Drug-related problems with special emphasis on drug : Drug interactions

The aim of this thesis was to address some aspects of drug related problems with special regard to drug-drug interactions. In paper 1 we aimed to describe the scenario and frequency of drug-related problems (DRPs) in in-patients and to determine whether a pharmacotherapeutic advisory intervention aiming at reducing DRPs could affect rates of re-hospitalisation and / or death within 6 months. A total of 299 DRPs among 71% (106/150) of the patients were found, who had not previously been identified in the usual care. Thirty-five per cent (106/299) of DRPs in 39% (58/150) of the patients were judged to be of such importance that advice was given to the physician in charge. The proportion of re-hospitalisation and death in the intervention group was 49% (73/150) compared to 46% (69/150) in the control group (Risk ratio: 1.06, 95% confidence interval: 0.84 to 1.32, P=0.64). In conclusion, drug-related problems were common. The impact of drug-related problems on hard endpoints such as re-hospitalisation and death may however be overestimated. It is of importance to clarify if and in what way drug-related problems are preventable. The purpose in paper II was to evaluate the clinical relevance of the Janus Web application in screening for potential drug-drug interactions. One hundred and fifty DDIs, regarding 58 different interaction pairs, were classified as significant. 126 interactions that were significant by definition did not result in advice. A look at the alerts which featured most frequently in such combinations illustrates the nature of this discrepancy. With the aim to develope a drug-drug interaction software with the goal of achieving and maintaining a general use on a routine basis, it is of great importance that the alerts are clinically relevant. Equally important may be to present the warnings in an adequate way to give the prescribing physician a balanced picture of the problem and thereby avoid alert fatigue . In paper III we evaluated if steady-state plasma levels of risperidone or the corresponding active moiety differed between patients exposed to 1 or several drugs defined as either substrates or inhibitors of the hepatic cytochrome P450 enzyme 2D6 (CYP2D6). The median concentration-to-dose (C/D) ratio of risperidone in patients with 0, 1 or >1 was 2.6, 8.5, and 17 nmol/L/mg, respectively (p<0.001). All of the medication lists in the 7 patients with >1 inhibitor of CYP2D6, included fluoxetine, paroxetine, thioridazine and/or levomepromazine, i.e. drugs known as potent inhibitors of CYP2D6. The active moiety (risperidone + 9-OH-risperidone), in patients with different numbers of concomitant CYP2D6 inhibitors was 17, 24 and 30 nmol/L/mg, respectively (p<0.01). We concluded that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should consequently include concomitant medication with established CYP inhibitors. In paper IV we used the Swedish prescribed drug register to determine whether doctors are taking potential drug-drug interactions (DDIs) for serotonin reuptake inhibitors into account in the prescribing decision. The use of CYP2D6-drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRI (paroxetine, fluoxetine) or SSRI that do not block CYP2D6 (citalopram, escitalopram, sertraline) was analysed, and related to the use of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Compared with patients who where dispensed citalopram/sertraline, patients dispensed fluoxetine/paroxetine faced a reduced risk of receiving metoprolol (adjusted odds ratio, 0.80; 95% CI, 0.76 to 0.85), donepezil (0.65; 0.49 to 0.86) and galantamine (0.58; 0.41 to 0.81). In contrast, the risk of receiving the prodrugs codeine (instead of propoxyphene) or tamoxifen (instead of anastrozole) was similar among patients on fluoxetine/paroxetine compared to citalopram /sertraline (adjusted odds ratios, 1.03; 95% CI, 0.94 to 1.12 and 1.29; 95% CI, 0.96 to 1.73 respectively). The results, suggest that drug-drug interactions (DDI) related to reduced bioactivation of pro-drugs may be more easily neglected in clinical practice, as compared to DDI that cause overt adverse drug reactions

Adherence to drug label recommendations for avoiding drug interactions causing statin-induced myopathy--a nationwide register study.

To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60-1.25 and 0.92; 95% CI 0.69-1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56-0.68 and low dose 0.63; CI 0.58-0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55-0.76 and low dose 0.70; CI 0.63-0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001).Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy

Adherence to guidelines for avoiding drug interactions associated with warfarin--a Nationwide Swedish Register Study.

PURPOSE: To investigate the extent to which clinicians avoid well-established drug-drug interactions associated with warfarin. We hypothesised that clinicians would avoid combining non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and sulfamethoxazole with warfarin. METHODS: A cross-sectional analysis of nationwide dispensing data was performed in Swedish individuals 18 years or older (n =  7,563,649). Odds ratios of interacting NSAIDs, tramadol and sulfamethoxazole versus respective prevalence of comparator drugs codeine, and ciprofloxacin in patients co-dispensed interacting warfarin versus patients unexposed was calculated. RESULTS: The odds of receiving an interacting NSAID versus the comparator codeine was markedly lower in patients with warfarin than in the remaining population (adjusted OR 0.21; 95% CI 0.20 - 0.22). Also, the interacting drugs tramadol and sulfamethoxazole were less common among patients dispensed warfarin as compared to the remaining population, although the decrease was much more modest (adjusted OR 0.83; CI 0.80-0.87 and 0.81; CI 0.73 - 0.90). CONCLUSIONS: In conclusion, Swedish doctors in the vast majority of cases refrain from prescribing NSAIDs to patients already on warfarin. Tramadol and sulfamethoxazole are however rarely avoided

Prevalence of potential drug-drug interactions in Swedish pediatric outpatients.

