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BACKGROUND:Clinicians often encounter information about drug-drug interactions (DDIs) during clinical practice. This information is found within product information (hardcopy and electronic) and various electronic systems. Prescribers may receive medication-related communications in practice that are distributed by facsimile (fax), mail, or telephone from pharmacies and pharmacy benefit managers (PBMs). The purpose of this study was to determine if near-real time fax alerts for potential drug-drug interactions (PDDIs) would influence prescribing.METHODS:A prospective study, in cooperation with a pharmacy benefit manager (PBM), was conducted targeting 18 clinically important PDDIs. Fax alerts included an individualized letter to the prescriber with a list of the interacting drugs, PDDI evidence summaries with citations, and recommended clinical management strategies. Among the 18 PDDIs, 13 PDDIs could be assessed for prescription therapy changes using pharmacy claims data. A prospective cohort design was used to evaluate changes in prescription dispensing 90-days following a PDDI fax alert.RESULTS:A total of 8,075 fax alerts were sent to prescribers and there were 4,712 alerts for the 13 PDDIs that could be assessed for change using pharmacy claims data. There were 2,019 patients (interventions) for which fax alerts were sent to their prescribers who were matched with a control group consisting of patients with the same PDDIs but for whom no fax alert was sent. Overall, this study found 154 (7.6%) of patients in the fax alert group compared to 132 (6.5%) in the control group had changes in therapy (p=0.177).CONCLUSIONS:This fax alert intervention program observed no statistically significant differences in prescribing with a fax alert compared to the control group. If PBMs chose to send individualized, evidence-based information to clinicians regarding drug-drug interactions, this study suggests it may not be an effective intervention to mitigate harm.

Nausea and vomiting of pregnancy (NVP) affects up to 90% of pregnancies. Diclectin (doxylamine/pyridoxine) is the only anti-emetic approved in Canada for NVP, at a maximum dose of 4 tablets/day. However, some women receive higher doses, up to 12 tablets/day. In this study we compared the neurocognitive development of children from four mother-child groups: (1) NVP and >4 tablets Diclectin, (2) NVP and ≤ 4 tablets Diclectin, (3) NVP and no treatment and (4) no NVP. Children received a full age-appropriate psychological assessment. All groups scored in the normal range for IQ and cognition tests. The Diclectin-exposed groups scored significantly higher on a small number of subtests, but none of the differences could be considered clinically significant. No dose-dependent effects were observed. Above manufacturer recommended doses of Diclectin do not appear to harm neurodevelopment and should be considered safe for the treatment of NVP.

Nausea and vomiting of pregnancy (NVP) affects up to 90% of pregnancies. Diclectin (doxylamine/pyridoxine) is the only anti-emetic approved in Canada for NVP, at a maximum dose of 4 tablets/day. However, some women receive higher doses, up to 12 tablets/day. In this study we compared the neurocognitive development of children from four mother-child groups: (1) NVP and >4 tablets Diclectin, (2) NVP and ≤ 4 tablets Diclectin, (3) NVP and no treatment and (4) no NVP. Children received a full age-appropriate psychological assessment. All groups scored in the normal range for IQ and cognition tests. The Diclectin-exposed groups scored significantly higher on a small number of subtests, but none of the differences could be considered clinically significant. No dose-dependent effects were observed. Above manufacturer recommended doses of Diclectin do not appear to harm neurodevelopment and should be considered safe for the treatment of NVP.

