The clinical investigator

, Volume 71, Issue 6, pp 483–487 | Cite as

Compliance and adverse drug reactions: a prospective study with ethinylestradiol using continuous compliance monitoring

  • W. Kruse
  • W. Eggert-Kruse
  • J. Rampmaier
  • B. Runnebaum
  • E. Weber
Clinical Pharmacology Original Article


This study examined the relationship between adverse reactions and patient compliance with ethinylestradiol at 40 μg twice daily versus 20 μg four times daily. In a randomized study 61 female patients with primary- infertility were prescribed the drug twice daily (n = 31) or four times daily (n = 30). Ethinylestradiol was administered for 7 days before the sperm cervical mucus penetration-test was performed for hormonal standardization of the cervical mucus quality. Drug compliance was measured by continuous monitoring using the Medication Event Monitoring System. Two parameters were evaluated: percentage of prescribed doses taken (administration compliance) and adherence to the prescribed dose schedule (regimen compliance, number of days with two or four dosing events recorded). Adverse drug reactions were assessed using a standardized questionnaire. Fourty-four women experienced side effects, of which 81% were rated by patients as being mild. Patient compliance was higher with the twice daily than with the four times daily regimen: 85% versus 65% prescribed doses taken (P<0.05). There was no significant difference in compliance comparing patients with and without adverse reactions (82% versus 72%, respectively), but compliance was lower and more irregular with at least 3 versus one or two adverse reactions reported: 54% versus 84% in administration compliance and 31% versus 58% in regimen compliance (P<0.05). Compliance was also lower in patients with nausea and vomiting than in those without these symptoms, 59% versus 91% and 34% versus 66% (P<0.005), respectively, and lower with moderate or severe compared to mild side effects; 48% versus 85% and 25% versus 59% (P<0.005). Thus the mere occurrence of side effects was not associated with low compliance. However, the number and nature of symptoms and their intensity as perceived by patients may have considerably influenced drug use behavior.

Key words

Drug compliance Adverse reactions Electronic compliance monitoring 



adverse drug reactions


sperm cervical mucus penetration-test


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  1. 1.
    Averbuch M, Weintraub M, Pollack DJ (1990) Compliance assessment in clinical trials: the MEMS device. J Clin Res Pharmacoepidemiol 4:199–204Google Scholar
  2. 2.
    Cramer JA (1991) Identifying and improving compliance patterns: a composite plan for health care providers. In: Cramer JA, Spilker B (eds) Patient compliance in medical practice and clinical trials. Raven, New York, pp 387–392Google Scholar
  3. 3.
    Cramer J, Mattson R, Prevey M, Scheyer R, Quellette V (1989) How often is medication taken as prescribed? JAMA 261:3273–3277Google Scholar
  4. 4.
    Eggert-Kruse W, Leinhos G, Gerhard I, Tilgen W, Runnebaum B (1989) Prognostic value of in vitro sperm penetration into hormonally standardized human cervical mucus. Fertil Steril 51:317–323Google Scholar
  5. 5.
    Gagnon M-A, Langlois Y, Boghen DR, Verdy M (1977) Effects of halazepam and diazepam on the motor coordination of geriatric subjects. Eur J Clin Pharmacol 11:443–448Google Scholar
  6. 6.
    Haynes RB (1979) Determinants of compliance: the disease and mechanics of treatment. In: Haynes RB, Taylor DW, Sackett DL (eds) Compliance in health care. Johns Hopkins University Press, Baltimore, pp 49–62Google Scholar
  7. 7.
    Joyce CRB (1962) Patient co-operation and the sensitivity of clinical trials. J Chron Dis 15:1025–1036Google Scholar
  8. 8.
    Klein LE, German PS, Levine DM, Feroli ER, Ardery J (1984) Medication problems among outpatients. Arch Intern Med 144:1185–1188Google Scholar
  9. 9.
    Kruse W, Weber E (1990) Dynamics of drug regimen compliance — its assessment by microprocessor-based monitoring. Eur J Clin Pharmacol 38:561–565Google Scholar
  10. 10.
    Kruse W, Eggert-Kruse W, Rampmaier J, Runnebaum B, Weber E (1990) Compliance with short-term high-dose ethinyl oestradiol in young patients with primary infertility. Risk factors for adverse drug reactions. Agents and Actions [Suppl], pp 105–115Google Scholar
  11. 11.
    Kruse W, Eggert-Kruse W, Rampmaier J, Runnebaum B, Weber E (1991) Dosage frequency and drug-compliance behaviour — a comparative study on compliance with a medication to be taken twice or four times daily. Eur J Clin Pharmacol 41:589–592Google Scholar
  12. 12.
    Kruse W, Koch-Gwinner P, Nikolaus T, Oster P, Schlierf G, Weber E (1992) Measurement of drug compliance by continuous electronic monitoring: a pilot study in elderly patients discharged from hospital. J Am Geriatr Soc 40:1151–1155Google Scholar
  13. 13.
    Matsui D, Hermann C, Braudo M, Ito S, Oliviere N, Koren G (1992) Clinical use of the Medication Event Monitoring System: a new window into pediatric compliance. Clin Pharmacol Ther 52:102–103Google Scholar
  14. 14.
    Moulding TS (1979) The unrealized potential of the medication monitor. Clin Pharmacol Ther 25:131–136Google Scholar
  15. 15.
    Murad F, Haynes RC Jr (1980) Estrogens and progestins. In: Goodman Gilman A, Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics. Macmillan, New York, pp 1420–1447Google Scholar
  16. 16.
    Potter L (1991) Oral contraceptive compliance and its role in the effectiveness of the method. In: Cramer JA, Spilker B (eds) Patient compliance in medical practice and clinical trials. Raven, New York, pp 195–207Google Scholar
  17. 17.
    Rubeo A, Cox C, Weintraub M (1992) Prediction of diltiazem plasma concentration curves from limited measurements using compliance data. Clin Pharmacokinet 22:238–246Google Scholar
  18. 18.
    Rudd P, Ahmed S, Zachary V, Barton C, Bonduelle D (1990) Improved compliance measures: applications in an ambulatory hypertensive drug trial. Clin Pharmacol Ther 48:676–685Google Scholar
  19. 19.
    Spriet A, Beiler D, Dechorgnant J, Simon P (1980) Adherence of elderly patients to treatment with pentoxifylline. Clin Pharmacol Ther 27:1–8Google Scholar
  20. 20.
    Spriet A, Simon P (1985) Methodology of clinical drug trials. Karger, Basel New York, pp 136–147Google Scholar
  21. 21.
    Weber E, Gundert-Remy U (1981) Side-effects of drugs and patient compliance. In: Jähnchen E, Meinertz T, Towse G (eds) Prognosis and pharmacotherapy of life-threatening arrhythmias. Royal Society of Medicine, Academic Press, London, pp 205–208Google Scholar
  22. 22.
    Weintraub M (1976) Intelligent noncompliance and capricious compliance. In: Lasagna L (ed) Patient compliance. Futura, Mount Kisco, pp 39–47Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • W. Kruse
    • 1
    • 3
  • W. Eggert-Kruse
    • 2
  • J. Rampmaier
    • 1
  • B. Runnebaum
    • 2
  • E. Weber
    • 1
  1. 1.Abteilung für Klinische PharmakologieMedizinische UniversitätsklinikHeidelberg
  2. 2.Abteilung für Gynäkologische EndokrinologieUniversitäts-FrauenklinikHeidelberg
  3. 3.Krankenhaus BethanienHeidelbergGermany

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