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Denosumab is an injectable antiresorptive therapy. Due to its more potent inhibitory effect on bone resorption compared with other antiresorptive drugs, it may cause more severe hypocalcemia. The risk for hypocalcemia is heightened in patients with chronic kidney disease (CKD) because they have an impaired ability to regulate calcium levels. This retrospective cohort study aims to compare the risk for severe hypocalcemia in patients with CKD receiving denosumab, intravenous bisphosphonates, or oral bisphosphonates. Visual Abstract. The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease: Denosumab is an injectable antiresorptive therapy. Due to its more potent inhibitory effect on bone resorption compared with other antiresorptive drugs, it may cause more severe hypocalcemia. The risk for hypocalcemia is heightened in patients with chronic kidney disease (CKD) because they have an impaired ability to regulate calcium levels. This retrospective cohort study aims to compare the risk for severe hypocalcemia in patients with CKD receiving denosumab, intravenous bisphosphonates, or oral bisphosphonates. Background: There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD). Objective: To assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD–mineral and bone disorder (CKD-MBD). Design: Target trial emulation. Setting: Medicare fee-for-service data with prescription drug coverage, 2012 to 2020. Participants: Female patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis. Measurements: Hospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated. Results: A total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage (P  < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non–dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates. Limitation: Generalizability to men and non-Medicare populations. Conclusion: Risk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD. Primary Funding Source: U.S. Food and Drug Administration. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is there a difference in risk of severe hypocalcemia among female dialysis-dependent Medicare patients treated for osteoporosis with denosumab vs oral bisphosphonates? Findings: In this cohort study of 1523 dialysis-dependent patients initiating denosumab and 1281 initiating oral bisphosphonates, the weighted cumulative incidence of severe hypocalcemia (ie, <7.5 mg/dL [1.88 mmol/L] or emergent care) at 12 weeks was 41.1% with denosumab, 60 mg, vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]). Meaning: Treatment of older female dialysis-dependent patients with denosumab was associated with a statistically and clinically significant increased risk of severe hypocalcemia compared with oral bisphosphonates. Importance: Dialysis-dependent patients experience high rates of morbidity from fractures, yet little evidence is available on optimal treatment strategies. Chronic kidney disease–mineral and bone disorder is nearly universal in dialysis-dependent patients, complicating diagnosis and treatment of skeletal fragility. Objective: To examine the incidence and comparative risk of severe hypocalcemia with denosumab compared with oral bisphosphonates among dialysis-dependent patients treated for osteoporosis. Design, Setting, and Participants: Retrospective cohort study of female dialysis-dependent Medicare patients aged 65 years or older who initiated treatment with denosumab or oral bisphosphonates from 2013 to 2020. Clinical performance measures including monthly serum calcium were obtained through linkage to the Consolidated Renal Operations in a Web-Enabled Network database. Exposures: Denosumab, 60 mg, or oral bisphosphonates. Main Outcomes and Measures: Severe hypocalcemia was defined as total albumin-corrected serum calcium below 7.5 mg/dL (1.88 mmol/L) or a primary hospital or emergency department hypocalcemia diagnosis (emergent care). Very severe hypocalcemia (serum calcium below 6.5 mg/dL [1.63 mmol/L] or emergent care) was also assessed. Inverse probability of treatment-weighted cumulative incidence, weighted risk differences, and weighted risk ratios were calculated during the first 12 treatment weeks. Results: In the unweighted cohorts, 607 of 1523 denosumab-treated patients and 23 of 1281 oral bisphosphonate–treated patients developed severe hypocalcemia. The 12-week weighted cumulative incidence of severe hypocalcemia was 41.1% with denosumab vs 2.0% with oral bisphosphonates (weighted risk difference, 39.1% [95% CI, 36.3%-41.9%]; weighted risk ratio, 20.7 [95% CI, 13.2-41.2]). The 12-week weighted cumulative incidence of very severe hypocalcemia was also increased with denosumab (10.9%) vs oral bisphosphonates (0.4%) (weighted risk difference, 10.5% [95% CI, 8.8%-12.0%]; weighted risk ratio, 26.4 [95% CI, 9.7-449.5]). Conclusions and Relevance: Denosumab was associated with a markedly higher incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older compared with oral bisphosphonates. Given the complexity of diagnosing the underlying bone pathophysiology in dialysis-dependent patients, the high risk posed by denosumab in this population, and the complex strategies required to monitor and treat severe hypocalcemia, denosumab should be administered after careful patient selection and with plans for frequent monitoring. This cohort study assesses the incidence of severe and very severe hypocalcemia in female dialysis-dependent patients aged 65 years or older receiving denosumab compared with oral bisphosphonates. [ABSTRACT FROM AUTHOR]

