The Association Between Drospirenone and Hyperkalemia

A Comparative-safety Study

Steven T Bird; Salvatore R Pepe; Mahyar Etminan; Xinyue Liu; James M Brophy; Joseph AC Delaney

Disclosures

BMC Clin Pharmacol. 2011;11(23):1-6. 

In This Article

Background

Drospirenone is a novel synthetic progestin approved in combination with ethinyl estradiol as an oral contraceptive (OC).[1] Marketed as Yasmin® and Yaz®, drospirenone is one of the most popular oral contraceptives in the United States.[2] Drospirenone is a fourth generation OC and it possesses antimineralocorticoid effects not present in previous generations of OCs. Its antimineralocorticoid potency is approximately eight times greater than spironolactone,[3] thus a 3 mg tablet of drospirenone has a similar effect to 20–25 mg of spironolactone.[4] This activity enhances sodium, chloride, and water excretion, while reducing the excretion of potassium, ammonium, and phosphate.[5] The similarity in chemical structure between drospirenone and spironolactone and the known association between spironolactone and hyperkalemia both strengthen the plausibility that clinically significant hyperkalemia might result from drospirenone use.

In May of 2001, when drospirenone/ethinyl estradiol (Yasmin®) was first approved, the package insert included a bolded warning for hyperkalemia, stating that "Yasmin should not be used in patients with conditions that predispose to hyperkalemia".[1] The warning also instructs physicians to monitor potassium levels during the first cycle of treatment in patients taking concomitant medications known to cause hyperkalemia. Clinical evidence however has not shown a strong association between drospirenone and hyperkalemia.[6–13] Several studies have evaluated for hyperkalemia in postmenopausal women with hypertension or diabetes who use drospirenone to treat vasomotor spasms. These studies found no association between drospirenone and hyperkalemia in women with hypertension[6,7] or type 2 diabetes mellitus;[8] however, all three studies were twelve or fewer weeks in duration. Larger trials designed to evaluate the safety and efficacy of drospirenone either do not evaluate hyperkalemia or are not powered to detect it.[9–12] Only one large study, mandated by the FDA at approval, has been performed evaluating drospirenone for hyperkalemia in younger women, and it found no association between drospirenone and hyperkalemia.[13]

Hyperkalemia is a potentially serious condition that may be associated with numerous pathophysiological conditions. Clinically significant hyperkalemia reduces membrane excitability and disturbs the acid-base balance, manifesting as weakness, flaccid paralysis, hypoventilation, and metabolic acidosis. Hyperkalemia can also result in cardiac toxicity with electrocardiographic changes, which in severe cases may lead to the terminal events of ventricular fibrillation or asystole.[5]

The primary objective of the current study is to investigate the association between drospirenone and the diagnosis of hyperkalemia in a large unselected population. A secondary objective is to evaluate the impact of the package insert on medical prescribing as assessed by an examination of the 1) concomitant use of drospirenone and spironolactone and 2) respect for the stated potassium monitoring requirements.

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