The Effect of Isotretinoin on the Etonogestrel Contraceptive Implant
Conditions: Contraception
Sponsor: University of Colorado, Denver

Official Title: The effect of isotretinoin on the etonogestrel contraceptive implant 
NCT Number: NCT02967055 
Document date: 9/19/2016 
Principal Investigator: Aaron Lazorwitz MD 
 
 

Proposal Narrative 
Objective: This is an exploratory pharmacokinetic study to demonstrate the effect of concomitant isotretinoin 
therapy on ENG contraceptive implant use. 
Specific Aims:  
1. To describe serum ENG levels with concomitant use of the ENG implant and isotretinoin by comparing 
levels before and after four and eight weeks of isotretinoin therapy, and  
2. to characterize whether any reductions in serum ENG are below the level needed to maintain ovulation 
suppression (<90pg/mL). 
This study will fill a knowledge gap regarding the pharmacokinetic effects of isotretinoin on the ENG implant so 
that providers can appropriately counsel users about contraceptive effectiveness.  
Rationale 
 
The ENG implant (Nexplanon®, formerly Implanon®) is the most effective form of reversible 
contraception available with perfect and typical use effectiveness >99%.1 When cost is not prohibitive, up to 
11% of women chose this method.2 Little data, however, exists pertaining to drug interactions with the ENG 
implant, particularly with medications known to decrease the efficacy of oral contraceptives.3 We recently 
demonstrated that carbamazepine, a strong cytochrome P-450 enzyme inducer, significantly decreased serum 
ENG levels in reproductive-aged women (average and median decrease was 60%) and the majority (80%) of the 
post-therapy serum ENG levels were below the threshold for ovulatory suppression (<90pg/mL) (see Links with 
other projects). These findings highlight the need for more research on drug-drug interactions that may reduce 
contraceptive efficacy.  In particular, we must examine drugs that pose teratogenic risks given the added 
medical and social implications for women faced with unintended pregnancies.   
 
Acne is a common condition occurring in reproductive aged women, about half of whom are affected 
and at least 10-12% seek medical treatment.4 Isotretinoin (formerly branded as Accutane) is commonly used 
for treatment of severe acne in this group; in 1999, almost 300,000 women took isotretinoin.5.  Isotretinoin is a 
well-known teratogen that can result in abnormalities of the face, eyes, ears, skull, central nervous system, 
cardiovascular system, thymus, parathyroid glands, and neurodevelopmental delay without structural 
anomalies.6  Because of isotretinoin’s known teratogenicity, women taking this medication are required to use 
two forms of contraception, often including one hormonal and one barrier method. In 2006, the U.S Food and 
Drug Administration established the iPLEDGE Program to reduce the rate of isotretinoin-induced birth defects.  
The program requires a “pledge” from sexually active women to use two contraceptive methods during 
isotretinoin therapy.  Despite this program, each year 150 affected pregnancies are reported.7,8  A recent 
survey demonstrated that 20% of women on isotretinoin therapy who claimed abstinence had unprotected 
intercourse and 31% of contraceptive users reported using less than two forms of contraception during at least 

one episode of intercourse.8   
 
Isotretinoin is also a known cytochrome P-450 enzyme inducer.9 A prior pharmacokinetic study 
demonstrated small reductions in serum levels of ethinyl estradiol and norethindrone (9% and 11% decreases 
in area under the curves, respectively) that were variable and with a trend towards an increase in 
pharmacodynamic ovulation measures.10  The U.S. Centers for Disease Control Medical Eligibility Criteria (CDC 
MEC) currently has no safety recommendations regarding concomitant isotretinoin and hormonal 
contraceptive use.11 Given the severe teratogenic risks that isotretinoin incurs, further investigation is needed 
to better understand drug-drug interactions between isotretinoin and hormonal contraceptives.  In this study, 
we will describe and characterize the pharmacokinetic effect of isotretinoin on ENG levels in implant users. 
Research design and methods 
Outcome Measure: Current data suggests that a serum ENG concentration of at least 90pg/mL is needed to 
prevent ovulation.12  Given that there is little pharmacologic data about isotretinoin available, we cannot 
reliably predict how much of an effect concomitant isotretinoin use will have on serum ENG levels in implant 
users. Thus, we will perform an exploratory study to describe and characterize ENG levels during concomitant 
isotretinoin therapy. 
Description of Population to be enrolled:  
 
