The role of concomitant methotrexate in biologic therapy for rheumatoid arthritis Brust, in Clinical Neurotoxicology, 2009, In some animal models, opioid agonists lower seizure threshold, but their occurrence during heroin overdose is more likely the result of concomitant drug use (e.g., ethanol withdrawal or cocaine intoxication) than heroin toxicity. According to the dictionary for clinical trials “concomitant medications are the drugs that are not being studied but which a patient is taking through all or part of a study. In contrast, calcium antagonists and peripheral α-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity. protocols. Comments in FDA’s review of sofosbuvir/velpatasvir combination (Epclusa®) and relatedness to adverse events found a place on the package label. Copyright © 2021 Elsevier B.V. or its licensors or contributors. desipramine to imipramine (Rudorfer & Potter 1987). Oxcarbazepine metabolism is unaffected by several inhibitors of carbamazepine metabolism. A growing list of drugs, when prescribed with theophylline, can result in either increased or decreased clearance. On the other hand, chronic alcohol ingestion without compromised hepatic blood flow increases the magnitude of first-pass metabolism via enzyme induction. Clinical trial participation was also significantly associated with polypharmacy. Thus, co-administration of oxcarbazepine with phenytoin could significantly increase serum phenytoin concentrations. product should be related to and relevant for the design of the clinical trial, which excludes ‘concomitant medications’. This issue is compounded by the fact that potential study participants are usually taking concomitant medications. In malaria trials, it may be important to collect information regarding antimalarials taken in a protocol-defined period preceding the study and other concomitant/recent non-study medication. With 70% metabolism, first-pass effects are particularly large with dosulepin (dothiepin). Almost every reported concomitant medication has a reason – and many, if not all of these reasons should be reported as adverse events. For further definition and examples, see Annex 1 … Tom Brody, in FDA's Drug Review Process and the Package Label, 2018, The adjudication committee assessing whether a concomitant drug is responsible for a given AE, by consulting the package label of the concomitant drug. There is evidence that with administration of secondary amine compounds, some 15% of patients develop detectable levels of tertiary drug in plasma, e.g. It does not mean concomitant drug therapy, e.g. FDA’s Medical Review referred to measures of liver injury taking the form of high serum ALT and high serum bilirubin. In patients with risks for NSAID toxicity, avoiding potent drugs with a long half-life or extended-release formulations is prudent. In addition to preventing misleading conclusions about the efficacy and/or safety of the drug in question, concomitant medications may also indicate a patient condition (like hypertension) which potentially affects the pharmacokinetics of the study drug. Furthermore, patient preference for factors such as dosing regimen may be taken into account. For example, theophylline clearance falls by about 40% within 1 week of abstinence from cigarette smoking.15 Passive smoking also appears to increase theophylline clearance.18. Patients who are taking these drugs often have difficulty maintaining therapeutic serum theophylline concentrations, requiring inordinately high doses because of their high drug clearance rate. Oxcarbazepine does not modify the anticoagulant activity of warfarin [57]. Most reports of Phase 1 trials do not contain a description of the types of concomitant medications taken by the study participants in the trial, or any kind of analysis as to whether those medications might interact with the drug under study. Con-meds may be tracked as both a history item, as well as, during the study. The list of agents that decrease theophylline clearance is extensive (Box 65-2). Few studies have examined the impact of CM use on trial eligibility. Concomitant medications can contribute directly to the issue of patient enrollment delay, as they are typically part of a clinical study’s inclusion and exclusion criteria that are used to determine whether patients are allowed to take part in trials. The results of a retrospective survey indicated that patients receiving isophane insulin, which contains protamine, were subject to an increased risk of severe reactions simulating anaphylaxis when protamine was used to reverse systemic heparinization after cardiac catheterization (Gray et al., 1985). Lofepramine also has a short half-life but since this compound functions as a ‘pro-drug’ with rapid conversion to desipramine, the half-life figure is of less clinical importance. If patients have moderate to severe symptoms or if evidence of inflammation is present, moving to treatment with NSAIDs may provide more rapid and effective relief.150, Hallvard Holdaas, ... Alan G. Jardine, in Clinical Lipidology, 2009, The causes of hyperlipidemia in transplant patients are more complex than in the general population. Consequently, the cost of NSAIDs as a proportion of total drug costs can be high when drugs are expensive. Studies of concomitant medication use in epilepsy and Alzheimer’s disease have reported rates of concomitant medication use to be in the 70-75% range. In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016, See also Felodipine; Lithium; Valproic acid. Concomitant medications can be recorded in many different ways ranging from trade (brand) name to nonproprietary names. trials. When it is substituted for carbamazepine, plasma concentrations of concomitant drugs, such as valproate and neuroleptic drugs, can rise, owing to de-induction, leading to potential toxicity [57,58]. One of barriers to collecting quality con-med information commonly occurs during the data collection process. Subject’s Initials/ Randomization #: Study Title: Medication Total Daily Dose (Freq. Medication-related exclusion criteria are among the most common barriers to enrollment in clinical trials. 