The association between drospirenone and hyperkalemia: a comparative-safety study.
BACKGROUND
Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.


METHODS
A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone


RESULTS
The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.


CONCLUSIONS
A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.
Department of Health and Human Services/Food and Drug Administration/Center for Drug Evaluation and Research (CDER)/Office of Management/CDER Academic Collaboration Program, Bldg 22, 10903 New Hampshire Avenue, Silver Spring, MD USA 20993.|University of Florida, College of Pharmacy, Pharmaceutical Outcomes & Policy, 101 S. Newell Drive (HPNP), PO Box 100496, Gainesville FL, USA 32611.
Steven T
ST
Bird
Department of Health and Human Services/Food and Drug Administration/Center for Drug Evaluation and Research (CDER)/Office of Management/CDER Academic Collaboration Program, Bldg 22, 10903 New Hampshire Avenue, Silver Spring, MD USA 20993.|University of Florida, College of Pharmacy, Pharmaceutical Outcomes & Policy, 101 S. Newell Drive (HPNP), PO Box 100496, Gainesville FL, USA 32611.
Salvatore R
SR
Pepe
University of British Columbia, Pharmaceutical Outcomes Programme, 709-828 West 10th Avenue, Vancouver, British Columbia, Canada V5Z1M9.
Mahyar
M
Etminan
University of Florida, College of Pharmacy, Pharmaceutical Outcomes & Policy, 101 S. Newell Drive (HPNP), PO Box 100496, Gainesville FL, USA 32611.
Xinyue
X
Liu
McGill University, Royal Victoria Hospital, 687 Pine Street West, Montreal, Quebec H3A 1A1, Canada.
James M
JM
Brophy
University of Florida, College of Pharmacy, Pharmaceutical Outcomes & Policy, 101 S. Newell Drive (HPNP), PO Box 100496, Gainesville FL, USA 32611.
Joseph Ac
JA
Delaney
D000328:Adult; D000736:Androstenes / Q000008:administration & dosage / Q000009:adverse effects*; D015331:Cohort Studies; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects / Q000627:therapeutic use; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced*; D016912:Levonorgestrel / Q000627:therapeutic use; D016015:Logistic Models; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013148:Spironolactone / Q000627:therapeutic use
D000736:Androstenes; D003277:Contraceptives, Oral, Combined; C534342:drospirenone and ethinyl estradiol combination; D013148:Spironolactone; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; C035144:drospirenone