We will enroll reproductive-aged women (ages 18-45) who are under the care of a dermatologist for 
treatment of acne and planning to initiate therapy with isotretinoin. These women must have chosen an ENG 
contraceptive implant for their primary mechanism of birth control during isotretinoin therapy under the 
iPLEDGE agreement.6  The ENG contraceptive implant must have been placed at least four weeks prior to study 
enrollment, but in place no longer than three years. Our inclusion criteria includes the following 
recommendations that are followed for isotretinoin initiation:6 
• 
Have a secondary form of non-hormonal contraception or abstain during isotretinoin therapy and four 
weeks afterwards  
• 
Have at least two negative pregnancy tests at least 19 days apart prior to initiating isotretinoin 
therapy6 
• 
Not currently breastfeeding 
• 
Have normal baseline laboratory evaluation including liver function tests, basic metabolic panel, and 
complete blood count  
• 
Have no known contraindications to isotretinoin 
• 
Abstain from taking any Vitamin A supplement during the study period 
• 
Not currently taking any know cytochrome P-450 3A4 enzyme inducers or inhibitors (see Appendix A) 
• 
Have a BMI ≥18.5 due to concerns for abnormal metabolism and higher risk for side effects in 

underweight women. We have no upper BMI limit, as pharmacokinetic and efficacy studies in 
overweight and obese women using the ENG implant are reassuring.13,14   
Study Design 
 
We are conducting a pre-post study to determine the pharmacokinetic effects of concomitant 
isotretinoin use on serum ENG levels. We will recruit potential participants via the University of Colorado 
research email, flyers located on campus, our Family Planning Divisional research registry, and informative 
postcards available at the University of Colorado Dermatology clinic and the Adolescent Medicine Dermatology 
clinic at the Children’s Hospital of Colorado. We also plan to reach out to private dermatology clinics in the 
Denver metro area for purposes of advertising. The dermatologists at these sites have agreed to offer 
information about the study verbally and in the form of a postcard, but these providers will not be involved in 
the study beyond advertising purposes. Interested participants will call and speak to our professional research 
assistant (PRA).  Eligible participants must be under the care of a dermatologist and planning to initiate 
isotretinoin therapy.  Interested participants must also have an ENG implant in place for at least 4 weeks prior 
to study enrollment. The ENG implant has an initial pharmacologic burst that peaks at four days after insertion, 
thus a delay of at least four weeks after insertion will both allow for serum ENG levels to plateau and satisfy the 
iPLEDGE requirement for a month of reliable contraception prior to initiating isotretinoin therapy.6,15 
 
We will invite eligible participants for a screening visit at CWHC approximately one week prior to 
initiation of isotretinoin therapy.  We will complete informed consent.  During screening, the PRA will obtain a 
history including current medications and supplements and palpate whether the implant is in place.  
Participants will take a urine pregnancy test and have their height, weight, and blood pressure measured. 
Interested participants who plan to initiate isotretinoin therapy routinely undergo a four-week evaluation 
period prior to initiation by their dermatologist.  During this time, the dermatologist performs at least two 
pregnancy tests and a baseline evaluation of kidney and liver function. We will request medical record 
confirmation of these tests from interested participants and review their results to confirm eligibility. Prior to 
starting therapy, dermatologists enroll patients into the iPLEDGE program.6  They are also thoroughly 
counseled by their dermatologist on the importance of maintaining a back-up contraceptive method or 
abstaining from intercourse during isotretinoin therapy and for an additional four weeks afterwards. We will 
then determine eligibility, and enroll participants. Enrolled participants will undergo an initial blood draw 
(including a back-up tube for a total of no more than 20cc of blood drawn) to measure their baseline serum 
ENG level.  All participants will be compensated $30.00 after their initial blood draw. 
 
