ‘‘The [11]. implant As matchsticks is a flexible come plastic in different sizes the consumer might prefer measurements in of a liver disease); severe pain, swelling, or tenderness in the sleeping, lack of energy, tiredness, feeling of sadness terms of international units. On a general note, the question lower stomach or ; lump in the breast; problems must be raised as to whether or not each consumer reading bleeding. (indicative of depressed mood); and intense menstrual Concerning breast feeding, the manufacturer explicates to some important risks and potential complications, which that ‘‘A small amount of the hormone contained in the Patient Information Leaflet will pay sufficient attention breast-fed children whose mothers were using the implant Intrauterineare not always sufficientlyDevices: underscored. hasNEXPLANON been studied passes up to into 3 years your of breast age in milk. a small The number health of Besides implants, intrauterine devices are considered as children. No effects on the growth and development of the children were seen’’ [11]. devices are in use, namely copper-containing and belonging to LARC by most authors. Two kinds of intrauterine J Pharm Sci Exp Pharmacol 2019: 87-104. 94 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: 87-104.

Figure 2: Levonorgestrel. levonorgestrel- containing. The releasing individual variations in levonorgestrel concentrations seen levonorgestrel is marketed as Mirena (levonorgestrel- in women using levonorgestrel-containing contraceptive releasing intrauterine system) by one of the largest German products. ‘‘The elimination half-life of levonorgestrel after pharmaceutical companies, which provides information in a 36-page document [10]. As regards clinical pharmacology, drug and its metabolites are primarily excreted in the urine’’ [10]. daily oral doses is approximately 17 hours; both the parent the device is intended to provide an initial release rate As contraindications the manufacturer lists the following: pregnancy or suspicion of pregnancy, congenital yn-3-one,of 20 μg/day the active of levonorgestrel ingredient in [10]. Mirena, Levonorgestrel has a molecular USP, (-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20- or acquired uterine anomaly including fibroids (if they following structural formula (Figure 2 ): theredistort has the been uterine a subsequent cavity), acute intrauterine pelvic inflammatory pregnancy), weight of 312.4, a molecular formula of C21H28O2, and the According to the manufacturer low doses of levonorgestrel postpartumdisease or a endometritishistory of pelvic or infected inflammatory disease in the (unless past 3 can be administered into the uterine cavity with the Mirena months, known or suspected uterine or cervical neoplasia intrauterine delivery system. Initially, levonorgestrel is (or unresolved), abnormal Pap smear, genital bleeding of unknown etiology, untreated acute cervicitis or vaginitis decreases progressively to half that value after 5 years. (including bacterial vaginosis or other lower genital tract released at a rate of approximately 20 μg/day. This rate infections until infection is controlled), acute liver disease Mirena has mainly local progestogenic effects in the or liver tumor (benign or malignant), conditions associated uterine cavity. Morphological changes of the endometrium with increased susceptibility to pelvic infections, a previously are observed, including stromal pseudodecidualization, inserted IUD that has not been removed, hypersensitivity to any component of the product, and ‘‘known or suspected glandular and stromal mitoses. Studies of Mirena prototypes carcinoma of the breast’’[10]. haveglandular suggested atrophy, several a leukocytic mechanisms infiltration that prevent and a decreasepregnancy, in Warnings issued by the manufacturer pertain to namely thickening of cervical mucus (which prevents passage ectopic pregnancy, intrauterine pregnancy, sepsis, pelvic of sperm into the uterus), inhibition of sperm capacitation or survival, and alteration of the endometrium [10]. Concerning ectopic pregnancy loss of fertility is emphasized. inflammatory disease, embedment and perforation. of levonorgestrel into the uterine cavity subsequent to Regarding clinical pharmacokinetics, the initial release place,Regarding septic intrauterineabortion—with pregnancy, septicemia, the septic manufacturer , and death—mayspecifies: ‘‘In occur’’[10]. patients becoming pregnant with an IUD in insertion of Mirena is 20 μg/day. A stable plasma level of Particular emphasis is placed on group A streptococcal levonorgestrel of 150-200 pg/mL occurs after the first after long-term use of 12, 24, and 60 months were 180 sepsis. ‘‘As of September 2006, 9 cases of Group A few weeks after insertion of Mirena. Levonorgestrel levels streptococcal sepsis (GAS) out of an estimated 9.9 million Mirena users had been reported. In some cases, severe pain concentrations(plus-minus 66) achieved pg/mL, by 192 Mirena (plus-minus are lower 140) than pg/mL, those occurred within hours of insertion followed by sepsis within seenand 159 with (plus-minus levonorgestrel 59) contraceptivepg/mL, respectively. implants The and plasma with days’’ [10]. Since death due to GAS is more likely when there oral contraceptives. Unlike oral contraceptives, plasma is a delay in the treatment the manufacturer recommends levels with Mirena do not display peaks and troughs [10]. alertness with respect to these serious infections albeit In serum, levonorgestrel is mainly bound to proteins they are rare. ‘‘Aseptic technique during insertion of Mirena is essential. GAS sepsis may also occur postpartum, after (primarily to sex hormone binding globulin) and is surgery, and from wounds’’ [10]. metabolized to a large number of inactive metabolites. Metabolic clearance rates can differ among individuals death-bearing complications are appropriately mentioned With respect to pelvic inflammatory disease (PID), considerably,J Pharm Sci Exp Pharmacol and this 2019: might 87-104. be the reason for significant 95 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: 87-104. by the manufacturer. ‘‘ . . .PID can cause tubal damage Mirena and the implant Nexplanon discussed above, the leading to ectopic pregnancy or infertility, or infrequently can necessitate , or cause death’’[10]. For the treatment of a PID the manufacturer provides appropriate drawsconsumer attention wonders to whyserious the adverse scholarly events literature and onpotential Long- guidelines and states that subsequent to the initiation of complications,Acting Reversible including Contraception death-bearing (LARC) conditions. only sporadically In fact, antibiotic therapy removal of Mirena might be indicated: is usually appropriate. Guidelines for PID treatment are authorsone of the conclude most noteworthy by suggesting studies global (2017) dissemination on LARC claims of available‘‘Removal from of Mirena the Centers after initiation for Disease of antibiotic Control therapy(CDC), that ‘‘almost all women can safely use IUDs;’’[18] and the Atlanta, Georgia.’’ [10]. their extremely findings: ‘‘Allhigh adolescents effectiveness, and safety, adult and women high rate should of Also, special attention is drawn to infection with continuation’’[18].be informed about the availability of LARC methods, given actinomycetes, including the problem of false positive carrier is controversial because actinomycetes can be found to many a reader because four years previously to the normallyfindings. ‘‘However,in the genital the managementtract cultures of in the healthy asymptomatic women publicationThis emphasis of 2017, on the authors safety of LARCa study comes devoted as a surprise to the