Purpose: Current algorithms to evaluate gestational age (GA) during pregnancy rely on hospital coding at delivery and are not applicable to non‐live births. We developed an algorithm using fertility procedures and fertility tests, without relying on delivery coding, to develop a novel GA algorithm in live‐births and stillbirths. Methods: Three pregnancy cohorts were identified from 16 health‐plans in the Sentinel System: 1) hospital admissions for live‐birth, 2) hospital admissions for stillbirth, and 3) medical chart‐confirmed stillbirths. Fertility procedures and prenatal tests, recommended within specific GA windows were evaluated for inclusion in our GA algorithm. Our GA algorithm was developed against a validated delivery‐based GA algorithm in live‐births, implemented within a sample of chart‐confirmed stillbirths, and compared to national estimates of GA at stillbirth. Results: Our algorithm, including fertility procedures and 11 prenatal tests, assigned a GA at delivery to 97.9% of live‐births and 92.6% of stillbirths. For live‐births (n = 4 701 207), it estimated GA within 2 weeks of a reference delivery‐based GA algorithm in 82.5% of pregnancies, with a mean difference of 3.7 days. In chart‐confirmed stillbirths (n = 49), it estimated GA within 2 weeks of the clinically recorded GA at delivery for 80% of pregnancies, with a mean difference of 11.1 days. Implementation of the algorithm in a cohort of stillbirths (n = 40 484) had an increased percentage of deliveries after 36 weeks compared to national estimates. Conclusions: In a population of primarily commercially‐insured pregnant women, fertility procedures and prenatal tests can estimate GA with sufficient sensitivity and accuracy for utility in pregnancy studies. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate an International Classification of Diseases, 10th Revision, Clinical Modification (ICD‐10‐CM)‐based algorithm to identify cases of stillbirth using electronic healthcare data. Methods: We conducted a retrospective study using claims data from three Data Partners (healthcare systems and insurers) in the Sentinel Distributed Database. Algorithms were developed using ICD‐10‐CM diagnosis codes to identify potential stillbirths among females aged 12–55 years between July 2016 and June 2018. A random sample of medical charts (N = 169) was identified for chart abstraction and adjudication. Two physician adjudicators reviewed potential cases to determine whether a stillbirth event was definite/probable, the date of the event, and the gestational age at delivery. Positive predictive values (PPVs) were calculated for the algorithms. Among confirmed cases, agreement between the claims data and medical charts was determined for the outcome date and gestational age at stillbirth. Results: Of the 110 potential cases identified, adjudicators determined that 54 were stillbirth events. Criteria for the algorithm with the highest PPV (82.5%; 95% CI, 70.9%–91.0%) included the presence of a diagnosis code indicating gestational age ≥20 weeks and occurrence of either >1 stillbirth‐related code or no other pregnancy outcome code (i.e., livebirth, spontaneous abortion, induced abortion) recorded on the index date. We found ≥90% agreement within 7 days between the claims data and medical charts for both the outcome date and gestational age at stillbirth. Conclusions: Our results suggest that electronic healthcare data may be useful for signal detection of medical product exposures potentially associated with stillbirth. [ABSTRACT FROM AUTHOR]

Warfarin was selected as a case study to examine confounding when comparing a product across different manufacturers because it is a narrow therapeutic index drug with prevalent beliefs for brand‐name superiority. Medicare beneficiaries aged ≥65 years with atrial fibrillation and an incident outpatient warfarin prescription from July 2006 through July 2015 were included in the study population (N = 746,098). Substantial imbalances were observed between brand‐name warfarin and generics for (i) clinical comorbidity, (ii) socioeconomic status, (iii) prescriber specialty, (iv) recent ambulatory and emergent care, (v) drug adherence, (vi) pharmacy setting (e.g., retail, mail‐order), and (vii) risk scores for bleeding and thrombosis. Patients receiving brand‐name warfarin were healthier than patients receiving generic manufactured warfarin. Utilization of generic warfarin products also differed by geographic region and pharmacy setting. Manufacturer‐level comparative‐safety studies for causal inference should carefully consider the presence of these imbalances and their potential for introducing healthy user bias. [ABSTRACT FROM AUTHOR]