 
After the enrollment visit, participants will initiate isotretinoin therapy under the supervision of their 
dermatologist.  Participants’ dermatologists will monitor their treatment course and adjust isotretinoin therapy 
as deemed appropriate per the standard treatment protocol, which we will record. After four weeks of 
isotretinoin therapy, participants will return for their second ENG level blood draw (no more than 20cc of total 

blood drawn). After nine weeks of isotretinoin therapy, participants will return for their third and final ENG 
level blood draw (no more than 20cc of total blood drawn). Participants will be compensated $30.00 for each 
blood draw visit. No more than two blood draws will be performed in any eight week period during the study. 
Most patients receive isotretinoin for 16-20 weeks duration. We will call participants after they have 
completed their isotretinoin therapy, and up to four weeks after, to assess satisfaction with the contraceptive 
implant and whether there was an unintended pregnancy.  They will be compensated an additional $10.00 for 
completion of the telephone call. We will exclude from final analysis any participants discontinued from 
isotretinoin therapy secondary to adverse side effects, per their dermatologist's recommendations, or based on 
participant preference. 
 
At CWHC, collected ENG blood draws undergo centrifugation and the serum will be stored at -80ºC 
until analysis within the freezer located at CWHC. Upon completion of participant enrollment, we will remove  
personal identifiers, package, and ship all serum samples to Columbia University to undergo blinded, batched 
serum ENG measurement.  ENG levels will be determined using a LCMS protocol that has been previously 
validated (Dr. Serge Cremers lab).16  Samples for the entire study will be batched and run together to minimize 
assay variability. We will enter all data into a password-protected database via secure Internet connection 
(REDCap) using the participant ID numbers. The list of participant ID numbers and corresponding names will be 
stored separately on a password protected shared drive for the Division of Family Planning.  Participants serve 
as their own control and we will compare their serum ENG levels at baseline to their levels after four and eight 
weeks of the isotretinoin therapy using paired Wilcoxon-signed Rank test.  
There is no currently available literature regarding the pharmacokinetic effect of isotretinoin on the 
ENG implant, but we have demonstrated that a strong cytochrome P-450 enzyme inducer can reduce 80% of 
serum ENG levels to below the threshold for ovulatory suppression. We, therefore, plan to analyze 10 study 
compliant participants who complete isotretinoin therapy and all study procedures.  This is a feasible number 
for an exploratory study, feasible for study recruitment at our institution, and consistent with similar 
pharmacokinetic studies of this nature (see Links with other projects).  To account for an anticipated 25% drop-
out/noncompliance rate, we will enroll up to 14 participants and we will screen up to 30 participants to 
account for screening failures prior to actual enrollment.   