devices by enumerating numerous adverse events caused Papwithout smear IUDs. diagnosis False with positive cultures’’ findings [10]. of actinomycosis on byintrauterine them. On device the basis Gynefix of hadevidence-based criticized the researchconventional the Pap smears can be a problem. When possible, confirm the authors indicated ‘‘increased expulsion rates, complaints Concerning embedment, removal of Mirena is suggested, of pain and erratic or increased menstrual bleeding, and which might necessitate surgical intervention’’[10]. subsequent high rates of discontinuation” [19] in association Pertaining to perforation or penetration the manufacturer with the ‘‘conventional” devices hailed for their safety in the publication of 2017. To remedy the harm encountered by users of intrauterine devices a new device, marketed ‘‘surgeryspecifies thatmay the be uterinerequired’’[10]. wall or If detection might beof affectedperforation and orsurgery penetration indicated. is delayed, ‘‘Mirena serious must be conditions located and may removed; result, manufacturer. In its Information for the User (Information such as ‘‘migration outside the uterine cavity, adhesions, as Gynefix, was introduced into the market by a Belgian , intestinal perforations, intestinal obstruction, draws attention to the difference between older devices and abscesses and erosion of adjacent viscera’’ [10]. destinée aux utilisatrices) the manufacturer of Gynefix were not favoured by women, many of whom complained of bleeding or pain may indicate partial or complete expulsion. pain,its own discomfort, product:” Howeverheavy bleeding older intrauterine and unintended devices expulsion (IUDs) As regardsConcerning ovarian expulsion, cysts, it the is explained manufacturer that specifiesatresia of thatthe follicle can be delayed so that the growth of the follicle designed to be virtually trouble free whilst maintaining the in use. The new generation GyneFix® has been specially continues. In approximately 12 per cent of the women using superior levels of reliability, ease of use and spontaneity in Mirena enlarged follicles have been found. Concerning breast relationships which women and their partners welcome” cancer the manufacturer claims that no increased risk could be revealed by studies. ‘‘Two observational studies have been disapproved, alas, already in 2002 when British authors [20]. The precarious claim that Gynefix is ‘‘trouble free” has not provided evidence of an increased risk of breast cancer published as study on cases of perforation associated with during the use of Mirena’’ [10]. As can be seen from the above analysis, the manufacturer the Inuse light of Gynefix of such [21]. contradictory statements it is important provides extensive information on various risks and that the consumer be critical in the face of claims made not potential complications. In particular, attention is drawn only by manufacturers but also by research on contraceptive appropriately to death due to intrauterine pregnancy, due to interest. A critical attitude is in place also for research on products -- which is frequently adulterated by conflicts of disease. What remains unresolved, however, is the question one of the most convenient forms of contraception, namely asgroup to Awhether streptococcal nomenclature sepsis, and used due into pelvicthis information inflammatory is emergency or better post-coitus contraception. comprehensible for the average consumer. Not all consumers Post-coitus (Emergency) Contraception capacitation refers to the fact that ‘‘the capacity of sperm that (EC) can be considered as one might be sufficiently educated to know that sperm to produce fertilization is further enhanced if they spend of theAt presentmost convenient there seems forms to exist of birth sufficient control, evidence especially to claim for some additional time in the female reproductive tract’’[17]. women with diminishing sexual activity. After all, it requires Along the same line, not all readers will be familiar with the administration of pills only twice within 12 hours and thus nomenclature ‘‘stromal pseudodecidualization’’ and know avoids the burden of daily administration. In addition, it that ‘‘’’ designates ‘‘the endometrium of pregnancy, does not require assistance by a physician. Several forms which is cast off at parturition’’ [8]. of EC have been described in the literature, namely oral In view of the numerous precautions and warnings administration of ulipristal acetate, oral administration of issued by the manufacturer of the intrauterine device standard contraceptive pills, and intrauterine devices [22].

