Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012–2016

Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012–2016 Drugs - Real World Outcomes (2018) 5:129–136 https://doi.org/10.1007/s40801-018-0135-z OR IGINAL RESEARCH ARTIC L E Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012–2016 1 1 2 2 3 • • • • • Anneli Uusku ¨ la Heti Pisarev Katrin Kurvits Ott Laius Made Laanpere Maia Uusku ¨ la Published online: 22 May 2018 The Author(s) 2018 Abstract The odds for full coverage with effective contraception Background Isotretinoin is an effective treatment for sev- increased with the age of the patient, with the duration of ere acne; no alternative treatment has an equal therapeutic isotretinoin treatment and over the period of observation. effect. The teratogenic effects of isotretinoin can be avoi- Conclusion Our study adds to the existing literature doc- ded, and numerous recommendations and regulations are in umenting limited compliance with pregnancy prevention force to minimize the risk of pregnancy during treatment. programs for isotretinoin-containing products, and calls for Objectives To describe isotretinoin prescription patterns program assessment to identify whether new measures for women aged 15–45 years, assess the concomitancy of should be taken or whether weaknesses in policy or isotretinoin and contraceptive use, and determine the rate implementation can be corrected. of potential isotretinoin-exposed pregnancies in Estonia. Methods This retrospective, nationwide, population-based, cohort study derived data from national health insurance Key Points databases and included female patients aged 15–45 years in Estonia for whom one or more prescriptions for iso- This nationwide population-based study conducted tretinoin were dispensed between 2012 and 2016. The main in Estonia documented very low effective outcome was the proportion of women who used systemic contraceptive coverage during isotretinoin treatment isotretinoin and had a concomitant record of (hormonal or among women of reproductive age. intrauterine) contraception use covering the isotretinoin We also documented a very low risk of unintended treatment period when pregnancy is contraindicated. pregnancies in the group of women on isotretinoin Results Of the 2792 women aged 15–45 years filling an and partially or not covered by contraception, isotretinoin prescription, 15.7% (95% CI 14.4–17.1) had full and 13.9% (95% CI 12.7–15.3) partial (not covering perhaps due to abstinence, a contraceptive choice that has not yet been quantified in this population. the whole period during which pregnancy is contraindi- cated) contraceptive coverage. The risk for potential iso- A multinational evaluation of pregnancy prevention tretinoin-exposed pregnancy was 3.6 (95% CI 2.0–7.0) per programmes is needed to detect the underlying 1000 treated women over the 5-year observation period. factors contributing to the wide disparities in contraceptive coverage. & Anneli Uusku ¨ la Policymakers and public health professionals can use anneli.uuskula@ut.ee these risk factors to address weaknesses in prevention programme policy or implementation, or Department of Family Medicine and Public Health, University of Tartu, Ravila 19, 50411 Tartu, Estonia both, to reduce the number of potentially exposed pregnancies. Agency of Medicines, 50411 Tartu, Estonia Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia ¨ 130 A. Uuskula et al. 2 Materials and Methods 1 Introduction This retrospective, nationwide, population-based, cohort Isotretinoin is an effective treatment for severe acne; no study included female patients aged 15–45 years in Estonia alternative treatment has an equal therapeutic effect [1]. for whom one or more prescriptions for isotretinoin were However, isotretinoin is also teratogenic in humans, thus dispensed between 2012 and 2016. numerous recommendations and regulations are in force to minimize the risk of pregnancy during treatment. Follow- 2.1 Data Source ing a European Commission decision in October 2003, each member state implemented a defined Pregnancy We obtained data from the Estonian Health Insurance Fund Prevention Programme (PPP) for isotretinoin-containing (EHIF). Since the early 2000s, the EHIF has maintained a products, e.g. use of effective contraception before and complete record of in- and out-patient healthcare services throughout the treatment; medically supervised pregnancy provided and prescriptions issued. In the EHIF, both the testing before, during and after the treatment; limiting International Nonproprietary Name (INN) and the prescriptions should a 30-day supply; and dispensing Anatomical Therapeutic Chemical (ATC) Classification within 7 days of prescribing [2]. Although the basic Systems allow medications and purchase amounts to be requirements for PPP are harmonised across EU member extracted. In addition, the date of prescription, purchase states, there are several marketing authorisation holders for and prescribing doctor (including location and specialty) isotretinoin, and their educational materials may differ in are available. International Classification of Diseases (ICD- some details (e.g. wording or layout). This may lead to 10) diagnostic codes are also available. In Estonia, the discrepancies in the PPP messaging between countries. A requirement for a physician’s prescription to obtain iso- study conducted in 2009 among the pharmaceutical regu- tretinoin is strictly enforced. There are three reimburse- latory agencies of member states found that 95% of ment rates for isotretinoin for those insured by the EHIF: responding countries (n = 22) had implemented PPP, and 90% (for those aged B 16 years, 75% (in case the pre- in 82% all required elements had been incorporated [3]. scription is issued by dermatovenerologist or by other However, 73% reported a total of 143 isotretinoin-exposed physicians continuing the treatment initiated by derma- pregnancies since implementation of the harmonized PPP. tovenerologists) and 50% (all physicians). Similarly, a systematic review of isotretinoin prescribing in As of 31 December 2014, the EHIF had 1232,819 Europe suggested a failure of PPP implementation [4]. members (individuals covered with insurance) representing A study assessing concomitant use of isotretinoin and 93.9% of the Estonian population [8]. It should be noted contraceptives before and after a similar program (iPledge) that prescriptions for uninsured individuals are also cap- was introduced in the USA found isotretinoin prescriptions tured, although their medications are not reimbursed. declined; however, no changes were found in contraceptive use during treatment [5]. In the 12 years since Estonia 2.2 Data implemented a PPP, three isotretinoin-exposed pregnancies were reported to the Agency of Medicines. Data were obtained to (1) identify females receiving iso- However, aside from these reports of exposed preg- tretinoin; (2) describe contraceptives concomitant to iso- nancies, few national or subnational studies have assessed tretinoin used by these women; and (3) determine the the concomitant use of contraceptives with isotretinoin occurrence of isotretinoin-exposed pregnancies during the therapy and the rate of pregnancies among isotretinoin- 5-year study period. treated women (Netherlands [3, 6], Canada [7]). To identify individuals who had been treated with iso- This study advances our understanding of population- tretinoin, we retrieved data on all prescriptions for iso- based behaviours related to pregnancy prevention guideline tretinoin (ATC D10BA01) issued to women during the adherence by: (1) describing isotretinoin prescription pat- period 1 January 2012–31 October 2016 from EHIF. Next, terns among women aged 15–45 years, (2) assessing the we identified contraception via prescription data for hor- relationship between isotretinoin and contraceptive use, monal contraception, or healthcare data regarding services and (3) determining the rate of pregnancy during iso- provided for the insertion or management of intrauterine tretinoin treatment in Estonia. contraceptives. The following data were abstracted for hormonal contraception: (1) intrauterine contraceptives (ATC code beginning with G02BA); (2) intravaginal con- traceptives (ATC code G02BB01); and (3) hormonal con- traceptives for systemic use-oral, transdermal, implants Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 131 (ATC codes beginning with G03A) (for the period of 1 2.4 Use of Contraceptives November 2011–31 December 2016). For each prescription (isotretinoin or contraceptive) the Effective contraceptive methods were defined as following data were recorded: medication/device (includ- intrauterine devices (IUDs) and oral, vaginal, transdermal and implant hormonal contraceptives. Records for oral ing ATC code, trade name, amount prescribed and pur- chased); prescribing physician specialty; prescription date contraceptives indicating 21-day treatments, transdermal contraceptive patches and similarly for one vaginal ring and prescription status (filled/not filled); date of filling; patient’s age and delinked identifier to allow longitudinal supply, were treated as 28 days. Records for one implant were treated as 3 years’ duration. The period of guaranteed tracking without personal identification. Healthcare service data related to the insertion or man- contraception for IUDs was considered to be 5 years agement of intrauterine contraceptives were captured from (3 years for levonorgestrel 13.5 mg IUDs). In addition, claims by ICD 10 codes, including the date of service, adequate contraception was defined as a healthcare claim patient’s delinked identification, and physician specialty, as indicating an insertion or follow-up for an IUD with a follows: Z30.1—insertion of (intrauterine) contraceptive 5-year duration of coverage since the date of the procedure. device; Z30.5—surveillance of (intrauterine) contraceptive 2.5 Concomitant Use of Contraceptives device during the study period (1 January 2011–31 December 2016). with Isotretinoin Pregnancy-related healthcare services were abstracted from claims by ICD 10 codes for the study period (1 As the main outcome, we estimated the proportion of January 2012–31 October 2016) as follows: O00–O08 women who used systemic isotretinoin and had a con- (pregnancy with abortive outcome), Z32.1 (pregnancy comitant record of contraceptive use. Concomitant ade- confirmed), Z33 (pregnant state, incidental), Z34 (super- quate contraceptive coverage was defined as contraception vision of normal pregnancy), and Z35 (high-risk preg- 30 days before isotretinoin treatment started, during and nancy). For all the above, dates of service provision were 30 days after the use of isotretinoin ended. Absence of concomitant contraception was defined as no record of also captured. In Estonia, abortion has been legal and accessible for a long period of time. Since 1955, women contraception in the period of 30 days before, during and 30 days after isotretinoin use. Partial coverage was defined have been legally allowed to request an abortion up until the 12th week of pregnancy. Termination on medical as no evidence of contraception for at least one of the (sub)periods: 30 days before, during or after isotretinoin grounds is allowed until the 22nd week of pregnancy. treatment. 2.3 Cohort Entry and Definitions 2.6 Identification of Isotretinoin-exposed Female patients were included in the cohort upon filling a Pregnancies prescription for isotretinoin during the study period. A series of prescriptions was considered a continuous episode Diagnostic codes were used to detect pregnancy timing in of drug therapy if a prescription was filled less than relation to isotretinoin treatment. Pregnancy was consid- 61 days after the previous prescription. The episode dura- ered to be isotretinoin-exposed when healthcare service data coincided with isotretinoin use, until 60 days after tion was calculated as the period (in days) from the first to the last (continuous) filling date of the prescription plus treatment ended. We used 60 days after the end of iso- tretinoin treatment as the cut-off value for exposed preg- 30 days. Gaps between prescriptions [ 60 days from the length of the previous prescription were considered a break nancy because * 88% of Estonian women are diagnosed in therapy (and thus ending the period). The [ 60-day gap as being pregnant within 8–9 weeks of gestation [10]. was chosen to account for Estonian regulations, which state that for chronic diseases and/or prolonged treatment, the 2.7 Other Variables prescription should be made for an amount of drug needed for at least 2 months of treatment [9]. Only the first episode Specialists who prescribe isotretinoin were identified (dermatologists, family medicine, other), as were the dis- of isotretinoin treatment was included in the analysis. The daily dose taken (mg/daily) was calculated by dividing the eases for which isotretinoin was prescribed (seborrhoeic dermatitis, acne, rosacea, other follicular disorders, and total amount of isotretinoin (in milligrams) purchased by the duration of the period (in days). other). ¨ 132 A. Uuskula et al. 2.8 Statistical Analysis other conditions (seborrhoeic dermatitis, n = 12; other follicular diseases, n = 20). Descriptive statistics summarized patient characteristics, prescribed isotretinoin treatment and use of contraception. 3.2 Use and Concomitant Use of Contraceptives Subgroup analyses stratified by age (15–19, 20–29, 30–39, 40–45 years) were performed to account for hypothesized During the 5-year study period, 1716 women aged differences in contraceptive use patterns between younger 15–45 years used the specified contraceptive methods. and older women. Concomitant to isotretinoin use, contraception could be We estimated cumulative risk (for isotretinoin-exposed) documented for 828 women (n = 647, 78.1% hormonal pregnancy (per 1000 women) together with the 95% con- contraception and n = 181, 21.9% IUD). Among all fidence intervals (binomial exact) for the age groups women receiving isotretinoin, only 15.7% (95% CI specified above and for women covered, partially covered 14.4–17.1) had full contraceptive coverage (including and not covered by contraception. Statistical differences 30 days before and 30 days after taking isotretinoin); between age groups were tested by Fisher’s exact test. We 13.9% (95% CI 12.7–15.3) of women had partial coverage. further estimated incidence rate (per 100 months exposed Full coverage was highest among women over 30 years of to isotretinoin) for isotretinoin-exposed pregnancy together age, and partial coverage tended to be more common with (Poisson) confidence intervals. among women in their twenties and thirties (Table 1). Factors associated with contraceptive coverage during isotretinoin treatment were assessed using logistic regres- 3.3 Pregnancies Recorded During and After sion analysis. We generated univariate and multivariable Treatment with Isotretinoin estimates using stepwise regression and present odds ratios together with 95% confidence estimates. Over the 5-year period of observation, 19.8% (555/2792) of All statistical analyses were performed using STATA the women had a healthcare visit during which a pregnancy version 14.2. was recorded. Of these 555 women, ten were pregnant The study procedures were in accordance with local data during the isotretinoin treatment-related period under protection regulations. The analysis used existing patient observation defined by the following ICD 10 codes: Z32.1 records containing only non-identifiable data and was (n = 3), Z33 (n = 2), O04.9 (n = 2), O00.1 (n = 3). These therefore exempt from ethical review. women potentially had isotretinoin-exposed pregnancies. Eight of the women in this analysis were not using con- traception while the other two women with potentially 3 Results exposed pregnancies were either partially or fully covered. One woman received the first isotretinoin prescription 3.1 Characteristics of Study Subjects 2 months earlier than the prescription for oral contracep- and Treatment Courses tion (G03AA16) and had a pregnancy termination (ICD 10: O04.9) a month after filling the contraception prescription. Over the study period, a total of 3115 women filled an The second woman had an IUD placed 34 months