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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]

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]

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]

Objective: To characterize risk of hypotension requiring admission to hospital in middle aged and older men treated with tamsulosin for benign prostatic hyperplasia., Design: Population based retrospective cohort study (between patient methodology) and self controlled case series (within patient methodology)., Setting: Healthcare claims data from the IMS Lifelink database in the United States., Participants: Men aged 40-85 years with private US healthcare insurance entering the cohort at their first dispensing for tamsulosin or for a 5α reductase inhibitor (5ARI) between January 2001 and June 2011 after a minimum of six months' enrolment., Main Outcomes Measures: Hypotension requiring admission to hospital. Cox proportional hazards models estimated rate ratios at time varying intervals during follow-up: weeks 1-4, 5-8, and 9-12 after tamsulosin initiation; weeks 1-4, 5-8, and 9-12 after restarting tamsulosin (after a four week gap); and maintenance tamsulosin treatment (remaining exposed person time). Covariates included age, calendar year, demographics, antihypertensive use, healthcare use, and a Charlson comorbidity score. A self controlled case series, having implicit control for time invariant covariates, was additionally conducted., Results: Among 383,567 new users of study drugs (tamsulosin 297,596; 5ARI 85,971), 2562 admissions to hospital for severe hypotension were identified. The incidence for hypotension was higher for tamsulosin (42.4 events per 10,000 person years) than for 5ARIs (31.3 events per 10,000 person years) or all accrued person time (29.1 events per 10,000 person years). After tamsulosin initiation, the cohort analysis identified an increased rate of hypotension during weeks 1-4 (rate ratio 2.12 (95% confidence interval 1.29 to 3.04)) and 5-8 (1.51 (1.04 to 2.18)), and no significant increase at weeks 9-12. The rate ratio for hypotension also increased at weeks 1-4 (1.84 (1.46 to 2.33)) and 5-8 (1.85 (1.45 to 2.36)) after restarting tamsulosin, as did maintenance tamsulosin treatment (1.19 (1.07 to 1.32)). The self controlled case series gave similar results as the cohort analysis., Conclusions: We observed a temporal association between tamsulosin use for benign prostatic hyperplasia and severe hypotension during the first eight weeks after initiating treatment and the first eight weeks after restarting treatment. This association suggests that physicians should focus on improving counseling strategies to warn patients regarding the "first dose phenomenon" with tamsulosin.

Background: Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin-angiotensin-system blockers., Methods: We formed a nested cohort of men aged 40-85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time-control design for our secondary analysis., Results: We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74-2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66-1.16) or past (RR 0.86, 95% CI 0.66-1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin-angiotensin-system blockers had an RR of 4.46 (95% CI 2.84-6.99) for acute kidney injury. Our case-time-control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52-3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury., Interpretation: We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin-angiotensin-system blockers.

Background: There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown., Methods: We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18-46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS., Results: The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41-3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10-2.19)., Interpretation: We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.

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.