J Pharm Sci Exp Pharmacol 2019: 87-104. 96 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: 87-104.

for emergency contraception is ‘‘inhibition or delay of

Pertainingovulation; to however, pharmacodynamics, alterations to it is the stated endometrium that Ulipristal that acetatemay affect is a implantation selective may also contribute receptor tomodulator efficacy’’ [24].with antagonistic and partial agonistic effects (a progesterone

agonist/antagonist)The pharmacodynamics at the progesterone of ulipristal receptor. acetate, the in which the pill is administered. ‘‘Administrationmanufacturer specifies, in the mid-follicular depends phase on the causes phase inhibition of the of folliculogenesis and reduction of estradiol concentration. Figure 3: Ulipristal acetate (C30H37NO4). Administration at the time of the luteinizing hormone peak delays follicular rupture by 5 to 9 days. Dosing in the

(30 mg in a single dose) is regarded as the most effective pill maturation but decreases endometrial thickness by 0.6 ± 2.2 Concerning efficacy, the antiprogestin ulipristal acetate for EC in the US and in Europe, ‘‘with reported estimates of mmearly (mean luteal ± phase SD)’’ [24].does not significantly delay endometrial effectiveness ranging from 62% to 85%’’ [22]. If intrauterine Concerning pharmacokinetics absorption and plasma concentrations are explained: ‘‘Following a single (perfectdevices uses) are employedand 0.8 (typical for use) EC, thefor ParaGard efficacy (copper is even T) higher, [12]. dose administration of ella in 20 women under fasting ie, 0.2 (perfect and typical use) for Mirena (levonorgestrel); 0.6 conditions, maximum plasma concentrations of ulipristal Ulipristal acetate acetate and the active metabolite, monodemethyl-ulipristal Information on ulipristal acetate is provided at least by two prominent manufacturers, namely the manufacturer and 1 hour, respectively’’ [24]. Concerning distribution it is of Esmya, [23] offering a 27-page document, and the explainedacetate, were that 176 ulipristal and 69 acetate ng/ml isand ‘‘highly were boundreached (> at 94%) 0.9 manufacturer of ella, [24] offering an 11-page document. to plasma proteins, including high density lipoprotein, The former describes a 5 mg tablet used for the treatment alpha-l-acid glycoprotein, and albumin’’ [24]. Ulipristal acetate is metabolized to two metabolites, namely mono- ‘‘Ulipristal acetate is indicated for pre-operative treatment of fibroids, either pre-operatively or intermittently. is stated that ‘‘the terminal half-life of ulipristal acetate in intermittent treatment of moderate to severe symptoms of plasmademethylated following and a di-demethylated. single 30 mg dose Regarding is estimated excretion, to 32.4 it± of moderate to severe symptoms of uterine fibroids . . . for 6.3 hours’’ [24]. treatment,uterine fibroids which in may adult last women up to 3 months,of reproductive should be age’’ initiated [23]. Besides ulipristal acetate as one of the most recently subsequentConcerning to posology, menstruation the manufacturer and consist specifiesof one tablet that of the 5 advocated options for EC, there are of course other mg to be administered daily. pills available, and they can be divided into three types, namely combined ECPs containing both estrogen and indicated for the prevention of pregnancy subsequent an antiprogestin (either ulipristal acetate or ). to Theunprotected manufacturer coitus: of ‘‘ella ella specifies that its product is Accordingprogestin; to progestin-only a publication ECPs; of 2017, and progestin-only ECPs which contain ECPs antagonist emergency contraceptive indicated for prevention have replaced the older combined ECPs ‘‘because they are of pregnancy following unprotectedis a intercourse progesterone or a agonist/ known more effective and cause fewer side effects’’[22]. or suspected contraceptive failure. ella is not intended for routine use as a contraceptive’’ [24].