 
Citations 
1. Hatcher RA, Trussel J, Nelson AL, Cates W, Kowal D, Policar MS. Contraceptive Technology, 20th Ed (New York: 
Ardent Media, 2011). 
2. Daniels K, Daughterty J, Jones J, “Current Contraceptive Status among Women Aged 15–44: United States, 2011–
2013,” NCHS Data Brief 173 (2014): 1–8. 
3. Le J & Tsourounis C, “Implanon: A Critical Review,” The Annals of Pharmacotherapy 35, no. 3 (March 2001): 329–
36. 
4. Holzmann R & Shakery K. “Postadolescent acne in females.” Skin Pharmacol Physiol 2014; 27 (Suppl 1): 3-8. doi: 
10.1159/0000354887. 
5. U.S. Food and Drug Administration, “2.2 Estimating Accutane Use” (Historical Dockets, 2000), 
http://www.fda.gove/ohrms/dockets/ac/00/backgrd/3639b1c_05.pdf. 
6. “iPLEDGE Program,” iPLEDGE: Committed to Pregnancy Prevention, 2005, https://www.ipledgeprogram.com/. 
7. Werner CA, Papic MJ, Ferris LK, Lee JK, Borrero S, Prevost N, Schwarz EB. “Women’s Experiences with Isotretinoin 
Risk Reduction Counseling,” JAMA Dermatology 150, no. 4 (April 2014): 366–71, 
doi:10.1001/jamadermatol.2013.6862. 
8. Collins MK, Moreau JF, Opel D, Swan J, Prevost N, Hastings M, Bimla Schwarz E, Korb Ferris L. “Compliance with 
pregnancy prevention measures during isotretinoin therapy.” J Am Acad Dermatol 2014; 70 (1): 55-9. doi: 
10.1016/j.jaad.2013.08.034. 
9. Goerz G, Bolsen K, Kalofoutis A, Tsambaos D. “Influence of oral isotretinoin on hepatic and cutaneous P-450-
dependent isozyme activities.” Arch Dermatol Res 1994: 286 (2): 104-6 
10. Hendrix CW, Jackson KA, Whitmore E, Guidos A, Kretzer R, Liss CM, Shah LP, Khoo K, McLane J, Trapnell CB. “The 
Effect of Isotretinoin on the Pharmacokinetics and Pharmacodynamics of Ethinyl Estradiol and Norethindrone,” 
Clinical Pharmacology & Therapeutics 75, no. 5 (May 2004): 464–75, doi:10.1016/j.clpt.2004.01.003. 
11. “U.S. Medical Eligibility Criteria for Contraceptive Use, 2010,” accessed March 10, 2016, 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5904a1.htm?s_cid=rr5904a1_e. 
12. Wenzl R, van Beek A, Schnabel P, Huber J. “Pharmacokinetics of Etonogestrel Released from the Contraceptive 
Implant Implanon,” Contraception 58, no. 5 (November 1998): 283–88. 
13. Xu H, Wade JA, Peipert JF, Zhao Q, Madden T, Secura GM, “Contraceptive Failure Rates of Etonogestrel 
Subdermal Implants in Overweight and Obese Women,” Obstetrics and Gynecology 120, no. 1 (July 2012): 21–26, 
doi:10.1097/AOG.0b013e318259565a.G.0000000000000690. 
14. Morrell KM, Cremers S, Westhoff CL, Davis AR. “Relationship between etonogestrel level and BMI in women using 
the contraceptive implant for more than 1 year.” Contraception 93, no 3 (March 2016): 263-265, 
doi:10.1016/j.contraception.2015.11.005. 
15. Bennink HJ. “The pharmacokinetics and pharmacodynamics of Implanon, a single rod etonogestrel contraceptive 
implant.” The European Journal of Contraception & Reproductive Health Care2000; 5 (Suppl 2): 12-20. 
16. Thomas T, Petrie K, Shim J, Abildoskov KM, Westhoff CL, Cremers S.“A UPLC-MS/MS Method for Therapeutic Drug 
Monitoring of Etonogestrel,” Therapeutic Drug Monitoring 35, no. 6 (December 2013): 844–48, 
doi:10.1097/FTD.0b013e31829a10fa 
17. Tocce KM, Sheeder JL, Teal SB. “Rapid repeat pregnancy in adolescents: do immediate postpartum contraceptive 
implants make a difference?” Am J Obstet Gynecol 2012; 206(6): 481.e1-7. doi:10.1016/j.ajog.2012.04.015. 
18. Guiahi M, McBride M, Sheeder J, Teal S. “Short-Term Treatment of Bothersome Bleeding for Etonogestrel Implant 
Users Using a 14-Day Oral Contraceptive Pill Regimen: A Randomized Controlled Trial.” Obstet Gynecol 2015; 126 
(3): 508-13. doi: 10.1097/AOG.0000000000000974. 
19. Huber J. and Wenzl R. “Pharmacokinetics of Implanon: An integrated analysis,” Contraception 58, suppl 6 (Dec 
1998): 85S-90S. 
 
 
 

Appendix A 
Screening list of known CYP-3A4 Inducers and Inhibitors 
 
Bergamottin 
Norfloxacin 
Butalbital 
Orphenadrine 
Cafestol 
Oxcarbazepine 
Carbamazepine 
Phenobarbital 
Chloramphenicol 
Phenytoin 
Cimetidine 
Pioglitazone 
Ciprofloxacin 
Piperine 
Delavirdine 
Quercetin 
Dithiocarbamate 
Rifabutin 
Efavirenz 
Rifampin 
Fluoxetine 
St John's wort 
Fluvoxamine 
Star Fruit 
Gestodene 
Troglitazone 
Ginkgo biloba 
Valerian 
Glucocorticoids 
Voriconazole 
Isoniazid 
Ziprasidone 
Mibefradil 
 
Mifepristone 
 
Milk thistle 
 
Modafinil