Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies.

Background: Exposure in utero to certain medications can disrupt processes of fetal development, including brain development, leading to a continuum of neurodevelopmental difficulties. Recognizing the deficiency of neurodevelopmental investigations within pregnancy pharmacovigilance, an international Neurodevelopmental Expert Working Group was convened to achieve consensus regarding the core neurodevelopmental outcomes, optimization of methodological approaches and barriers to conducting pregnancy pharmacovigilance studies with neurodevelopmental outcomes. Methods: A modified Delphi study was undertaken based on stakeholder and expert input. Stakeholders (patient, pharmaceutical, academic and regulatory) were invited to define topics, pertaining to neurodevelopmental investigations in medication-exposed pregnancies. Experts were identified for their experience regarding neurodevelopmental outcomes following medicinal, substances of misuse or environmental exposures in utero. Two questionnaire rounds and a virtual discussion meeting were used to explore expert opinion on the topics identified by the stakeholders. Results: Twenty-five experts, from 13 countries and professionally diverse backgrounds took part in the development of 11 recommendations. The recommendations focus on the importance of neurodevelopment as a core feature of pregnancy pharmacovigilance, the timing of study initiation and a core set of distinct but interrelated neurodevelopmental skills or diagnoses which require investigation. Studies should start in infancy with an extended period of investigation into adolescence, with more frequent sampling during rapid periods of development. Additionally, recommendations are made regarding optimal approach to neurodevelopmental outcome measurement, comparator groups, exposure factors, a core set of confounding and mediating variables, attrition, reporting of results and the required improvements in funding for potential later emerging effects. Different study designs will be required depending on the specific neurodevelopmental outcome type under investigation and whether the medicine in question is newly approved or already in widespread use. Conclusion: An improved focus on neurodevelopmental outcomes is required within pregnancy pharmacovigilance. These expert recommendations should be met across a complementary set of studies which converge to form a comprehensive set of evidence regarding neurodevelopmental outcomes in pregnancy pharmacovigilance.

Implementation and clinical benefit of DPYD genotyping in a Danish cancer population.

BACKGROUND: In 2020, the European Medicines Agency recommended testing patients for dihydropyrimidine dehydrogenase (DPD) deficiency before systemic treatment with fluoropyrimidines (FP). DPD activity testing identifies patients at elevated risk of severe FP-related toxicity (FP-TOX). The two most used methods for DPD testing are DPYD genotyping and DPD phenotyping (plasma uracil concentration). The primary objective of this study was to compare the overall frequency of overall grade ≥3 FP-TOX before and after the implementation of DPYD genotyping. PATIENTS AND METHODS: Two hundred thirty Danish, primarily gastrointestinal cancer patients, were DPYD-genotyped before their first dose of FP, and blood was sampled for post hoc assessment of P-uracil. The initial dose was reduced for variant carriers. Grade ≥3 FP-TOX was registered after the first three treatment cycles of FP. The frequency of toxicity was compared to a historical cohort of 492 patients with post hoc determined DPYD genotype from a biobank. RESULTS: The frequency of overall grade ≥3 FP-TOX was 27% in the DPYD genotype-guided group compared to 24% in the historical cohort. In DPYD variant carriers, DPYD genotyping reduced the frequency of FP-related hospitalization from 19% to 0%. In the control group, 4.8% of DPYD variant carriers died due to FP-TOX compared to 0% in the group receiving DPYD genotype-guided dosing of FP. In the intervention group, wild-type patients with uracil ≥16 ng/ml had a higher frequency of FP-TOX than wild-type patients with uracil <16 ng/ml (55% versus 28%). CONCLUSIONS: We found no population-level benefit of DPYD genotyping when comparing the risk of grade ≥3 FP-TOX before and after clinical implementation. We observed no deaths or FP-related hospitalizations in patients whose FP treatment was guided by a variant DPYD genotype. The use of DPD phenotyping may add valuable information in DPYD wild-type patients.

An analysis of the level of evidence behind treatments recommended by the Danish Medicines Council.