Letrozole is an aromatase inhibitor that has an unapproved use for ovulation induction with infertility. Because of the proximity of this use to conception, we selected letrozole to study the effect of 3 different methods for identifying the pregnancy start date and their impact on exposure misclassification. Using electronic health data from the US Sentinel database (2001–2015), we identified live-birth pregnancies conceived through in-vitro fertilization or intrauterine insemination. The pregnancy start was calculated using 1) a validated algorithm to estimate the last menstrual period (LMP), 2) LMP + 14 days (i.e. conception estimate), and 3) the fertility-procedure date. We identified 47,628 live-births after intrauterine insemination (n = 24,962) and in-vitro fertilization (n = 22,666), in which 2,458 (5.3%) mothers received letrozole. The algorithm-based conception estimate occurred within 14 days of the fertility procedure for 78.3% of pregnancies. Defining pregnancy start as LMP (45.7/1,000 pregnancies) or LMP + 14 days (12.7/1,000 pregnancies) overestimated letrozole exposure during pregnancy by 8.4-fold and 2.3-fold, respectively, compared with defining it at the date of the fertility procedure (5.5/1,000 pregnancies). While most studies of drug utilization in pregnancy use LMP as the conventional pregnancy start, this introduced substantial exposure misclassification in the example of letrozole. LMP + 14 days was less biased. Researchers should carefully consider the impact of the method for identifying the pregnancy start date on the potential for exposure misclassification. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To describe the utilization of drugs with pregnancy exposure registries by trimester during pregnancy, in comparison with matched nonpregnant episodes and a pre‐pregnancy period. Methods: We identified live‐born deliveries from women aged 10 to 54 years and matched the pregnancies 1:1 with nonpregnant episodes from a comparator cohort not delivering live‐born infants, using data from 2001 to 2013 in the Sentinel Distributed Database. We evaluated the utilization of 34 drugs with pregnancy exposure registries, comparing utilization during pregnancy to the matched nonpregnant episodes, and to the 90 days before pregnancy. Results: We identified 1 895 597 pregnancies ending in live births in 1 598 697 women and 1 895 597 matched nonpregnant episodes in 1 582 581 women. We observed a lower prevalence of use for most drugs during pregnancy compared with the matched nonpregnant episodes, and the 90‐day pre‐pregnancy period. The median (interquartile range) prevalence ratio of use, at any time during pregnancy, for all products was 0.2 (0.1‐0.3) comparing pregnant to nonpregnant episodes. Overall, there was a decrease in drug utilization by trimester; from 2.6% in the 90 days preceding pregnancy to 2.1% in the first trimester, 1.1% in the second trimester, and 0.9% in the third trimester. Conclusions: Among drugs with pregnancy exposure registries, use was less during pregnancy compared with before pregnancy and to the matched nonpregnant episodes. The lower utilization during pregnancy suggests that women may be avoiding these drugs to minimize potentially harmful exposure during pregnancy. This lower utilization may increase the challenges of further studying the safety of these drugs using pregnancy exposure registries. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy registries and spontaneous reports are essential pharmacovigilance tools to evaluate drug safety during pregnancy.Objectives: The aim of this study was to evaluate postmarket capture of exposed pregnancies.Methods: Pregnancy registries for drugs and biologics were identified in a systematic review. Through a standardized questionnaire, manufacturers provided information on (1) pregnancy registry enrollment and retention, and (2) worldwide receipt of spontaneous reports for exposed pregnancies. A validated algorithm for live-birth pregnancies allowed calculation of exposure rates per 100,000 live births using claims data.Results: Among 34 products with a pregnancy registry, median (interquartile range) registry enrollment was 36 pregnancies (5-258) and median spontaneous report capture was 450 pregnancies (89-1192). Products used in >20/100,000 live births had a median registry enrollment of 490 pregnancies and median capture of 1061 spontaneously reported exposed pregnancies. Lower median registry enrollment and spontaneous report capture was observed for products used in 0.5-20/100,000 live births (36 from registries, 541 spontaneous reports) and <0.5/100,000 live births (3 from registries, 41 spontaneous reports). Among 24 registries enrolling ≥10 pregnancies, median capture of pregnancy outcomes (e.g. live birth, spontaneous abortion) was 83.9%. For 19 registries enrolling ≥10 infants, the median proportion of infants achieving protocol-specified follow-up was 89.9% for up to 4 weeks post-birth, 75.0% for 1-5 months, and 57.1% for ≥6 months.Conclusions: Relatively higher product utilization among pregnant women predicted greater pregnancy registry enrollment. For products rarely used during pregnancy, registry enrollment was low and differences in registry enrollment compared with worldwide spontaneous report receipt were most pronounced. Products with very low utilization levels during pregnancy may require a combination of worldwide pharmacovigilance, pregnancy registries, and additional study methods to achieve adequate surveillance. [ABSTRACT FROM AUTHOR]