PurposeTo describe the occurrence of potential drug-drug interactions (DDIs) in prescribed drugs, dispensed to pediatric outpatients in Sweden.MethodsA cross sectional study was conducted based on data from a national register of prescribed drugs, dispensed at pharmacies, to children 0-17 years old. The study period was January 1 to April 30, 2010. Drug dispensing data was linked to the DDI database SFINX. Prevalence and frequencies of potential interactions were investigated, and drugs commonly involved in interactions were identified. The study focused on clinically relevant potential interactions, class D (should be avoided), and class C (can be handled, e.g. by dose adjustment).ResultsIn the Swedish pediatric population, 0 to 17 years of age, 12% (n = 231 078) of children had at least two dispensed drugs. In this group of patients, 0.14% had potential D-interactions and 1,3% had potential C-interactions. The number of D- and C-interactions that may lead to reduced effects were 181 (52%), and 1224 (32%) respectively. The ten most frequent drugs were involved in 78% and 65% of all potential D-, and C-interactions respectively. Furthermore, 80%, and 58% of the D-, and C-interactions respectively occurred in patients aged 12 to 17.ConclusionsWe identified a limited number of drugs that were represented in the majority of potential interactions. Interactions that can lead to a reduced treatment effect constituted approximately half of D-interactions, and a third of C-interactions. The frequency of potential interactions was higher in older children. The results may contribute to increased prescriber awareness of important potential drug interactions among pediatric outpatients

No impact of vitamin D on the CYP3A biomarker 4β-hydroxycholesterol in patients with abnormal glucose regulation.

PURPOSE:To investigate the effect of vitamin D3 on hepatic Cytochrome P450 enzyme (CYP) 3A4 in patients with abnormal glucose regulation using the endogenous marker 4β-hydroxycholesterol (4β-OHC):cholesterol ratio. METHODS:The present study took advantage of a trial primarily aiming to investigate the effect of vitamin D3 on beta cell function and insulin sensitivity in patients with abnormal glucose regulation. 44 subjects were randomized to receive vitamin D3, 30000 IU given orally once weekly or placebo for 8 weeks. The two sample t-test was used to test the means of the intra-individual differences of 4β-OHC:cholesterol ratio between the two groups. RESULTS:Mean (SD) 4β-OHC in the whole group of patients before and after the intervention was 26 (11) ng/ml and 26 (12). Mean (SD) 4β-OHC:cholesterol ratio in the whole group of patients before and after the intervention was 0.12 (0.046) and 0.13 (0.047). In the Vitamin D group mean (SD) serum 25-OH-vitamin D3 increased from 46 (16) to 85nM (13) during the corresponding time period. To investigate the impact of vitamin D3 on hepatic CYP3A4 we calculated the mean intra-individual differences in 4β-OHC:cholesterol ratio (delta 4β-OHC:cholesterol ratio) before versus after the intervention in the two treatment groups. The difference (95% CI) between delta 4β-OHC:cholesterol ratio in the control group and intervention group was -0.0010 (-0.0093, 0.0072), a difference being not statistically significant (p = 0.80). CONCLUSIONS:We provide further evidence that vitamin D3 may not substantially affect hepatic CYP3A4. This does not exclude the possibility of an impact of intestinal first-pass metabolism of orally administered drugs which should be investigated. TRIAL REGISTRATION:ClinicalTrials.gov NCT01497132

Rationale for the choice of study drugs.

1<p>The Swedish summary of product characteristics <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0069545#pone.0069545-FASS1" target="_blank">[35]</a>.</p>2<p>Anatomical Therapeutic Chemical code.</p>3<p>3-hydroxy-3-methylglutaryl-coenzyme A.</p>4<p>Cytochrome P450 enzyme (CYP) 3A4.</p>5<p>Cytochrome P450 enzyme (CYP) 2C9.</p

Associations between statins, in patients dispensed drugs with or without a pronounced inhibitory effect on their metabolism.

<p>Data are based on drug dispensing in individuals ≥18 years of age (n = 7 554 680), 15 August to 15 December, 2011.</p>1<p>High statin doses were defined as 40 mg or more for atorvastatin, fluvastatin, pravastatin.</p><p>and simvastatin and 20 mg or more for rosuvastatin.</p>2<p>Confidence Intervals.</p>3<p>Cytochrome P450 enzyme (CYP) 3A4.</p

Associations between statins, in patientś dispensed drugs with or without a pronounced inhibitory effect on their metabolism in primary care setting, specialist care setting, elderly individuals ≥65 years of age and in females under the study period 15 August to 15 December, 2011.

1<p>High statin doses were defined as 40 mg or more for atorvastatin, fluvastatin, pravastatin and simvastatin and 20 mg or more for rosuvastatin.</p>2<p>Estimates adjusted for gender and age.</p>3<p>Confidence Intervals.</p>4<p>Estimates adjusted for gender and medical setting.</p>5<p>Estimates adjusted for age and medical setting.</p>6<p>Cytochrome P450 enzyme (CYP) 3A4.</p

Prevalence of study drugs used in the adult Swedish population (≥18 years of age) and corresponding demographics, 15^th August to 15^th December, 2011.

1<p>Standard Deviation.</p>2<p>Defined as a seven-digit Anatomical Therapeutic Chemical (ATC) code. The remaining proportions were prescribed from a specialist care setting.</p>3<p>Mean dispensed Daily Defined Dose.</p>4<p>Cytochrome P450 enzyme (CYP) 3A4.</p>5<p>In addition to affect CYP3A4 erythromycin is a potent inhibitor of p-glycoprotein.</p>6<p>Non Applicable.</p

Patient flow chart.

<p>Patient flow chart.</p