before isotretinoin prescription in Estonia; the majority (n = 2792, starting isotretinoin and had a diagnosis of ectopic preg- 89.6%) were 15–45 years old (Fig. 1). Among the women nancy (ICD 10: O00.1) 6 weeks after filling the last iso- aged 15–45 years, 34.4% (n = 961) were 15–19 years old, tretinoin prescription. The risk for exposed pregnancy was 43.7% were 20–29 years old, 17.3% were 30–39 years old 3.6 (95% CI 2.0–7.0) per 1000 treated women (10/2792) and 4.6% (n = 127) were older. From 2012 to 2016, the over the 5-year observation period. The rates varied sub- number of women filling an isotretinoin prescription each stantially when stratified by age: 7.9 (95% CI 0.2–43.1) per year decreased (from 864 women in 2012 to 407 women in 1000 women aged 40–45 years (1/127), 4.1 (95% CI 2016, p = 0.07). Isotretinoin prescription intensity 0.5–14.8) per 1000 in women aged 30–39 (2/484), 4.9 decreased significantly from 3.3 to 1.6 per 1000 women (95% CI 1.8–10.7) (per 1000 in women aged 20–29 (6/ (p \ 0.001). Most prescriptions were issued by dermatol- 1220), and 1.0 (95% CI 0.3–5.8) per 1000 in women aged ogists (n = 2662, 95.3%), followed by family physicians 15–19 years (1/961) (p = 0.228). (n = 78, 2.8%). The risk for exposed pregnancy did not differ between The mean duration of isotretinoin treatment was women considered to be adequately covered (1/439; 2.3 per 108 days (SD 60, range 30–408 days) and the mean daily 1000 women, 95% CI 0.1–12.6), partially covered (1/389; dose was 36.6 mg (SD 16.5, range 6.9–210 mg). Iso- 2.6 per 1000 women, 95% CI 0.1–14.2) or not covered (8/ tretinoin was prescribed for acne (n = 2621, 93.9%), 1964; 4.1 per 1000 women, 95% CI 1.8–8.0) with contra- infrequently for rosacea (n = 129, 4.6%) and rarely for ception during isotretinoin treatment (p = 0.99). Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 133 All isotrenoin prescripons 01.01.2012–31.10.2016 (FEMALE ONLY) Excluded: females aged <15 yr (N=208, NoP=1145) females aged >45 yr (N=136, NoP=463) not filled isotrenoin prescripons for females aged 15–45 yr (N=169, NoP=1573) Females aged 15–45 yr with filled prescripons N=2792, NoP=13,093 Excluded: treatment episodes > 1 (N=653, NoP=2153) SAMPLE FOR ANALYSIS: Including data from only the 1st episode N=2792, NoP=10,940 Isotrenoin treatment: mean 4.7 prescripons per woman (SD=3, median=4) mean duraon of episode 108 days (SD=62, median=103) mean daily dose during the episode 36.6 mg (SD=16.5, median=35.8) Contracepon 30 days before/during/60 days aer isotrenoin treatment (number of woman): 439 (15.7%) acceptable coverage 389 (13.9%) covered partly 1964 (70.3%) not using any contracepon Fig. 1 Flow chart showing the data selection process for the analysis of the compliance with pregnancy prevention recommendations for isotretinoin in Estonia (2012–2016). N number of individuals, NoP number of prescriptions To describe the factors associated with adequate con- Factors associated with receiving adequate contracep- traception coverage during isotretinoin treatment, we tive coverage during isotretinoin treatment are presented in compared women with full coverage to those partially or Table 2. After adjustment, three factors remained signifi- not covered. The incidence rate for isotretinoin-exposed cantly associated with odds of coverage. Being covered pregnancy among women adequately covered was 0.047 with contraception increased with the age of the woman: per 100 months (95% CI 0.007–0.336) on isotretinoin and the youngest women had the lowest odds for being covered 0.081 per 100 months (95% CI 0.042–0.155) among (adjusted OR 0.19, 95% CI 0–0.27) in comparison to the women partially/not covered (p = 0.611). highest odds among women aged 30–39 years (adjusted ¨ 134 A. Uuskula et al. Table 1 Concomitant use of contraceptives by women aged 15–45 years receiving isotretinoin treatment, Estonia, 2012–2016 All women 15–19 years 20–29 years 30–39 years 40–45 years (n = 2792) (n = 961) (n = 1220) (n = 484) (n = 127) n % n % n % n % n % No use of contraception during isotretinoin treatment: 1964 70.3 823 85.6 778 63.8 272 56.2 91 71.7 Before (30 days), during, and after (60 days) treatment Partial coverage during isotretinoin treatment: 389 13.9 99 10.3 220 18 68 14 2 1.57 Concomitant use of contraception was missing for at least one of the periods before (30 days), during, and after (30 days) treatment Full coverage during isotretinoin treatment: 439 15.7 39 4.06 222 18.2 144 29.8 34 26.8 Concomitant use of contraception evident before (30 days), during, and after (30 days) treatment Table 2 Factors associated with receiving adequate contraceptive coverage during isotretinoin treatment among women aged 15–45 years, Estonia, 2012–2016 Not/partially Covered with Proportion (%) Univariate models Adjusted model covered with contraception of those fully contraception covered OR 95% CI p value OR 95% CI p value Age (years) 15–19 922 39 4.1 0.19 0 0.27 0 0.18 0.13 0.26 0 20–29 998 222 18.2 1 1 30–39 340 144 29.8 1.90 0 2.428 0 1.94 1.52 2.48 0 40–45 93 34 26.8 1.64 0 2.499 0 1.70 1.11 2.60 0.014 Diagnosis Acne 2228 393 15.0 1 Other 125 46 26.9 2.09 1.46 2.97 0 Specialty of prescribing physician Dermatovenerologist 2249 413 15.5 1 Other 39 13 25.0 1.82 0.96 3.43 0.066 Family physician 65 13 16.7 1.09 0.59 1.99 0.782 Mean daily dose of isotretinoin (SD) 36.8 35.3 0.99 0.99 1.00 0.067 16.3 17.3 The year of treatment episode (beginning) 2012 760 104 12.0 1 1 2013 466 85 15.4 1.33 0.98 1.82 0.068 1.35 0.98 1.85 0.07 2014 392 77 16.4 1.44 1.04 1.97 0.026 1.45 1.04 2.02 0.03 2015 403 98 19.6 1.78 1.31 2.40 0 1.78 1.30 2.44 0.00 2016 332 75 18.4 1.65 1.19 2.28 0.002 2.03 1.44 2.86 0.00 Mean duration of the treatment episode (months) (SD) 4.6 4.7 1.02 0.97 1.07 0.363 1.07 1.02 1.13 0.01 2.0 2.1 Statistically significant values are in bold OR 1.9, 95% CI 1.5–2.5); and with an increasing length of 4 Discussion treatment (adjusted OR 1.07, 95% CI 1.0–1.1 for a 1-month increase). We also saw the period/time effect with odds of This study of national data from Estonia documented very coverage increasing during the period under observation. low coverage of adequate contraception during isotretinoin treatment among women of reproductive age. For the Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 135 majority of women (70.3%), we were unable to detect any However, recommending prophylactic contraception record of contraceptive use concomitant to isotretinoin would obviously require careful economic, clinical and treatment, and 13.9% of women were only partially cov- socioemotional consideration, and potentially warrants a ered and therefore at risk for the teratogenic effects of the more individualised approach [15]. drug. Risk-minimization measures are an essential part of the In our study, effective contraception coverage increased life-cycle management of a drug [16]. Oral isotretinoin is a with the age of the patient, duration of treatment and period treatment of choice (with no meaningful alternative) for of observation. Low coverage among women aged many patients with severe acne. Whether instituting 15–19 years may suggest many were not yet sexually increasingly restrictive programs is the optimal approach active. Unlike some other medicines with strict pregnancy warrants further evidence [17]. Importantly, enhanced contraindications (thalidomide, valproate), the treatment measures such as PPP in the EU or iPledge in the USA course is shorter and usually has a predictable duration. pose an extra burden on the health system and patients, and Women with longer isotretinoin treatment courses were thus should be carefully justified and monitored to ascer- more likely to be covered with effective contraception, tain whether added value is expected [18]. The current which was clearly a positive sign. literature may not justify monthly visits during isotretinoin An interesting observation in our study was the annu- use, nor using two different contraceptive methods. Fur- alised risk of unintended pregnancies (analogue to the Pearl thermore, the requirements imposed on physicians and index) in the group of women partially or not covered by patients