Our knowledge of a drug’s potential for harm is incomplete at the time of drug licensing leaving residual questions about the long-term safety and effectiveness of drugs in the ‘real world’. Pharmacoepidemiologic research can contribute to the study of the unintended effects of drugs. The central aims of this dissertation were to create new knowledge about drug-related harm in the postmarketing environment using pharmacoepidemiologic methods and larged linked databases, and understand how various types of design and analytic strategies can be applied to reduce bias and threats to internal validity when studying drug harm. The aims of the thesis were achieved by performing three studies. The first study examined elderly individuals hospitalized with bradycardia and identified an association with recent initiation of cholinesterase inhibitor therapy (adjusted odds-ratio 2.13, 95% confidence interval 1.29 to 3.51). The second study examined the measurement properties of administrative diagnostic codes for subtrochanteric and femoral shaft fractures and found the positive predictive value and sensitivity of the codes to be reasonably good (90% and 81%, respectively). This study was linked to the third study which explored the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in postmenopausal women and found an increased risk of these unusual fractures in women with greater than 5 years of bisphosphonate use. The research performed as part of this thesis provides an example of the types of new knowledge about drug-related harm that can be generated using pharmacoepidemiologic designs and analytic strategies. The pharmacoepidemiologic studies will play an important and dynamic role in the larger evolving focus on post-marketing drug safety and effectiveness as new data sources become increasingly available and and the methods within the pharmacoepidemiologic discipline become more sophisticated and refined.

Our knowledge of a drug’s potential for harm is incomplete at the time of drug licensing leaving residual questions about the long-term safety and effectiveness of drugs in the ‘real world’. Pharmacoepidemiologic research can contribute to the study of the unintended effects of drugs. The central aims of this dissertation were to create new knowledge about drug-related harm in the postmarketing environment using pharmacoepidemiologic methods and larged linked databases, and understand how various types of design and analytic strategies can be applied to reduce bias and threats to internal validity when studying drug harm. The aims of the thesis were achieved by performing three studies. The first study examined elderly individuals hospitalized with bradycardia and identified an association with recent initiation of cholinesterase inhibitor therapy (adjusted odds-ratio 2.13, 95% confidence interval 1.29 to 3.51). The second study examined the measurement properties of administrative diagnostic codes for subtrochanteric and femoral shaft fractures and found the positive predictive value and sensitivity of the codes to be reasonably good (90% and 81%, respectively). This study was linked to the third study which explored the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in postmenopausal women and found an increased risk of these unusual fractures in women with greater than 5 years of bisphosphonate use. The research performed as part of this thesis provides an example of the types of new knowledge about drug-related harm that can be generated using pharmacoepidemiologic designs and analytic strategies. The pharmacoepidemiologic studies will play an important and dynamic role in the larger evolving focus on post-marketing drug safety and effectiveness as new data sources become increasingly available and and the methods within the pharmacoepidemiologic discipline become more sophisticated and refined.

Purpose To investigate associations between maternal use of selected medications during early pregnancy and the risk of hypospadias in male infants. Methods We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1,537 case infants with second or third degree isolated hypospadias and 4,314 male control infants born from 1997-2007. Exposure was based on reported use of any prescription or over-the-counter medication or herbal product, for which there were at least 5 exposed cases, from 1 month before to 4 months after conception, excluding topicals, vitamins, minerals, and products for which the components were unknown. Adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using multivariable logistic regression, adjusting for several confounders. Results Of the 195 medication components with at least 5 exposed cases, 89 components met the inclusion criteria and were assessed-28 herbal and 61 non-herbal components. Hypospadias was associated with reported use of cephalexin (aOR 3.06; 95% CI 1.02, 9.18), phenylpropanolamine HCl (aOR 2.68; 95% CI 1.06, 6.80), and ibuprofen (aOR 1.16; 95% CI 1.00, 1.34), in primary analyses. Conclusions We replicated a previously observed association between maternal exposure to phenylpropanolamine HCl and hypospadias. The associations with cephalexin and ibuprofen have not previously been reported. Given the exploratory nature of the analyses, these results should be considered hypothesis-generating. Better understanding of the potential fetal effects will allow clinicians and women of childbearing age to make more informed decisions regarding the use of medications during pregnancy.