Purpose To examine ondansetron use in pregnancy in the context of other antiemetic use among a large insured United States population of women delivering live births. Methods We assessed ondansetron and other antiemetic use among pregnant women delivering live births between 2001 and 2015 in 15 data partners contributing data to the Mini-Sentinel Distributed Database. We identified live birth pregnancies using a validated algorithm, and all forms of ondansetron and other available antiemetics were identified using National Drug Codes or procedure codes. We assessed the prevalence of antiemetic use by trimester, calendar year, and formulation. Results In over 2.3 million pregnancies, the prevalence of ondansetron, promethazine, metoclopramide, or doxylamine/pyridoxine use anytime in pregnancy was 15.2, 10.3, 4.0, and 0.4%, respectively. Ondansetron use increased from <1% of pregnancies in 2001 to 22.2% in 2014, with much of the increase attributable to oral ondansetron beginning in 2006. Promethazine and metoclopramide use increased modestly between 2001 (13.8%, 3.2%) and 2006 (16.0%, 6.0%) but decreased annually through 2014 (8.0%, 3.2%). Doxylamine/pyridoxine, approved for management of nausea and vomiting in pregnancy in 2013, was used in 1.8% of pregnancies in 2014. For all antiemetics, use was highest in the first trimester. Conclusions We observed a marked increase in ondansetron use by study year, prescribed to nearly one-quarter of insured pregnant women in 2014, occurring in conjunction with decreased use of promethazine and metoclopramide. Given the widespread use of ondansetron in pregnancy, data establishing product efficacy and methodologically rigorous evaluation of post-marketing safety are needed. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

The October 2010 ESHRE/ASRM polycystic ovary syndrome (PCOS) workshop concluded: (1) all combined oral contraceptives (COC) appear to have equal efficacy for PCOS, (2) addition of antiandrogens (spironolactone) to COCs has little treatment benefit and (3) metformin does not improve the live-birth rate and should only be used with impaired glucose tolerance. We compared these guidelines to current practice in the United States IMS claims-database. Time-series analyses were conducted by calendar-year in women with PCOS to evaluate prescribing preferences for COCs, concomitant use of spironolactone, and utilization of metformin. Trends were analyzed with linear regression. Our cohort included 1.6 million women taking COCs, 46 780 with a PCOS claim. Drospirenone utilization increased by 1.52% (SE:0.48%, p = 0.007) per-year more in women with PCOS (4.16%, SE:0.45%, p < 0.001) than in women without PCOS (2.64%, SE:0.17%, p < 0.001)). Concomitant use of drospirenone and spironolactone was common (14.26%) and increased by 0.75% (SE:0.15%, p = 0.002) per-year. Although plasma glucose tests were unavailable, women with PCOS were more likely to take metformin than have a diabetes claim (45.8% versus 15.2%, p < 0.001), indicating some women likely receive metformin solely for PCOS. Our data suggests further attention is needed to medication management of PCOS to bridge the gap between guidelines and practice. [ABSTRACT FROM AUTHOR]

The authors discuss research on the risk of cardiac arrhythmias and mortality among patients taking citalopram. They reference the study "Evaluation of the FDA Warning Against Prescribing Citalopram at Doses Exceeding 40 mg." by K. Zivin and colleagues published in the current issue of the journal. They conclude that the work does not mitigate the concern that led to the recommendation by the U.S. Food and Drug Administration (FDA) to avoid the 60 milligrams per day dosage.