must align with the existing regulations. For contraception, 0.97 (derived from the risk estimate of example, Estonian prescription regulations [9] requiring at potentially exposed pregnancies of 0.081/100 months). least 2 months of treatment create an inherent conflict This estimate is comparable with that of combined hor- between PPP requirements and local laws, leaving physi- monal contraceptives or copper-IUD Pearl indexes [11]. cians in a potentially vulnerable position. This finding might be explained by the high proportion of Based on our results we speculate that filing information women on isotretinoin who are not sexually active, or on pregnancies occurring during isotretinoin treatment is choose to be abstinent while on isotretinoin [12] in addition suboptimal even though the PPP highlights the importance to using contraceptive methods not captured in our analysis of reporting on exposed pregnancies. Therefore, essential (i.e. condoms). information for marketing authorisation holders and com- To our knowledge, few studies have assessed compli- petent authorities is missing, and this may lead to the false ance with recommended contraceptive use according to conclusion that PPP is effective in eliminating the risk of official pregnancy prevention programs. Prevalence esti- pregnancy during isotretinoin exposure. mates for contraception during isotretinoin vary from about The limitations of administrative data apply here as one-third (Canada [7], USA [5]) to half (Netherlands [3, 6]) well. It is possible that we may have underestimated the to above 80% (USA [14]). In the US study, the authors proportion of women covered with effective contraception, concluded that concomitant contraception was less com- and we may have missed other effective contraceptive mon for younger than older women [5], but no similar trend methods like sterilization or infertility. This misclassifica- was observed in the Netherlands [3]. The rate of contra- tion is unlikely to be substantial because sterilization ception in our study (15.7%) appears to be about half of the among women younger than 44 years is very rare in lowest published estimate [5, 7]. Estonia: \ 1% [18]. Per approved labelling of the drug, While these estimates of contraceptive coverage vary appropriate birth control assumes parallel use of two widely, the rates of isotretinoin-exposed pregnancies are methods of birth control. We have no information on dual quite constant, varying between 2 and 6 per 1000 treated contraceptive coverage, especially for condoms (the women (4–6/1000 in Canada [7], 2.7–3.5/1000 in the USA method of choice among one in three Estonian women) [12–14]. Interestingly, there is no clear association between [19]. In addition, while we might have missed some con- contraception coverage rates and exposed pregnancy inci- comitant use of previously inserted intrauterine contra- dence. This discrepancy may be partially explained by ceptives, we did capture data for health services related to methodological differences in studies, and it is difficult to monitoring and control of IUDs, most likely capturing estimate patient adherence to prescribed treatment regi- some of these women. To minimize mis-classification bias, mens. One remaining consideration that has not been elu- we limited the analysis to treatment periods defined by cidated by research to date is the proportion of women pharmacy prescription fill dates. Still, we cannot be sure taking isotretinoin who choose abstinence, and thus do not that patients for whom the drug was dispensed actually need contraception. We acknowledge that while these took it. (young) women may not be sexually active upon beginning Finally, the number of pregnancies potentially exposed treatment the situation is likely very unpredictable. to isotretinoin was small and derived estimates are ¨ 136 A. Uuskula et al. 3. 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Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care Funding This work was supported grant # IUT34-17 from the system. J Am Acad Dermatol. 2011;65(6):1117–25. Estonian Ministry of Education and Research 13. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-pre- vention program in women of childbearing age receiving iso- Conflicts of interest AU, HP, KK, OL, ML, and MU report no tretinoin. N Engl J Med. 1995;333(2):101–6. conflicts of interest. 14. Brinker A, Kornegay C, Nourjah P. Trends in adherence to a revised risk management program designed to decrease or elim- Ethics approval The study procedures were in accordance with local inate isotretinoin-exposed pregnancies: evaluation of the accutane data protection regulations. The analysis used existing patient records SMART program. Arch Dermatol. 2005;141(5):563–9. containing only non-identifiable data and was therefore exempt from 15. Pierson JC, Ferris LK, Schwarz EB. We pledge to change ethical review. iPLEDGE. JAMA Dermatol. 2015;151(7):701–2. 16. European Medicine Agency 2012. Guideline on good pharma- Open Access This article is distributed under the terms of the covigilance practices (GVP) Module V—Risk management sys- Creative Commons Attribution-NonCommercial 4.0 International tems. http://www.ema.europa.eu/docs/en_GB/document_library/ License (http://creativecommons.org/licenses/by-nc/4.0/), which per- Scientific_guideline/2012/06/WC500129134.pdf. Accessed 27 mits any noncommercial use, distribution, and reproduction in any Nov 2017. medium, provided you give appropriate credit to the original 17. Thiboutot D, Gollnick H, Bettoli V, et al. Oral isotretinoin and author(s) and the source, provide a link to the Creative Commons pregnancy prevention programmes. Br J Dermatol. license, and indicate if changes were made. 2012;166:466–7. 18. Zomerdijk IM, Ruiter R, Houweling LM, et al. Isotretinoin exposure during pregnancy: a population-based study in The References Netherlands. BMJ Open. 2014;4(11):e005602. 19. Lippus H, Laanpere M, Part Ket al. Estonian Womens Health 2014: sexual and reproductive health, health behaviour, attitudes 1. Goodfield MJ, Cox NH, Bowser A, et al. Advice on the safe and use of healthcare services. Survey report. Tartu; 2015. https:// introduction and continued use of isotretinoin in acne in the U.K. sisu.ut.ee/sites/default/files/naisteterviseuuring/files/ 2010. Br J Dermatol. 2010;162(6):1172–9. uusestre2014_loppraport.pdf. Accessed 27 Nov 2017. 2. Commission decision background information on Article 29 referral isotretinoin 2003. http://www.ema.europa.eu/docs/en_ GB/document_library/Referrals_document/Isotretinoin_29/ WC500010881.pdf. Accessed 25 Jul 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drugs - Real World Outcomes Springer Journals

Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012–2016

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Drugs - Real World Outcomes (2018) 5:129–136 https://doi.org/10.1007/s40801-018-0135-z OR IGINAL RESEARCH ARTIC L E Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia in 2012–2016 1 1 2 2 3 • • • • • Anneli Uusku ¨ la Heti Pisarev Katrin Kurvits Ott Laius Made Laanpere Maia Uusku ¨ la Published online: 22 May 2018 The Author(s) 2018 Abstract The odds for full coverage with effective contraception Background Isotretinoin is an effective treatment for sev- increased with the age of the patient, with the duration of ere acne; no alternative treatment has an equal therapeutic isotretinoin treatment and over the period of observation. effect. The teratogenic effects of isotretinoin can be avoi- Conclusion Our study adds to the existing literature doc- ded, and numerous recommendations and regulations are in umenting limited compliance with pregnancy prevention force to minimize the risk of pregnancy during treatment. programs for isotretinoin-containing products, and calls for Objectives To describe isotretinoin prescription patterns program assessment to identify whether new measures for women aged 15–45 years, assess the concomitancy of should be taken or whether weaknesses in policy or isotretinoin and contraceptive use, and determine the rate implementation can be corrected. of potential isotretinoin-exposed pregnancies in