OBJECTIVES: We aimed to investigate the quality of evidence and the expected added clinical value of treatments recommended by the Danish Medicines Council (DMC). STUDY DESIGN: This was an observational study. METHODS: The DMC prepares reports on drugs considered for possible new standard treatments in Danish hospitals. These reports evaluate the available evidence on efficacy and safety. The quality of evidence is systematically rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, and estimates of added clinical value are presented. The recommendations take into account expected economic implications of new treatments. The publicly available reports up until December 29, 2021, were downloaded from the DMC Web page. Reports on drugs marked "recommended" were included. Data on quality of evidence, expected clinical value, and economic implications were imputed in a Microsoft Excel spreadsheet. RESULTS: Seventy-nine reports were included in the analysis. In 79% of these, the quality of evidence was rated low (24%) or very low (55%), whereas no recommendations were based on evidence rated as high quality. Three (5%) of recommended treatments were expected to add large clinical value. CONCLUSIONS: Most recommendations by the DMC are based on evidence formally rated as low or very low quality by GRADE, and no recommendations were based on evidence rated as high quality. The added clinical value of the treatments was often not documented and rarely large. Continued attention to improve the clinical evidence behind national recommendations is necessary.

Trends in antidepressant use among children and adolescents: a Scandinavian drug utilization study.

OBJECTIVE: To compare antidepressant utilization in individuals aged 5-19 years from the Scandinavian countries. METHODS: A population-based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden. RESULTS: In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3-18.0/1000) compared to Norway (5.1-7.6/1000) and Denmark (9.3-7.5/1000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors were 5611/1000 inhabitants in Sweden, 2709/1000 in Denmark, and 1848/1000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1000) compared to Denmark (225/1000) and Norway (170/1000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30-42 per 1000. The proportion of antidepressant users was highest among 15- to 19-year-old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63). CONCLUSION: Even in highly comparable healthcare systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers.

Association between use of phthalate-containing medication and semen quality among men in couples referred for assisted reproduction.

STUDY QUESTION: Does phthalate exposure from prescription drugs affect semen quality? SUMMARY ANSWER: Exposure to phthalate-containing drugs is associated with poor semen quality. WHAT IS KNOWN ALREADY: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans. STUDY DESIGN, SIZE, DURATION: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality. LIMITATIONS, REASONS FOR CAUTION: The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest.

Use of Pregabalin - A Nationwide Pharmacoepidemiological Drug Utilization Study with Focus on Abuse Potential.

INTRODUCTION: Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used in dosages that exceed the approved therapeutic range. METHODS: To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (≥600 mg/day) or very high use (≥1 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker. RESULTS: Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2 765 (6.5%) for more than 12 months. Male gender and prescription of antipsychotics and benzodiazepines were associated with increased risk of use of above the recommended dosage. DISCUSSION: Use of pregabalin above recommended dosages was rare but abuse may occur in susceptible patients.

Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study.

UNLABELLED: ESSENTIALS: It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs. BACKGROUND: It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. OBJECTIVES: The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. PATIENTS/METHODS: We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. RESULTS: Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of -0.3 [95% CI: -0.1; -0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. CONCLUSION: Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.

Relapse Prevention in Major Depressive Disorder After Successful Acute Electroconvulsive Treatment: a 6-month Double-blind Comparison of Three Fixed Dosages of Escitalopram and a Fixed Dose of Nortriptyline - Lessons from a Failed Randomised Trial of the Danish University Antidepressant Group (DUAG-7).

INTRODUCTION: Electroconvulsive treatment (ECT) is an effective treatment for severe depression but carries a risk of relapse in the following months. METHODS: Major depressive disorder patients in a current episode attaining remission from ECT (17-item Hamilton Depression Rating Scale (HAM-D17) score≤9) received randomly escitalopram 10 mg, 20 mg, 30 mg or nortriptyline 100 mg as monotherapies and were followed for 6 months in a multicentre double-blind set-up. Primary endpoint was relapse (HAM-D17≥16). RESULTS: As inclusion rate was low the study was prematurely stopped with only 47 patients randomised (20% of the planned sample size). No statistically significant between-group differences could be detected. When all patients receiving escitalopram were compared with those receiving nortriptyline, a marginal superiority of nortriptyline was found (p=0.08). One third of patients relapsed during the study period, and one third completed. DISCUSSION: Due to small sample size, no valid efficacy inferences could be made. The outcome was poor, probably due to tapering off of non-study psychotropic drugs after randomisation; this has implications for future study designs. ClinicalTrials.gov Identifier: NCT00660062.