explaining:Concerning ‘‘If all efficacy, 100 women attention used must progestin-only be drawn to emergency the WHO the ulipristal acetate-containing tablet ella is for oral use contraception,table of 2017 which one wouldindicates likely an estimatebecome ofpregnant’’[13] 99% efficacy byIn In the description, the manufacturer specifies that and contains 30 mg of a single active steroid ingredient, the same vein, German research argued as early as 2000 namely ulipristal acetate, which is a synthetic progesterone ‘‘interceptive pills’’ in case of perfect use is as effective as dimethylaminophenyl)-19-norpregna-4,9-diene-3,20- 99%that the[25]. efficacy The latter of Emergency research, Contraceptionwhich ranks contraceptive by means of dione].agonist/antagonist Among the [17alphainactive ingredients acetoxy-11beta-(4-N,N- are ‘‘lactose methods according to the Pearl Index (PI), explains that the monohydrate, povidone K-30, croscarmellose sodium and morning-after-pill interrupts the synchronisation between magnesium stearate’’ [24]. The structural formula (Figure 3) blastocyst development and endometrial preparedness for is the following: nidation. According to this rather outdated research, the In discussing the clinical pharmacology, the manufacturer explains that the likely primary mechanism of action 0.25 mg levonorgestrel) are taken within 60 hours: 2 are 4 pills used for interception (50 μg ethinyl estradiol and J Pharm Sci Exp Pharmacol 2019: 87-104. 97 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: 87-104. taken within 48 hours of unprotected cohabitation and the result suggests that oral contraceptive pills containing remaining 2 are taken after an interval of 12 hours. progestins other than levonorgestrel may also be used for emergency contraception’’ [22]. In studies on dosage of levonorgestrel it could be found withStrangely the estimate enough, presentedefficacy specified by the in Food2000 byand German Drug that administration of a single dose proved to be equally Administrationauthors and the (FDA) WHO inestimate a survey of of 2017 contraceptive do not harmonize methods [14]. This survey, which appeared in 2013, indicates 85% 1.5 mg is as effective as two 0.75 mg doses 12 hours apart’’. Oneeffective. of these ‘‘However, studies studiesshowed have no difference shown that between a single the dose two of typical use - which is described as ‘‘7 out of 8 women would regimens regarding adverse events, ‘‘while the other found notefficacy get inpregnant case of perfectafter using use andEmergency 87.5% efficacy Contraceptives’’. in case of greater levels of headache and breast tenderness (but not What confuses the reader of the FDA survey are the estimates other side effects) among study participants taking 1.5 mg of which indicate that typical use (87.5%) would be more levonorgestrel at once’’ [22]. effective than perfect use (85%). Furthermore, the reader of Concerning marketing, it has been stated that by 2017 the FDA survey seeks in vain information on non-hormonal, levonorgestrel was marketed internationally increasingly ie, fertility awareness-based (periodic abstinence) methods. in a one-dose formulation (one 1.5 mg pill) rather than the In addition to pills, intrauterine devices are suitable for two-dose formulation (two 0.75 mg tablets, taken 12 hours EC, namely a Copper T intrauterine contraceptive (IUC), and apart) [22]. a levonorgestrel-releasing IUC. The copper-containing IUC Antiprogestins (Ulipristal acetate, mifepristone, (ParaGard) is a non-hormonal device and contains 380 mm2 COX2-inhibitor) of copper around the arms and stem. ‘‘The copper-containing IUD releases copper ions that are toxic to sperm’’[18]. Ulipristal acetate (30 mg in a single dose), considered a second-generation antiprogestin, entails according to some The levonorgestrel-releasing (non-copper) intrauterine authors no noteworthy discomfort and is well-tolerated system (sold as Mirena in the U.S.) has been described besides being highly effective. ‘‘The second-generation antiprogestin ulipristal acetate (30 mg in a single dose) has The device consists of a T-shaped frame (T-body) made out been studied for use as emergency contraception and has ofcomprehensively polyethylene and by athe steroid manufacturer reservoir in (hormone a consumer elastomer leaflet. been found to be highly effective and well-tolerated’’ [22]. core) around the vertical stem. ‘‘The T-body is 32 mm in both the horizontal and vertical directions. The polyethylene Mifepristone of the T-body is compounded with barium sulfate, which Another antiprogestin, mifepristone, has also been studied for use as an emergency contraceptive pill.[22,p.2] removal thread is attached to a loop at the end of the vertical stemmakes of it the radiopaque. T-body’’[10]. A monofilament brown polyethylene receptor modulator, is approved in several countries for Mifepristone, considered a first-generation progesterone Pills used for EC has been shown to be highly effective for use as emergency Originally, pills for EC have been known also under the contraception,early first-trimester with few medication side effects abortion. (delayed ‘‘Mifepristonemenstruation designation ‘‘morning-after-pill’’ [25]. This label, despite its following the administration of mifepristone is one notable wide use, is inappropriate since ECPs may be initiated earlier side effect)’’ [22]. As of 2017, its availability was limited to than the morning after, ie, immediately after unprotected intercourse -- the sooner the better, but within 120 hours. COX-2Armenia, inhibitor Moldova, Ukraine, China, Russia, and Vietnam. Combined ECPs contain the hormones estrogen and The COX-2 inhibitor Meloxicam is considered an effective progestin. The estrogen ethinyl estradiol and the progestin emergency contraceptive measure if 30 mg are administered levonorgestrel or norgestrel (which contains two isomers, only one of them being bioactive, ie, levonorgestrel) have has no bearing on the endocrine status. ‘‘This regimen does been studied extensively in clinical trials, according to a for five consecutive days during the late follicular phase and study of 2017 [22]. With respect to these hormones it has menstrual disturbance’’ [22]. On the other hand, the COX-2 been noted that products dedicated as EC, ie, specially inhibitornot alter celecoxib the endocrine has been profile considered of the cycle as not and possessing causes no a packaged for use as EC, are not the only ones that can be potential for emergency contraception. combinations are also effective as emergency contraception. As can be seen from the above survey of pills for EC, Theused. regimen In fact, certain is one ordinarydose followed birth control by a secondpills in specifieddose 12 ongoing studies lead to new insights on their dosage and hours later, where each dose consists of 4, 5, or 6 pills, administration. The most important insights are the absence depending on the brand. As of 2017, 26 brands of combined of harm in case of repeated use of ECPs and the possibility of administering one larger dose once in lieu of two smaller oral contraceptives were approved in the US for use as doses twice. Concerning mechanism of action the important claim emergency contraception. ‘‘Research has demonstrated has been made that there is no abortogenicity associated the safety and efficacy of an alternative regimen containing ethinylJ Pharm Sciestradiol Exp Pharmacol and the2019: progestin 87-104. norethindrone; . . . this 98 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: 87-104.

emergency contraception primarily by stopping or delaying the release of an egg from the . It is possible that ella may also work by preventing attachment (implantation) to the uterus’’ [22].