Estonia. Methods This retrospective, nationwide, population-based, cohort study derived data from national health insurance Key Points databases and included female patients aged 15–45 years in Estonia for whom one or more prescriptions for iso- This nationwide population-based study conducted tretinoin were dispensed between 2012 and 2016. The main in Estonia documented very low effective outcome was the proportion of women who used systemic contraceptive coverage during isotretinoin treatment isotretinoin and had a concomitant record of (hormonal or among women of reproductive age. intrauterine) contraception use covering the isotretinoin We also documented a very low risk of unintended treatment period when pregnancy is contraindicated. pregnancies in the group of women on isotretinoin Results Of the 2792 women aged 15–45 years filling an and partially or not covered by contraception, isotretinoin prescription, 15.7% (95% CI 14.4–17.1) had full and 13.9% (95% CI 12.7–15.3) partial (not covering perhaps due to abstinence, a contraceptive choice that has not yet been quantified in this population. the whole period during which pregnancy is contraindi- cated) contraceptive coverage. The risk for potential iso- A multinational evaluation of pregnancy prevention tretinoin-exposed pregnancy was 3.6 (95% CI 2.0–7.0) per programmes is needed to detect the underlying 1000 treated women over the 5-year observation period. factors contributing to the wide disparities in contraceptive coverage. & Anneli Uusku ¨ la Policymakers and public health professionals can use anneli.uuskula@ut.ee these risk factors to address weaknesses in prevention programme policy or implementation, or Department of Family Medicine and Public Health, University of Tartu, Ravila 19, 50411 Tartu, Estonia both, to reduce the number of potentially exposed pregnancies. Agency of Medicines, 50411 Tartu, Estonia Department of Obstetrics and Gynaecology, University of Tartu, Tartu, Estonia ¨ 130 A. Uuskula et al. 2 Materials and Methods 1 Introduction This retrospective, nationwide, population-based, cohort Isotretinoin is an effective treatment for severe acne; no study included female patients aged 15–45 years in Estonia alternative treatment has an equal therapeutic effect [1]. for whom one or more prescriptions for isotretinoin were However, isotretinoin is also teratogenic in humans, thus dispensed between 2012 and 2016. numerous recommendations and regulations are in force to minimize the risk of pregnancy during treatment. Follow- 2.1 Data Source ing a European Commission decision in October 2003, each member state implemented a defined Pregnancy We obtained data from the Estonian Health Insurance Fund Prevention Programme (PPP) for isotretinoin-containing (EHIF). Since the early 2000s, the EHIF has maintained a products, e.g. use of effective contraception before and complete record of in- and out-patient healthcare services throughout the treatment; medically supervised pregnancy provided and prescriptions issued. In the EHIF, both the testing before, during and after the treatment; limiting International Nonproprietary Name (INN) and the prescriptions should a 30-day supply; and dispensing Anatomical Therapeutic Chemical (ATC) Classification within 7 days of prescribing [2]. Although the basic Systems allow medications and purchase amounts to be requirements for PPP are harmonised across EU member extracted. In addition, the date of prescription, purchase states, there are several marketing authorisation holders for and prescribing doctor (including location and specialty) isotretinoin, and their educational materials may differ in are available. International Classification of Diseases (ICD- some details (e.g. wording or layout). This may lead to 10) diagnostic codes are also available. In Estonia, the discrepancies in the PPP messaging between countries. A requirement for a physician’s prescription to obtain iso- study conducted in 2009 among the pharmaceutical regu- tretinoin is strictly enforced. There are three reimburse- latory agencies of member states found that 95% of ment rates for isotretinoin for those insured by the EHIF: responding countries (n = 22) had implemented PPP, and 90% (for those aged B 16 years, 75% (in case the pre- in 82% all required elements had been incorporated [3]. scription is issued by dermatovenerologist or by other However, 73% reported a total of 143 isotretinoin-exposed physicians continuing the treatment initiated by derma- pregnancies since implementation of the harmonized PPP. tovenerologists) and 50% (all physicians). Similarly, a systematic review of isotretinoin prescribing in As of 31 December 2014, the EHIF had 1232,819 Europe suggested a failure of PPP implementation [4]. members (individuals covered with insurance) representing A study assessing concomitant use of isotretinoin and 93.9% of the Estonian population [8]. It should be noted contraceptives before and after a similar program (iPledge) that prescriptions for uninsured individuals are also cap- was introduced in the USA found isotretinoin prescriptions tured, although their medications are not reimbursed. declined; however, no changes were found in contraceptive use during treatment [5]. In the 12 years since Estonia 2.2 Data implemented a PPP, three isotretinoin-exposed pregnancies were reported to the Agency of Medicines. Data were obtained to (1) identify females receiving iso- However, aside from these reports of exposed preg- tretinoin; (2) describe contraceptives concomitant to iso- nancies, few national or subnational studies have assessed tretinoin used by these women; and (3) determine the the concomitant use of contraceptives with isotretinoin occurrence of isotretinoin-exposed pregnancies during the therapy and the rate of pregnancies among isotretinoin- 5-year study period. treated women (Netherlands [3, 6], Canada [7]). To identify individuals who had been treated with iso- This study advances our understanding of population- tretinoin, we retrieved data on all prescriptions for iso- based behaviours related to pregnancy prevention guideline tretinoin (ATC D10BA01) issued to women during the adherence by: (1) describing isotretinoin prescription pat- period 1 January 2012–31 October 2016 from EHIF. Next, terns among women aged 15–45 years, (2) assessing the we identified contraception via prescription data for hor- relationship between isotretinoin and contraceptive use, monal contraception, or healthcare data regarding services and (3) determining the rate of pregnancy during iso- provided for the insertion or management of intrauterine tretinoin treatment in Estonia. contraceptives. The following data were abstracted for hormonal contraception: (1) intrauterine contraceptives (ATC code beginning with G02BA); (2) intravaginal con- traceptives (ATC code G02BB01); and (3) hormonal con- traceptives for systemic use-oral, transdermal, implants Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 131 (ATC codes beginning with G03A) (for the period of 1 2.4 Use of Contraceptives November 2011–31 December 2016). For each prescription (isotretinoin or contraceptive) the Effective contraceptive methods were defined as following data were recorded: medication/device (includ- intrauterine devices (IUDs) and oral, vaginal, transdermal and implant hormonal contraceptives. Records for oral ing ATC code, trade name, amount prescribed and pur- chased); prescribing physician specialty; prescription date contraceptives indicating 21-day treatments, transdermal contraceptive patches and similarly for one vaginal ring and prescription status (filled/not filled); date of filling; patient’s age and delinked identifier to allow longitudinal supply, were treated as 28 days. Records for one implant were treated as 3 years’ duration. The period of guaranteed tracking without personal identification. Healthcare service data related to the insertion or man- contraception for IUDs was considered to be 5 years agement of intrauterine contraceptives were captured from (3 years for levonorgestrel 13.5 mg IUDs). In addition, claims by ICD 10 codes, including the date of service, adequate contraception was