Use of psychotropic drugs during pregnancy and breast-feeding.

OBJECTIVE: To write clinical guidelines for the use of psychotropic drugs during pregnancy and breast-feeding for daily practice in psychiatry, obstetrics and paediatrics. METHOD: As we wanted a guideline with a high degree of consensus among health professionals treating pregnant women with a psychiatric disease, we asked the Danish Psychiatric Society, the Danish Society of Obstetrics and Gynecology, the Danish Paediatric Society and the Danish Society of Clinical Pharmacology to appoint members for the working group. A comprehensive review of the literature was hereafter conducted. RESULTS: Sertraline and citalopram are first-line treatment among selective serotonin reuptake inhibitor for depression. It is recommended to use lithium for bipolar disorders if an overall assessment finds an indication for mood-stabilizing treatment during pregnancy. Lamotrigine can be used. Valproate and carbamazepin are contraindicated. Olanzapine, risperidone, quetiapine and clozapine can be used for bipolar disorders and schizophrenia. CONCLUSION: It is important that health professionals treating fertile women with a psychiatric disease discuss whether psychotropic drugs are needed during pregnancy and how it has to be administered.

Possible drug-drug interaction between pregabalin and clozapine in patients with schizophrenia: clinical perspectives.

INTRODUCTION: Pregabalin is an antiepileptic drug with anti-anxiety properties and is approved for treatment of generalized anxiety disorder. Anxiety is common in patients with schizophrenia and pregabalin has been suggested as an off-label add-on treatment. METHODS: Pregabalin was added to clozapine in 2 patients with schizophrenia, who both suffered from severe anxiety symptoms. RESULTS: Both patients experienced falls and consequently bone fractures. Increased plasma levels of clozapine likely contributed to the outcome. One patient had confirmed seizures whereas the mechanism in the other patient was less clear. DISCUSSION: This short report discusses the possible mechanism of a pregabalin-clozapine interaction.

Increasing use of antibiotics in pregnancy during the period 2000-2010: prevalence, timing, category, and demographics.

OBJECTIVE: The aim of this study was to describe the use of antibiotics in a national population-based cohort of pregnant Danish women between 2000 and 2010. DESIGN: Register-based, population-wide, cohort study. SETTING: Denmark, from 2000 to 2010. POPULATION: All pregnancies among Danish residents during the period 2000-2010 were included for analysis. METHODS: Data were obtained from the Danish Medical Birth Registry, the Danish National Patient Registry, and the Registry of Medicinal Product Statistics. The filled prescriptions for systemic antibacterial, antimycotic, and antiviral drugs, as well as intravaginally applied antibiotics, were analysed. Associations with demographic variables were assessed using multivariate analysis. MAIN OUTCOME MEASURES: Filled prescriptions for antibiotic drugs during pregnancy. RESULTS: We included 987 973 pregnancies in Denmark from 2000 to 2010; 38.9% of women with a delivery and 14.8% of women with a miscarriage or termination of pregnancy had one or more antibiotic treatments during pregnancy. Systemic antibacterial drugs were the most frequently used drug group, with filled prescriptions for 33.4% of all deliveries and 12.6% of all abortions. This proportion increased from 28.4% in 2000 to 37.0% in 2010 among deliveries. The biggest change was seen for pivmecillinam, which increased among deliveries from 6.3% in 2000 to 19.5% in 2010. Obese (odds ratio 1.51; 95% CI 1.47-1.56), young (odds ratio 1.35; 95% CI 1.30-1.39), and low-educated women (odds ratio 1.37; 95% CI 1.35-1.1.39) tended to fill more prescriptions of antibiotics during pregnancy. CONCLUSIONS: Overall, the number of women who filled prescriptions of antibiotics increased during the 11-year study period. In 2010, at least 41.5% of all deliveries were exposed to antibiotic therapy during pregnancy.