Information, Full Prescribing Information and FDA Approved It should be noted also that the Highlights of Prescribing by the manufacturer Ella contain no more than 11 pages and providePatient Labeling/Patientonly limited information. Counseling Thus, Information concerning furnished ectopic

of the possibility of severe threats to the health of the user. Moreover,pregnancy, regarding the patient liver information and renal leaflet impairment makes no mentiondata can Figure 4: Norethindrone. be furnished as there are no studies available. ‘‘No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella. . . . No studies have been conducted to evaluate the effect of renal disease on the disposition of ella’’ [24]. Combined oral contraceptives In the past, combined oral contraceptives were the most widely used form of contraception, but with the appearance

apparently has already changed. of implants and refined IUD-systems, this prevalence Norethindrone/Ethinyl estradiol containing tablets [26]: Modicon). Figure 5: Ethinyl estradiol. norethindrone/ethinyl estradiol (Ortho-Novum and

The chemical name for norethindrone is 17-Hydroxy-19- attachment of human embryos to an in vitro endometrial nor-17α-pregn-4-en-20-yn-3-one, and for ethinyl estradiol constructwith levonorgestrel. and has no effect ‘‘Levonorgestrel on the expression does notof endometrial impair the Their structural formulas (Figure 4 and 5 ) are as follows: 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol [26]. receptivity markers’’ [22]. The claim made in favor of Concerning clinical pharmacology, the manufacturer levonorgestrel is also made for ECPs in general, but its explains that combined oral contraceptives act by suppressing gonadotropin secretion. Although the primary mechanism of this action is inhibition of ovulation, other validity depends on the definition of pregnancy. ‘‘ECPs medical authorities such as the United States Food and alterations are effected also, such as changes in the cervical do not interrupt an established pregnancy, defined by the American College of Obstetricians and Gynecologists uterus) and the endometrium (which reduce the likelihood Drug Administration/National Institutes of Health and as beginning with implantation. Therefore, ECPs are not ofmucus implantation). (which increase the difficulty of sperm entry into the abortifacient’’ [22]. Concerning contraindications, the manufacturer lists In contrast to this claim, physiological research holds that the question of abortogenicity is by no means resolved so th history of deep vein thrombophlebitis or thromboembolic that the problem discussed already during the 20 century thrombophlebitis or thromboembolic disorders; a past is being perpetuated. ‘‘The synthetic steroid mifepristone valvulardisorders; heart known disease thrombophilic with complications, conditions; persistent cerebral blood shock protein, and it blocks the binding of progesterone. vascular or coronary artery disease (current or history); Since(RU-486) the bindsmaintenance to the receptor of early but pregnancy does not dependsrelease the on heat the stimulatory effect of progesterone on endometrial growth pressure values of 160 mm Hg (or higher) systolic and and its inhibition of uterine contractility, mifepristone causes 100 mg Hg (or higher) diastolic; diabetes with vascular abortion. In some countries mifepristone combined with a involvement; headaches with focal neurological symptoms; prostaglandin is used to produce elective ’’[17]. endometriummajor surgery or with other prolonged known immobilization;or suspected estrogen- known The question of abortogenicity is of course also addressed or suspected carcinoma of the breast; carcinoma of the by the manufacturer of ulipristal acetate in the ‘‘Patient Counseling Information’’ [24]. It is considered only a dependent neoplasia; undiagnosed abnormal genital possible mechanism of action, while the primary mechanism bleeding; cholestatic jaundice of pregnancy or jaundice with concerns the release of an ovum. ‘‘ella is thought to work for prior pill use; acute or chronic hepatocellular disease with abnormal liver function; hepatic adenomas or carcinomas; J Pharm Sci Exp Pharmacol 2019: 87-104. known or suspected pregnancy; hypersensitivity to99 any 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: 87-104. component of the product. The manufacturer also states that may persist, breast changes (tenderness, enlargement, the use of oral contraceptives is associated with increased secretion), change in weight (increase or decrease), change risks of myocardial infarction, thromboembolism, stroke, in cervical erosion and secretion, diminution in lactation hepatic neoplasia, and gallbladder disease. when given immediately postpartum, cholestatic jaundice, migraine, allergic reaction (including rash, urticaria, Concerning thromboembolism, the manufacturer angioedema), mental depression, reduced tolerance to correctly calls to mind that risks are well established. ‘‘An carbohydrates, vaginal candidiasis, change in corneal increased risk of thromboembolic and thrombotic disease curvature (steepening), and intolerance to contact lenses. associated with the use of oral contraceptives is well established’’ [26]. in users of oral contraceptives where a causal relationship The manufacturer also takes pain to underline the Listed are also adverse reactions that have been reported importance of certain