Study Objective: Drug-related problems (DRPs) are associated with increased rates of infection, rejection, and graft loss in kidney transplant recipients. This study aimed to develop a model to predict which patients are at highest risk of DRPs to streamline pharmacists’ workflow in a chronic kidney transplant clinic. Design: Prospective observational study. Setting: Chronic kidney transplant clinic at a large, tertiary care, academic hospital. Patients: Two hundred thirty-seven adults seen in the kidney transplant clinic between September 16, 2015, and November 30, 2015, who were at least 90 days posttransplantation at the time of their clinic visit. Measurements and Main Results: Prospective data detailing DRPs and a survey assessing baseline characteristics and patient-related outcomes were used to generate a predictive model to identify patients at risk of having six or more DRPs; the cutoff of six DRPs provided a threshold for identifying a subset of high-risk patients on whom the transplant pharmacists could focus their efforts. DRPs were categorized as nonadherence, overdosing or underdosing, duplication of therapy, preventable adverse drug reaction, missing medication, erroneous medication, conflicting provider information, undermonitoring or lack of monitoring, and wrong medication received. In total, 865 unique DRPs were identified, and the most common were erroneous medication, missing medication, and nonadherence, accounting for 38%, 21%, and 16% of the DRPs, respectively. A nine-variable model with a sensitivity of 62.5% and specificity of 66.7% (area under the receiver operating characteristic curve of 0.720) was developed to identify patients at risk of having six or more DRPs. The model included the following variables: age, Medicaid for prescription insurance, current employment status, medication affordability, difficulty or lack of difficulty obtaining medications from the pharmacy, negative impact of medications on quality of life, medication nonadherence, poor rating of current health status, and moderate or poor medication understanding. Conclusion: These results demonstrated that a straightforward, 5-minute survey completed by renal transplant recipients prior to their clinic visit may be capable of effectively determining those at risk of having six or more DRPs, potentially allowing use as a screening tool for transplant pharmacists’ workflow prioritization. External validation is needed before this tool can be used in the outpatient setting.

The research presented in this dissertation harnesses two secondary data sources, administrative databases of patient-level healthcare data and adverse event (AE) data reported in randomized clinical trials (RCTs), to assess the relationship between intravenous immune globulin (IVIg) and the risk of clinically serious thromboembolic adverse events (TEEs). Since 2013, IVIg products have carried a boxed warning concerning TEE risk, a determination supported by numerous case reports, a large claims-based risk assessment, and laboratory evaluations of the thrombogenecity of IVIg products. Questions remain concerning the magnitude of the risk overall and across subgroups of IVIg users. Taken together, our results are compatible with the conclusion that the absolute risk of TEE following IVIg use is likely to be low overall. While these results are reassuring, a clinically meaningful elevation in risk cannot be ruled out in certain patient sub-groups, such as older adults and others with a high baseline risk of TEE. A limitation of our research is that differences in TEE risk across products could not be evaluated with sufficient statistical power.

Idiosyncratic drug reactions (IDRs) represent a significant medical problem and pose a great challenge to drug development. Circumstantial evidence suggests that, in most cases, reactive metabolites of the drug are responsible. The major focus of this thesis is the identification of reactive metabolites and the synthesis of analogs required to test several hypotheses related to involvement of metabolism and covalent binding in the mechanisms of IDRs. Minocycline is unique among tetracyclines in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. In this study, we demonstrated that minocycline is oxidized to reactive intermediates by myeloperoxidase/H2O2/Cl-, HOCl, horseradish peroxidase/H2O2, or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N, N-dimethylamino group, implying that the reactive intermediate was a quinone iminium ion. The other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings, suggesting that the HOCl added across the double bond of the B ring leading to a reactive molecule, and then NAC displaced the chloride ion. Nevirapine, an anti-HIV drug, is associated with idiosyncratic skin rashes in humans. The goal of this project was to investigate whether the 12-hydroxylation pathway is responsible for the skin rash. To test a part of this hypothesis, 12-trideuteronevirapine, 12-OH-NVP sulfate, and several other analogs of nevirapine were synthesized. D-penicillamine is known to cause idiosyncratic autoimmune reactions in humans. The goal of this project was to test whether D-penicillamine covalently binds to macrophages and triggers downstream events leading to autoimmunity. To test a part of this hypothesis, D-penicillamine conjugated to biotin was synthesized. In summary, reactive metabolites of minocycline were found that likely explain why minocycline has an IDR profile unique among the tetracyclines. In addition, analogs of nevirapine and D-penicillamine required for mechanistic studies of nevirapine and D-penicillamine-induced IDRs were synthesized. These studies provide additional support for the involvement of reactive metabolites in the mechanisms of IDRs.