BackgroundThe safety of gadolinium-based contrast agent (GBCA) exposure during pregnancy has not been established, and the use of GBCAs during pregnancy is not recommended unless it is essential to the health of the woman or fetus.PurposeTo examine the prevalence of GBCA exposure in a large sample of pregnancies resulting in a live birth.Materials and MethodsThe Sentinel Distributed Database was used to retrospectively identify U.S. pregnancies that resulted in live births between 2006 and 2017 from 16 data partners. The main outcome was the prevalence of MRI procedures with and without GBCAs, sorted by anatomic location and trimester, among pregnant and matched comparator women.ResultsAmong 4 692 744 pregnancies resulting in a live birth, we identified 6879 exposures to GBCAs in 5457 pregnancies, representing one contrast-enhanced MRI examination per 860 pregnancies (0.12% of all pregnancies). Most contrast-enhanced MRI examinations were performed in the head ( n = 3499), although pelvic and abdominal MRI constituted 22.3% ( n = 1536) of all contrast-enhanced MRI examinations during pregnancy. The majority (70.2%) of GBCA exposures occurred during the first trimester, with a 4.3-fold greater prevalence compared with that in the second trimester and a 5.1-fold greater prevalence compared with that in the third trimester.ConclusionThis study identified higher rates of gadolinium-based contrast agent (GBCA) exposure during the first few weeks of pregnancy compared with the later weeks of pregnancy, suggesting inadvertent exposure to GBCAs might occur before pregnancy is recognized.© RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kallmes and Watson in this issue.

Background: We aimed to determine how single and combination antihypertensive therapy alters risk for diabetes mellitus (DM).Thiazide diuretics (TD), β blockers (BB), and renin-angiotensin system blockers (RASB) impact DM risk while calcium channel blockers (CCB) are neutral. DM risk associated with combinations is unclear., Methods and Results: We enrolled nondiabetic patients from Kaiser Permanente Northwest with a fasting plasma glucose (FPG) <126 mg/dL between 1997 and 2010. DM cases were defined by a FPG ≥ 126 mg/dL, random plasma glucose ≥ 200 mg/dL, HbA1c ≥ 7.0%, or new DM prescription (index date). We used incidence density sampling to match 10 controls per case on the date of follow-up glucose test (to reduce detection bias), in addition to age and date of cohort entry. Exposure to antihypertensive class was assessed during the 30 days prior to index date. Our cohort contained 134 967 patients and had 412 604 glucose tests eligible for matching. A total of 9097 DM cases were matched to 90 495 controls (median age 51 years). Exposure to TD (OR 1.54, 95% CI 1.41 to 1.68) or BB (OR 1.19, 95% CI 1.11 to 1.28) was associated with an increased DM risk, while CCB and RASB exposure was not. TD+BB combination resulted in the fully combined diabetogenic risk of both agents (OR 1.99, 95% CI 1.80 to 2.20; interaction OR 1.09, 95% CI 0.97 to 1.22). In contrast, combination of RASB with either TD or BB showed significant negative interactions, resulting in a smaller DM risk than TD or BB monotherapy., Conclusions: Diabetogenic potential of combination therapy should be considered when prescribing antihypertensive therapy.

Background: Mineralocorticoids are thought to play a role in tissue repair, including fibrous tissue formation. The antimineralocorticoid activity of spironolactone has been linked to an increased risk of gastrointestinal bleeding. Drospirenone is a synthetic progestin approved in combination with ethinyl-estradiol as an oral contraceptive (OC). It is a spironolactone-derivative, and its antimineralocorticoid effects could irritate the gastrointestinal tract leading to symptoms of irritable bowel syndrome (IBS)., Methods: A retrospective cohort study was conducted evaluating women 18-46 years of age in the IMS claims-database. New-users of progestin-based OCs were identified between 1997-2009. Ninety days of OC therapy and one year of prior enrollment with no prior diagnosis of IBS were required for inclusion. Cases were identified using a previously validated method for the diagnosis of IBS. Cox proportional hazards models were used to estimate the hazard ratio (HR) for developing IBS with the different OC formulations using levonorgestrel as a reference., Results: The cohort included 939,281 women, averaging 29.1 years of age and 247 days of OC therapy. 3,050 incident cases of IBS were detected. The annualized incidence for IBS with drospirenone was 0.77% (1083 cases) while that for levonorgestrel was 0.46% (483 cases). The crude HR for development of IBS with drospirenone compared to levonorgestrel was 1.70 (95%CI 1.53-1.90), while the adjusted HR was 1.63 (95%CI 1.46-1.82). Multiple sensitivity analyses confirmed this association. Other OCs were unassociated with IBS., Conclusion: Our study found a positive association between drospirenone and a diagnosis of IBS that was not observed with other OCs.

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.