conditions, such as hypertension, menstrual syndrome, cataracts, changes in appetite, cystitis- and of the users’ life style. ‘‘In a large study, the relative risk likehas syndrome, been neither headache, confirmed nervousness, nor refuted, dizziness, such hirsutism, as: pre- of thrombotic strokes has been shown to range from 3 for loss of scalp hair, erythema multiforme, erythema nodosum, normotensive users to 14 for users with severe hypertension. hemorrhagic eruption, vaginitis, porphyria, impaired renal The relative risk of hemorrhagic stroke is reported to be function, hemolytic uremic syndrome, acne, changes in 1.2 for non-smokers who used oral contraceptives, 2.6 libido, colitis, and Budd-Chiari Syndrome [26]. for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive As can be seen from the above analysis, the manufacturer users and 25.7 for users with severe hypertension. The of Ortho Novum pills presents extensive information attributable risk is also greater in older women’’ [26]. and appropriately mentions the possibility of death due to rupture of hepatic adenomas. Similar information is Concerning carcinomas of the reproductive organs and provided by other manufacturers of oral contraceptive pills such as for levonorgestrel and ethinyl estradiol containing be a slightly increased risk of breast cancer risk ‘‘among currentthe breast, and therecent manufacturer users of COCs’’ specifies [26]. that There there is also might a ethinyl estradiol containing tablets (Mircette), [28] and for reference to studies suggesting ‘‘that oral contraceptive use thetablets minipill (Allesse), [29]. [27] for desogestrel/ethinyl estradiol and has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women’’ The manufacturer of Alesse provides 44 pages to inform [26]. the consumer about the 28 tablets containing levonorgestrel Concerning hepatic adenomas, reference is made to and ethinyl estradiol, namely 7 light-green inert tablets statistical data, and the possibility of lethal sequelae is and 21 pink active tablets each containing 0.10 mg of appropriately mentioned: ‘‘Indirect calculations have levonorgestrel (an entirely synthetic progestogen) and 0.2 estimated the attributable risk to be in the range of 3.3 mg of ethinyl estradiol, ie, d(-)-13β-ethyl-17α-ethinyl-17β- manufacturer, increases after four or more years of use, hydroxygon-4-en-3-one (progestogen) and 17α-ethinyl- abovecases/100,000 all in cases for where users’’. oral Thiscontraceptives risk, according of higher to dose the 1,3,5(10)-estratriene-3,Concerning hepatic 17β-dioladenomas (ethinyl the possibility estradiol).[27,p.1] of death may cause death through intra-abdominal hemorrhage’’ [26]. hepatic adenomas may cause death through intraabdominal are administered. ‘‘Rupture of benign, hepatic adenomas Adverse reactions associated with the use of oral hemorrhage’’is mentioned due[27]. toNoteworthy rupture. ‘‘Rupture is the ofmanufacturer’s rare, benign, contraceptives include thrombophlebitis and venous warning about sexually transmitted diseases for which pills thrombosis with or without embolism, arterial or devices --- except condoms -- do not provide protection. thromboembolism, pulmonary embolism, myocardial ‘‘Oral contraceptives do not protect against transmission of infarction, cerebral hemorrhage, cerebral thrombosis, hypertension, gallbladder disease, hepatic adenomas or such as , genital herpes, genital warts, , benign liver tumors. Evidence of an association is assumed hepatitisHIV (AIDS) B, andand othersyphilis.’’ sexually And transmittedin this context, diseases it is warned (STDs) for the use of oral contraceptives and mesenteric thrombosis about death to due to disease: ‘‘But there are some women as well as retinal thrombosis. Concerning fat metabolism who are at high risk of developing certain serious diseases the manufacturer states: ‘‘A small proportion of women will that can be life-threatening or may cause temporary or have persistent hypertriglyceridemia while on the pill’’ [26]. permanent disability or death’’ [27]. The manufacturer lists also adverse reactions ‘‘that have been reported in patients receiving oral contraceptives and conjunction with blood clots: ‘‘Blood clots and blockage of are believed to be drug-related’’ [26]: nausea, vomiting bloodLife-threatening vessels are the most conditions serious are side mentionedeffects of taking also oral in gastrointestinal symptoms (such as abdominal cramps contraceptives and can cause death or serious disability’’[27]. and bloating), breakthrough bleeding, spotting, change in heart attacks are underlined: ‘‘The use of combination discontinuation of treatment, edema, which oralMore contraceptives specifically, the also lethal increases consequences the risk of of other strokes clotting and menstrual flow, amenorrhea, temporary infertility after J Pharm Sci Exp Pharmacol 2019: 87-104. 