defined as a healthcare claim patient’s delinked identification, and physician specialty, as indicating an insertion or follow-up for an IUD with a follows: Z30.1—insertion of (intrauterine) contraceptive 5-year duration of coverage since the date of the procedure. device; Z30.5—surveillance of (intrauterine) contraceptive 2.5 Concomitant Use of Contraceptives device during the study period (1 January 2011–31 December 2016). with Isotretinoin Pregnancy-related healthcare services were abstracted from claims by ICD 10 codes for the study period (1 As the main outcome, we estimated the proportion of January 2012–31 October 2016) as follows: O00–O08 women who used systemic isotretinoin and had a con- (pregnancy with abortive outcome), Z32.1 (pregnancy comitant record of contraceptive use. Concomitant ade- confirmed), Z33 (pregnant state, incidental), Z34 (super- quate contraceptive coverage was defined as contraception vision of normal pregnancy), and Z35 (high-risk preg- 30 days before isotretinoin treatment started, during and nancy). For all the above, dates of service provision were 30 days after the use of isotretinoin ended. Absence of concomitant contraception was defined as no record of also captured. In Estonia, abortion has been legal and accessible for a long period of time. Since 1955, women contraception in the period of 30 days before, during and 30 days after isotretinoin use. Partial coverage was defined have been legally allowed to request an abortion up until the 12th week of pregnancy. Termination on medical as no evidence of contraception for at least one of the (sub)periods: 30 days before, during or after isotretinoin grounds is allowed until the 22nd week of pregnancy. treatment. 2.3 Cohort Entry and Definitions 2.6 Identification of Isotretinoin-exposed Female patients were included in the cohort upon filling a Pregnancies prescription for isotretinoin during the study period. A series of prescriptions was considered a continuous episode Diagnostic codes were used to detect pregnancy timing in of drug therapy if a prescription was filled less than relation to isotretinoin treatment. Pregnancy was consid- 61 days after the previous prescription. The episode dura- ered to be isotretinoin-exposed when healthcare service data coincided with isotretinoin use, until 60 days after tion was calculated as the period (in days) from the first to the last (continuous) filling date of the prescription plus treatment ended. We used 60 days after the end of iso- tretinoin treatment as the cut-off value for exposed preg- 30 days. Gaps between prescriptions [ 60 days from the length of the previous prescription were considered a break nancy because * 88% of Estonian women are diagnosed in therapy (and thus ending the period). The [ 60-day gap as being pregnant within 8–9 weeks of gestation [10]. was chosen to account for Estonian regulations, which state that for chronic diseases and/or prolonged treatment, the 2.7 Other Variables prescription should be made for an amount of drug needed for at least 2 months of treatment [9]. Only the first episode Specialists who prescribe isotretinoin were identified (dermatologists, family medicine, other), as were the dis- of isotretinoin treatment was included in the analysis. The daily dose taken (mg/daily) was calculated by dividing the eases for which isotretinoin was prescribed (seborrhoeic dermatitis, acne, rosacea, other follicular disorders, and total amount of isotretinoin (in milligrams) purchased by the duration of the period (in days). other). ¨ 132 A. Uuskula et al. 2.8 Statistical Analysis other conditions (seborrhoeic dermatitis, n = 12; other follicular diseases, n = 20). Descriptive statistics summarized patient characteristics, prescribed isotretinoin treatment and use of contraception. 3.2 Use and Concomitant Use of Contraceptives Subgroup analyses stratified by age (15–19, 20–29, 30–39, 40–45 years) were performed to account for hypothesized During the 5-year study period, 1716 women aged differences in contraceptive use patterns between younger 15–45 years used the specified contraceptive methods. and older women. Concomitant to isotretinoin use, contraception could be We estimated cumulative risk (for isotretinoin-exposed) documented for 828 women (n = 647, 78.1% hormonal pregnancy (per 1000 women) together with the 95% con- contraception and n = 181, 21.9% IUD). Among all fidence intervals (binomial exact) for the age groups women receiving isotretinoin, only 15.7% (95% CI specified above and for women covered, partially covered 14.4–17.1) had full contraceptive coverage (including and not covered by contraception. Statistical differences 30 days before and 30 days after taking isotretinoin); between age groups were tested by Fisher’s exact test. We 13.9% (95% CI 12.7–15.3) of women had partial coverage. further estimated incidence rate (per 100 months exposed Full coverage was highest among women over 30 years of to isotretinoin) for isotretinoin-exposed pregnancy together age, and partial coverage tended to be more common with (Poisson) confidence intervals. among women in their twenties and thirties (Table 1). Factors associated with contraceptive coverage during isotretinoin treatment were assessed using logistic regres- 3.3 Pregnancies Recorded During and After sion analysis. We generated univariate and multivariable Treatment with Isotretinoin estimates using stepwise regression and present odds ratios together with 95% confidence estimates. Over the 5-year period of observation, 19.8% (555/2792) of All statistical analyses were performed using STATA the women had a healthcare visit during which a pregnancy version 14.2. was recorded. Of these 555 women, ten were pregnant The study procedures were in accordance with local data during the isotretinoin treatment-related period under protection regulations. The analysis used existing patient observation defined by the following ICD 10 codes: Z32.1 records containing only non-identifiable data and was (n = 3), Z33 (n = 2), O04.9 (n = 2), O00.1 (n = 3). These therefore exempt from ethical review. women potentially had isotretinoin-exposed pregnancies. Eight of the women in this analysis were not using con- traception while the other two women with potentially 3 Results exposed pregnancies were either partially or fully covered. One woman received the first isotretinoin prescription 3.1 Characteristics of Study Subjects 2 months earlier than the prescription for oral contracep- and Treatment Courses tion (G03AA16) and had a pregnancy termination (ICD 10: O04.9) a month after filling the contraception prescription. Over the study period, a total of 3115 women filled an The second woman had an IUD placed 34 months before isotretinoin prescription in Estonia; the majority (n = 2792, starting isotretinoin and had a diagnosis of ectopic preg- 89.6%) were 15–45 years old (Fig. 1). Among the women nancy (ICD 10: O00.1) 6 weeks after filling the last iso- aged 15–45 years, 34.4% (n = 961) were 15–19 years old, tretinoin prescription. The risk for exposed pregnancy was 43.7% were 20–29 years old, 17.3% were 30–39 years old 3.6 (95% CI 2.0–7.0) per 1000 treated women (10/2792) and 4.6% (n = 127) were older. From 2012 to 2016, the over the 5-year observation period. The rates varied sub- number of women filling an isotretinoin prescription each stantially when stratified by age: 7.9 (95% CI 0.2–43.1) per year decreased (from 864 women in 2012 to 407 women in 1000 women aged 40–45 years (1/127), 4.1 (95% CI 2016, p = 0.07). Isotretinoin prescription intensity 0.5–14.8) per 1000 in women aged 30–39 (2/484), 4.9 decreased significantly from 3.3 to 1.6 per 1000 women (95% CI 1.8–10.7) (per 1000 in women aged 20–29 (6/ (p \ 0.001). Most prescriptions were issued by dermatol- 1220), and 1.0 (95% CI 0.3–5.8) per 1000 in women aged ogists (n = 2662, 95.3%), followed by family physicians 15–19 years (1/961) (p = 0.228). (n = 78, 2.8%). The risk for exposed pregnancy did not differ between The mean duration of isotretinoin treatment was women considered to be adequately covered (1/439; 2.3 per 108 days (SD 60, range 30–408 days) and the mean daily 1000 women, 95% CI 0.1–12.6), partially covered (1/389; dose was 36.6 mg (SD 16.5, range 6.9–210 mg). Iso- 2.6 per 1000 women, 95% CI 0.1–14.2) or not covered (8/ tretinoin was prescribed for acne (n = 2621, 93.9%), 1964; 4.1 per 1000 women, 95% CI 1.8–8.0) with contra- infrequently for rosacea (n = 129, 4.6%) and rarely for ception during isotretinoin treatment (p = 0.99). Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 133 All isotrenoin prescripons 01.01.2012–31.10.2016 (FEMALE ONLY) Excluded: females aged <15 yr (N=208, NoP=1145) females aged >45 yr (N=136, NoP=463) not filled isotrenoin prescripons for females aged 15–45 yr (N=169, NoP=1573) Females aged 15–45 yr with filled prescripons N=2792, NoP=13,093 Excluded: treatment episodes > 1 (N=653, NoP=2153) SAMPLE FOR ANALYSIS: Including data from only the 1st episode N=2792, NoP=10,940 Isotrenoin treatment: mean 4.7 prescripons per woman (SD=3, median=4) mean duraon of episode 108 days (SD=62, median=103) mean daily dose during the episode 36.6 mg (SD=16.5, median=35.8) Contracepon 30 days before/during/60 days aer isotrenoin treatment (number of woman): 439 (15.7%) acceptable coverage 389 (13.9%) covered partly 1964 (70.3%) not using any contracepon Fig. 1 Flow chart showing the data selection process for the analysis of the compliance with pregnancy prevention recommendations for isotretinoin in Estonia (2012–2016). N number of individuals, NoP number of prescriptions To describe the factors associated with adequate con- Factors associated with receiving adequate contracep- traception coverage during isotretinoin treatment, we tive coverage during isotretinoin treatment are presented in compared women with full coverage to those partially or Table 2. After adjustment, three factors remained signifi- not covered. The incidence rate for isotretinoin-exposed cantly associated with odds of coverage. Being covered pregnancy among women adequately covered was 0.047 with contraception increased with the age of the woman: per 100 months (95% CI 0.007–0.336) on isotretinoin and the youngest women had the lowest odds for being covered 0.081 per 100 months (95% CI 0.042–0.155) among (adjusted OR 0.19, 95% CI 0–0.27) in comparison to the women partially/not covered (p = 0.611). highest odds among women aged 30–39 years (adjusted ¨ 134 A. Uuskula et al. Table 1 Concomitant use of contraceptives by women aged 15–45 years receiving isotretinoin treatment, Estonia, 2012–2016 All women 15–19 years 20–29 years 30–39 years 40–45 years (n = 2792) (n = 961) (n = 1220) (n = 484) (n = 127) n % n % n % n % n % No use of contraception during isotretinoin treatment: 1964 70.3 823 85.6 778 63.8 272 56.2 91 71.7 Before (30 days), during, and after (60 days) treatment Partial coverage during isotretinoin treatment: 389 13.9 99 10.3 220 18 68 14 2 1.57 Concomitant use of contraception was missing for at least one of the periods before (30 days), during, and after (30 days) treatment Full coverage during isotretinoin treatment: 439 15.7 39 4.06 222 18.2 144 29.8 34 26.8 Concomitant use of contraception evident before (30 days), during, and after (30 days) treatment Table 2 Factors associated with receiving adequate contraceptive coverage during isotretinoin treatment among women aged 15–45 years, Estonia, 2012–2016 Not/partially Covered with Proportion (%) Univariate models Adjusted model covered with contraception of those fully contraception covered OR 95% CI p value OR 95% CI p value Age (years) 15–19 922 39 4.1 0.19 0 0.27 0 0.18 0.13 0.26 0 20–29 998 222 18.2 1 1 30–39 340 144 29.8 1.90 0 2.428 0 1.94 1.52 2.48 0 40–45 93 34 26.8 1.64 0 2.499 0 1.70 1.11 2.60 0.014 Diagnosis Acne 2228 393 15.0 1 Other 125 46 26.9 2.09 1.46 2.97 0 Specialty of prescribing physician Dermatovenerologist 2249 413 15.5 1 Other 39 13 25.0 1.82 0.96 3.43 0.066 Family physician 65 13 16.7 1.09 0.59 1.99 0.782 Mean daily dose of isotretinoin (SD) 36.8 35.3 0.99 0.99 1.00 0.067 16.3 17.3 The year of treatment episode (beginning) 2012 760 104 12.0 1 1 2013 466 85 15.4 1.33 0.98 1.82 0.068 1.35 0.98 1.85 0.07 2014 392 77 16.4 1.44 1.04 1.97 0.026 1.45 1.04 2.02 0.03 2015 403 98 19.6 1.78 1.31 2.40 0 1.78 1.30 2.44 0.00 2016 332 75 18.4 1.65 1.19 2.28 0.002 2.03 1.44 2.86 0.00 Mean duration of the treatment episode (months) (SD) 4.6 4.7 1.02 0.97 1.07 0.363 1.07 1.02 1.13 0.01 2.0 2.1 Statistically significant values are in bold OR 1.9, 95% CI 1.5–2.5); and with an increasing length of 4 Discussion treatment (adjusted OR 1.07, 95% CI 1.0–1.1 for a 1-month increase). We also saw the period/time effect with odds of This study of national data from Estonia documented very coverage increasing during the period under observation. low coverage of adequate contraception during isotretinoin treatment among women of reproductive age. For the Compliance with Pregnancy Prevention Recommendations for Isotretinoin in Estonia 135 majority of women (70.3%), we were unable to detect any However, recommending prophylactic contraception record of contraceptive use concomitant to isotretinoin would obviously require careful economic, clinical and treatment, and 13.9% of women were only partially cov- socioemotional consideration, and potentially warrants a ered and therefore at risk for the teratogenic effects of the more individualised approach [15]. drug. Risk-minimization measures are an essential part of the In our study, effective contraception coverage increased life-cycle management of a drug [16]. Oral isotretinoin is a with the age of the patient, duration of treatment and period treatment of choice (with no meaningful alternative) for of observation. Low coverage among women aged many patients with severe acne. Whether instituting 15–19 years may suggest many were not yet sexually increasingly restrictive programs is the optimal approach active. Unlike some other medicines with strict pregnancy warrants further evidence [17]. Importantly, enhanced contraindications (thalidomide, valproate), the treatment measures such as PPP in the EU or iPledge in the USA course is shorter and usually has a predictable duration. pose an extra burden on the health system and patients, and Women with longer isotretinoin treatment courses were thus should be carefully justified and monitored to ascer- more likely to be covered with effective contraception, tain whether added value is expected [18]. The current which was clearly a positive sign. literature may not justify monthly visits during isotretinoin An interesting observation in our study was the annu- use, nor using two different contraceptive methods. Fur- alised risk of unintended pregnancies (analogue to the Pearl thermore, the requirements imposed on physicians and index) in the group of women partially or not covered by patients must align with the existing regulations. For contraception, 0.97 (derived from the risk estimate of example, Estonian prescription regulations [9] requiring at potentially exposed pregnancies of 0.081/100 months). least 2 months of treatment create an inherent conflict This estimate is comparable with that of combined hor- between PPP requirements and local laws, leaving physi- monal contraceptives or copper-IUD Pearl indexes [11]. cians in a potentially vulnerable position. This finding might be explained by the high proportion of Based on our results we speculate that filing information women on isotretinoin who are not sexually active, or on pregnancies occurring during isotretinoin treatment is choose to be abstinent while on isotretinoin [12] in addition suboptimal even though the PPP highlights the importance to using contraceptive methods not captured in our analysis of reporting on exposed pregnancies. Therefore, essential (i.e. condoms). information for marketing authorisation holders and com- To our knowledge, few studies have assessed compli- petent authorities is missing, and this may lead to the false ance with recommended contraceptive use according to conclusion that PPP is effective in eliminating the risk of official pregnancy prevention programs. Prevalence esti- pregnancy during isotretinoin exposure. mates for contraception during isotretinoin vary from about The limitations of