Optimizing clozapine treatment.

OBJECTIVE: Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed. METHOD: Studies of clozapine available in MEDLINE were reviewed. RESULTS: A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine. CONCLUSION: Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h⁻¹ (range 176-726 l h⁻¹). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).

Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain.

Tramadol is O-demethylated to the active metabolite (+)-O-desmethyltramadol ((+)-M1) via CYP2D6, an enzyme that is weakly inhibited by escitalopram. We investigated the possibility of a pharmacokinetic (PK) and pharmacodynamic (PD) effect of escitalopram on tramadol metabolism. Fifteen healthy subjects completed this randomized, double-blind, three-phase, crossover trial. Combinations of escitalopram 20 mg/day or placebo together with tramadol 150 mg or placebo were used. Blood samples for pharmacokinetics were drawn at 0-24 h after medication. The analgesic effect of (+)-M was assessed by the cold pressor test (CPT) (area under effect curve, 1-12 h after medication (AUEC(1-12))). The median area under plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) of (+)-M1 was 2.75 micromol/l.h after placebo pretreatment compared with 1.95 micromol/l.h after escitalopram (P = 0.0027). The mean AUEC(1-12) of CPT were 4,140 and 4,388 cm.s after placebo and escitalopram, respectively (P = 0.71). Although escitalopram is a weak inhibitor of CYP2D6, it does not impair the analgesic effect of tramadol.

Impact of CYP2C19 phenotypes on escitalopram metabolism and an evaluation of pupillometry as a serotonergic biomarker.

PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype groups. CONCLUSIONS: The CYP2C19 polymorphism affects escitalopram metabolism, but the difference does not justify dose adjustment. The puzzling results from pupillometry can be due to interplay between a central and a local serotonergic effect. Based on these results, pupillometry can not be recommended as a serotonergic biomarker.

Problem-oriented drug information: physicians' expectations and impact on clinical practice.

PURPOSE: Problem-oriented drug information (POD) is a service in which health professionals provide evidence-based answers to clinical questions posed by physicians. The objective of this study was to evaluate the user satisfaction and clinical impact of POD, to investigate predictors for use and to examine the kind of sources physicians search before applying for POD. METHODS: To evaluate POD, a questionnaire was distributed with problem-oriented answers sent from a drug information centre to physicians during the period of April 2006 to March 2007. RESULTS: Of 197 questionnaires, 183 (93%) were returned. The information from the POD service was highly valued by the physicians, and 90% of the answers led to reported impact on clinical practice in the specific clinical situation. Furthermore, 74% of the answers were intended to be used in a wider context either for future patients (67%) or for dissemination to colleagues (51%). Secondary-care physicians more often than general practitioners (GPs) used the information for dissemination to colleagues (63 vs. 39%, P = 0.0008), while GPs more often used the answer to support patient information (88 vs. 70%, P = 0.0029). The most prominent motive for applying for POD was a request for evidence-based information (78%), and the service was used to overcome barriers to practicing evidence-based medicine such as lack of time (36%), skills for searching (26%), and appraising the literature (13%). Before inquiring, 74% of the physicians had tried other information sources; the most frequent sources used were a drug reference (68%) and consulting a colleague (24%). Secondary-care physicians reported fewer barriers than GPs when seeking information, and secondary-care physicians searched other sources more often than GPs before contacting the service (81 vs. 67%, P = 0.031). CONCLUSION: POD represents a useful source for acquiring evidence-based drug information by physicians. POD is highly valued by the users. It was reported to have an impact on clinical practice for the specific patient but is also intended to be used in a wider context for future patients or for dissemination to colleagues. GPs' and secondary-care physicians' use of POD differs with GPs having more focus on patient information and secondary-care physicians having more focus on dissemination of the information to colleagues.