100 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: 87-104. disorders, including heart attack and stroke. Blood clots in The manufacturer of the minipill mentions also hepatic veins cause death in 1% to 2% of cases’’[27]. Attention is drawn also to transient ischemic attacks and angina pectoris: the danger of death due to hemorrhage. ‘‘Case-control ‘‘Oral contraceptives may increase the tendency to develop studiesneoplasia have under indicated the heading that the Precautionsrisk of these and tumours specifies may strokes or transient ischemic attacks (blockage or rupture increase in association with the use and duration of use of of blood vessels in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these may cause death through intra-abdominal hemorrhage’’ conditions can cause death or serious disability’’ [27]. [29].oral contraceptives.Concerning death Rupture due to ofother benign, conditions, hepatic reference adenomas is made only to an outdated study of 1968 on deaths due to The topic of lethal sequelae is addressed also for the more pulmonary, coronary, cerebral thrombosis and embolism in general question of death due to the use of a contraceptive women of child-bearing age [29]. method. For this purpose, a widely used table is presented containing statistical data on the number of birth-related Popularizing information on the minipill is provided also by institutions of higher education and clinics. Most trustworthy information emanates from such institutions as or method related deaths entitled ‘‘ANNUAL NUMBER the Mayo Clini [30] and draws attention to side effects such OF BIRTH-RELATED OR METHOD-RELATED DEATHS as irregular menstrual bleeding, acne, breast tenderness, ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 decreased sex drive (libido), depression, headaches, nausea, NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD and ovarian cysts. ANDThe ACCORDING manufacturer TO ofAGE’’ Mircette [27]. offers an 39-page document and introduces its product by describing the tablets to be Additional methods of contraception administered according to a precise schedule. ‘‘Mircette® hormonal contraception, and of Emergency Contraception, provide an oral contraceptive regimen of 21 white round adverseDespite events, undeniable risks and advantages complications of LARCs,can be ofserious oral (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets tablets each containing 0.15 mg desogestrel (13-ethyl11- so that some women might be willing to embark on birth methylene-18,19-dinor-17 alpha-pregn- 4-en- 20-yn-17- control only under the condition that risks can be precluded. ol), 0.02 mg ethinyl estradiol (19-nor17 alpha-pregna-1,3,5 Prevention of harm seems possible owing to the existence (10)-trien-20-yne-3,17-diol), and inactive ingredients’’ [28]. of non-hormonal methods. While condom and coitus Quite appropriately, the manufacturer provides not only interruptus have a long history, non-hormonal methods statistical data contained in the above mentioned table of known under the designation fertility awareness-based birth-related or method-related deaths, but draws attention (natural family planning, periodic abstinence) methods came into existence only during the last century. Some of cerebrovascular and cardiovascular conditions. Concerning these methods -- whose greatest drawback is irregularity of also to specific risks, such a hepatic adenomas, blood clots, menstrual cycles -- deserve attention because they might be benign, hepatic adenomas may cause death through intra- the solution for the increasing number of women who do not abdominalhepatic adenomas hemorrhage’’ it is [28]. specified that ‘‘rupture of rare, tolerate hormones and devices [31] or women with certain cultural and religious backgrounds who are determined to use only natural, non-hormonal methods. and blockage of blood vessels are one of the most serious sideRegarding effects of taking blood oral clots contraceptives it is reminded and that can ‘‘blood cause death clots Non-hormonal (fertility awareness-based, periodic or serious disability’’ [28]. As regards circulatory disorders abstinence, natural family planning) methods: estimates are discussed for women aged 15 to 34 years. ‘‘For Under the designation ‘‘natural family planning’’ some oral contraceptive users in general, it has been estimated that non-hormonal methods have been known since the last in women between the ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, investigations took place.[25,pp.61-64] Van de Velde from whereas for non-users the rate is about 1 in 50,000 per year’’ thecentury, Netherlands especially described in Western the Basal Europe Body where Temperature the first [28]. Also addressed are strokes, angina pectoris, and heart method als early as 1927. The Japanese Ogino (1932) and attacks.’’Oral contraceptives may increase the tendency to the Austrian Knaus (1933) were instrumental in developing develop strokes (stoppage or rupture of blood vessels in the the Calendar method (also designated as ‘‘rhythm’’), and in brain) and angina pectoris and heart attacks (blockage of 1964 the Australian John Billings delineated the Ovulation or blood vessels in the heart). Any of these conditions can cause Cervical Mucus method as a result of extensive research on death or serious disability’’ [28]. fertility. The latter was then combined with other methods tablets) presents information in the form of a 32-page and defined as symptothermal method by the Austrian ProductThe manufacturerMonograph where of the Norethindrone MINIPILL (Norethindrone is described assessments have been presented recently in a scholarly investigationRötzer. Extensive [32]. discussion of these methods and their 4-en-20-yn-3-one. Its molecular weight is 298.42, and its Additional methods are available on the international under the chemical name 17-hydroxy-19-nor-17α-pregn- molecular formula is C20 26O2 [29]. market. They are included in a table entitled ‘‘Safety -