administrative data apply here as one-third (Canada [7], USA [5]) to half (Netherlands [3, 6]) well. It is possible that we may have underestimated the to above 80% (USA [14]). In the US study, the authors proportion of women covered with effective contraception, concluded that concomitant contraception was less com- and we may have missed other effective contraceptive mon for younger than older women [5], but no similar trend methods like sterilization or infertility. This misclassifica- was observed in the Netherlands [3]. The rate of contra- tion is unlikely to be substantial because sterilization ception in our study (15.7%) appears to be about half of the among women younger than 44 years is very rare in lowest published estimate [5, 7]. Estonia: \ 1% [18]. Per approved labelling of the drug, While these estimates of contraceptive coverage vary appropriate birth control assumes parallel use of two widely, the rates of isotretinoin-exposed pregnancies are methods of birth control. We have no information on dual quite constant, varying between 2 and 6 per 1000 treated contraceptive coverage, especially for condoms (the women (4–6/1000 in Canada [7], 2.7–3.5/1000 in the USA method of choice among one in three Estonian women) [12–14]. Interestingly, there is no clear association between [19]. In addition, while we might have missed some con- contraception coverage rates and exposed pregnancy inci- comitant use of previously inserted intrauterine contra- dence. This discrepancy may be partially explained by ceptives, we did capture data for health services related to methodological differences in studies, and it is difficult to monitoring and control of IUDs, most likely capturing estimate patient adherence to prescribed treatment regi- some of these women. To minimize mis-classification bias, mens. One remaining consideration that has not been elu- we limited the analysis to treatment periods defined by cidated by research to date is the proportion of women pharmacy prescription fill dates. Still, we cannot be sure taking isotretinoin who choose abstinence, and thus do not that patients for whom the drug was dispensed actually need contraception. We acknowledge that while these took it. (young) women may not be sexually active upon beginning Finally, the number of pregnancies potentially exposed treatment the situation is likely very unpredictable. to isotretinoin was small and derived estimates are ¨ 136 A. Uuskula et al. 3. Crijns I, Straus S, Luteijn M, et al. Implementation of the har- therefore imprecise. Our study period captured pregnancies monized EU isotretinoin Pregnancy Prevention Programme: a up to 60 days after discontinuation of isotretinoin. The questionnaire survey among European regulatory agencies. Drug overwhelming majority of women in Estonia are diagnosed Saf. 2012;35(1):27–32. with pregnancy by gestational week 9, thus some poten- 4. Crijns HJ, Straus SM, Gispen-de Wied C, et al. Compliance with pregnancy prevention programmes of isotretinoin in Europe: a tially exposed pregnancies may have been missed. While systematic review. Br J Dermatol. 2011;164(2):238–44. these biases may slightly influence estimates of coverage 5. Pinheiro SP, Kang EM, Kim CY, et al. Concomitant use of iso- and exposed pregnancies, they seem unlikely to have tretinoin and contraceptives before and after iPledge in the United caused the clear patterns observed in this study. Strengths States. Pharmacoepidemiol Drug Saf. 2013;22(12):1251–7. 6. Teichert M, Visser LE, Dufour M, et al. Isotretinoin use and of the study include a true nationwide, population-based compliance with the Dutch Pregnancy Prevention programme: a analysis capturing extensive administrative and utilization retrospective cohort study in females of reproductive age using data for Estonian women. pharmacy dispensing data. Drug Saf. 2010;33(4):315–26. 7. Henry D, Dormuth C, Winquist B, et al. Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ. 2016;188(10):723–30. 5 Conclusion 8. Estonian health insurance fund (2017). https://www.haigekassa. ee/et/haigekassa/statistika/ravikindlustus. Accessed 26 Nov 2017. Our study adds to the existing literature documenting the 9. Conditions and procedure for preparation, dividing-up and checking of medicinal products in pharmacies, a list of medicinal limited effects of PPP. Obviously, it is imperative to pro- products prepared as officinal formulae in pharmacies (2014). vide oral isotretinoin to patients in the safest manner pos- https://www.riigiteataja.ee/en/eli/ee/MHL/reg/528032016009/ sible. The effectiveness of PPP at the population level, and consolide. Accessed 27 Nov 2017. thus the cost-effectiveness of enhanced isotretinoin PPP, 10. Estonian Medical Birth Registry. Estonian Abortion Registry. http://www.tai.ee/et/tegevused/registrid/meditsiiniline- remains unclear. A rigorous program assessment is neces- sunniregister-ja-raseduskatkestus-andmekogu/statistika. Acces- sary to identify whether new measures should be taken or sed 23 Nov 2017. whether weaknesses in policy or implementation can be 11. World Health Organization 2015. Medical eligibility criteria for corrected. contraceptive use, 5th ed. http://apps.who.int/iris/bitstream/ 10665/181468/1/9789241549158_eng.pdf?ua=1. Accessed 27 Nov 2017. Compliance with Ethical Standards 12. Shin J, Cheetham TC, Wong L, et al. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care Funding This work was supported grant # IUT34-17 from the system. J Am Acad Dermatol. 2011;65(6):1117–25. Estonian Ministry of Education and Research 13. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-pre- vention program in women of childbearing age receiving iso- Conflicts of interest AU, HP, KK, OL, ML, and MU report no tretinoin. N Engl J Med. 1995;333(2):101–6. conflicts of interest. 14. Brinker A, Kornegay C, Nourjah P. Trends in adherence to a revised risk management program designed to decrease or elim- Ethics approval The study procedures were in accordance with local inate isotretinoin-exposed pregnancies: evaluation of the accutane data protection regulations. The analysis used existing patient records SMART program. Arch Dermatol. 2005;141(5):563–9. containing only non-identifiable data and was therefore exempt from 15. Pierson JC, Ferris LK, Schwarz EB. We pledge to change ethical review. iPLEDGE. JAMA Dermatol. 2015;151(7):701–2. 16. European Medicine Agency 2012. Guideline on good pharma- Open Access This article is distributed under the terms of the covigilance practices (GVP) Module V—Risk management sys- Creative Commons Attribution-NonCommercial 4.0 International tems. http://www.ema.europa.eu/docs/en_GB/document_library/ License (http://creativecommons.org/licenses/by-nc/4.0/), which per- Scientific_guideline/2012/06/WC500129134.pdf. Accessed 27 mits any noncommercial use, distribution, and reproduction in any Nov 2017. medium, provided you give appropriate credit to the original 17. Thiboutot D, Gollnick H, Bettoli V, et al. Oral isotretinoin and author(s) and the source, provide a link to the Creative Commons pregnancy prevention programmes. Br J Dermatol. license, and indicate if changes were made. 2012;166:466–7. 18. Zomerdijk IM, Ruiter R, Houweling LM, et al. Isotretinoin exposure during pregnancy: a population-based study in The References Netherlands. BMJ Open. 2014;4(11):e005602. 19. Lippus H, Laanpere M, Part Ket al. Estonian Womens Health 2014: sexual and reproductive health, health behaviour, attitudes 1. Goodfield MJ, Cox NH, Bowser A, et al. Advice on the safe and use of healthcare services. Survey report. Tartu; 2015. https:// introduction and continued use of isotretinoin in acne in the U.K. sisu.ut.ee/sites/default/files/naisteterviseuuring/files/ 2010. Br J Dermatol. 2010;162(6):1172–9. uusestre2014_loppraport.pdf. Accessed 27 Nov 2017. 2. Commission decision background information on Article 29 referral isotretinoin 2003. http://www.ema.europa.eu/docs/en_ GB/document_library/Referrals_document/Isotretinoin_29/ WC500010881.pdf. Accessed 25 Jul 2017.

Journal

Drugs - Real World OutcomesSpringer Journals

Published: May 22, 2018

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