J Pharm Sci Exp Pharmacol 2019:H 87-104. 101 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: 87-104.

Table 1: Safety - Efficacy - Convenience Rating, 2019 Convenience % of Safety (no harm Efficacy women continuing Method in the sense of “nil Perfect-Typical Cost & Specifications use after one year nocere“) use of use No cost. Body temperature must be measured, cervical mucus must Symptothermal High 0.4-24 High be observed (clear texture), cervix must be palpated (soft consistency and open). Ovulation (based on No cost. High 3-24 High cervical mucus) Cervical mucus must be observed (“spinnbarkeit“) No cost. Coitus must be avoided during fertile days. Fertile days TwoDay (based on High 4-24 High determined by presence of cervical mucus (color and cervical mucus) consistency). Coitus may be resumed after 2 consecutive dry days (or absence of secretion). Standard Days No cost. Method (SDM) - High 5-24 High Fertile period is tracked and coitus avoided (usually days 8-19 based on calendar of each 26-32 day cycle). No cost. Fertile phase has passed when body temperature has risen Basal Body High 1-25 High (0.2-0.5° C) and remained such for 3 days. Conception is Temperature (BBT) unlikely from 4th day following rise of temperature until next menstruation. No cost. Menstrual cycle is monitored for at least 6 months. 18 is subtracted from shortest cycle (this is the estimated first Calendar (rhythm) High 9-25 High fertile day). 11 is subtracted from the longest cycle (this is method 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. Low cost. Male condoms Moderate 2-18 High/ 43% Protects against sexually transmitted diseases (STD) including HIV. Moderate cost. Prevents contact between sperm and egg. Female condom Moderate 5-21 Moderate/ 41% Protects against sexually transmitted diseases (STD) including HIV (according to WHO). High cost. Diaphragms Moderate 6-12 Low/57% Must be used for each coitus. Implant (Small, flexible rod or capsule placed High cost. under the skin of the Moderate 0.05-0.05 High/84% Implanted by clinician. Irregular vaginal bleeding common. upper arm; contains progestogen hormone only). Mirena (LNG) Intrauterine device (IUD) (T-shaped plastic High cost. device inserted Moderate 0.2-0.2 Moderate/80% Prevenis contact between sperm and egg by thickening into the uterus that cervical mucus. Amenorrhea. releases continuously small amounts of levonorgestrel). ParaGard (copper High cost. Moderate 0.6-0.8 Moderate/78% IUD) Copper component damages sperms. Depo-Provera Moderate 0.2-6 Moderate/56% High cost. Combined oral Moderate cost. contraceptive Moderate 0.3-9 Moderate/67% Contains estrogen and progestogen.. (COCs)= “the pill“ Progestogen-only pill Moderate cost. Moderate 1-3 (10) Moderate/67% (POP) or “minipill“ 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.

J Pharm Sci Exp Pharmacol 2019: 87-104. 102 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: 87-104.

Combined High cost. contraceptive patch 1-8(?) Continuously releases a progestin and an estrogen directly and combined Moderate (Research on Low through the skin (patch) or from the ring. contraceptive vaginal efficacy limited). Prevents ovulation, copper component damages sperms. ring (CVR) Pharmaco-kinetic profile comparable to COCs. Monthly injectables or High cost. combined injectable Moderate 1-3 Low Irregular vaginal bleeding. contraceptives (CIC) Injected monthly into muscle. High cost. Progestogen-only Injected into the muscle or under the skin every 2 or 3 Moderate 1-3 Low injectables months, depending on product. Irregular vaginal bleeding; delayed return to fertility after use. Moderate cost. Emergency Pills (ulipristal acetate 30 mg or levonorgestrel 1.5 mg) must Moderate - Low 15-15 Moderate Contraception taken twice to prevent pregnancy up to 5 days after coitus. Alternatively IUD (copper or levonorgestrel) to be inserted. No cost. Effective in preventing ovulation as long as monthly bleeding Lactational High 1-2 Moderate has not yet returned. Amenorrhea (LAM) Requires exclusive breastfeeding day and night of infant less than 6 months old. <1 (after 3-months semen High cost. Male sterilization evaluation). Moderate High/100% Surgical intervention. Permanent contraception by cutting vas (vasectomy) 2-3 (without deferens tubes which transport sperm from the testicles. semen evaluation). High cost. Female sterilization Moderate- Surgical intervention. Low 0.5-0.5 ( ) Low/100% Permanent contraception by blocking or cutting the fallopian tubes. 20-24 - parous women Moderate cost. Sponge Moderate Moderate/36% 9-12-nulliparous To be used for each coitus. women Spermicides Moderate 18-28 High/42% Moderate cost.

conspicuous because the instances where the consumer is from all other tables presented hitherto in the literature enabled to make an intelligent choice are rather an exception. asEfficacy it prioritizes - Convenience safety and - Costcontains Ranking,’’ additional which clinically differs It must stipulated therefore that translational important parameters such as convenience and cost. In a pharmacology assists pharmaceutical companies in ranking which prioritizes safety, non-hormonal methods increasing sensibility for the needs of the consumer by would be ranked highest, as can be seen from (Table 1) presenting information in such a way that there is no room for misunderstandings or misinterpretations. Besides Appendix. pharmacovigilance, which investigates the safety of (Safety - Efficacy - Convenience - Cost Ranking, 2019) in the substances, research in pharmaceuticovigilance is called Conclusions and consequences upon to assess the quality of information provided by manufacturers for the consumer. This information should The foregoing investigation proves that pharmacological avoid euphemistic nomenclature that misleads the reader research does not always stand up to the expectations into believing that a high-risk procedure is an uncomplicated of the consumer who looks for accurate, complete, and intervention involving no harm. Unadulterated information comprehensible information on contraceptive products. phrased in understandable language will contribute not only Especially with regard to the requirements of medical ethics to upholding ethical standards but also to averting forensic proceedings including costly lawsuits. and the principle of informed consent severe deficits are

J Pharm Sci Exp Pharmacol 2019: 87-104. 103 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: 87-104.

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