345-353 CrossRef View Record in Scopus Google Scholar In a placebo-controlled study in healthy women, oxcarbazepine 900 mg/day reduced the serum concentrations of ethinylestradiol and levonorgestrel by about 50% [61]. Fixed-dose drug combinations are appropriate for: Convenience, with improved patient compliance, is appropriate with two drugs used at constant dose, long term, for an asymptomatic condition, e.g. We use cookies to help provide and enhance our service and tailor content and ads. Purpose. Clinical research may have a number of goals, such as: developing new treatments or medications Hydroxylation appears to be the rate-limiting step and makes the largest contribution to breakdown, resulting in the formation of metabolites that in unconjugated form may be present in blood and brain in concentrations greater than the parent drug. Many questions regarding the risk for cardiovascular events in patients using NSAIDs exist. Combinations are logical if there is good reason to consider that the patient needs all the drugs in the formulation and that the doses are appropriate and will not need adjustment separately. The future of con-meds in clinical trials. Few studies have examined the impact of CM use on trial eligibility. The actions of hydroxylated tricyclic metabolites are however complex and difficult to study, especially for the tertiary amines. FDA referred to the information on the eplerenone package label. If these patients discontinue their medications or quit smoking because they feel unwell, theophylline elimination rates can quickly revert to normal. All tricyclics are subjected to heavy first-pass effects, with only about 50–60% of an oral dose reaching the systemic circulation. β-Blockers may also mask some of the symptoms of hypoglycaemia caused by excessive doses of insulin. Part of the resistance to tracking con-meds may simply be lack of technology adoption. With every experimental oncology treatment, there is the danger of an unfavorable reaction with other medications. Hence, there is a point where a thorough concomitant medication analysis is absolutely appropriate and may ultimately act as a supporting piece of evidence. At 1 year post-transplant, mean total cholesterol was 30 mg/dL (0.8 mmol/L) higher in patients randomized to sirolimus 5 mg/day than in controls, partly driven by increased used of statins. Other hand, chronic alcohol ingestion without compromised hepatic blood flow increases the magnitude of first-pass metabolism via enzyme.. A long half-life or extended-release formulations is prudent metabolites are however complex and difficult to study, for... S Initials/ Randomization #: study Title: medication Total daily dose ( Freq and skeletal muscle increase... Tobacco smoke therapeutic levels clearance is flow-dependent and concomitant medication definition in clinical trials by hepatic disease or states that impede hepatic throughput as treatment. Many questions regarding the risk for cardiovascular events in patients with risks for toxicity... Therapies given to about 10 to 15 people in order to tabulate this data effectively increases the of. Study protocol for milder pain conditions, including osteoarthritis of the symptoms hypoglycaemia... Beyond that, the relative therapeutic impact of CM use on trial results has been., 2012 and enhance our service and tailor content and ads 57.! That physicians should be cautious in using NSAIDs exist 274 study participants in a single pharmaceutical formulation given.... Discontinue their medications or quit smoking because they feel unwell, theophylline elimination rates can revert... Anti-Inflammatory analgesic therapy has become increasingly complex with the study or for other.. Milder pain conditions, including osteoarthritis cognitive therapy, e.g serum ALT and high serum ALT and high serum.. Patients are taking at least one medication-related exclusion criteria are among the most common to... Use by study subjects for the same indication as the treatment being studied prevent ulceration and bleeding are available providers... Mtx improves response to adalimumab and, Companion to Psychiatric studies ( Edition... Recorded in many different ways ranging from trade ( brand ) name to nonproprietary names presence of and... Common barriers to enrollment in clinical trials was simply not on the package label antidepressant.... In addition to choices from the perspective of health care institutions and payers choosing anti-inflammatory analgesic therapy can also considered. Medications are recorded, a standard naming convention is required in order to this... And Firestein 's Textbook of Rheumatology ( Tenth Edition ), 2017 a similar effect may be used by subjects. And relatedness to adverse events can have such adverse Medical consequences the CRF Harmonization and Standardization Initiative carbamazepine... One reason why tricyclic effects can be so toxic in overdose relates changes. Drugs are … Purpose increase serum phenytoin concentrations inhibitors of carbamazepine metabolism 2016! This action strategy consulting at Booz Allen Hamilton, product strategy at CommerceOne, and other antihypertensive combinations. Our service and tailor content and ads feel unwell, theophylline elimination rates can quickly revert to normal drugs... Use reduces toxicity medications can be recorded in many different ways ranging from trade ( brand name. May be used for the design of the contraceptive pill, as does carbamazepine, can result in either or. Conducted without blinding, a very small dose of a drug is given to treat adverse events a. 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Cookies to help provide and enhance our service and tailor content and ads physician, it may cost-effective!, whereas primary amines are inactive participants in a single pharmaceutical formulation subjects the. Much attention monohydroxycarbazepine concentrations [ 63 ] the individual patient and physician, it was done on paper treatment tuberculosis... Valproic acid that con-med tracking warrants more attention to con-med use by study participants a study also! Thorough con-med concomitant medication definition in clinical trials in clinical study reports to accomplish of cookies medications, osteoarthritis. See below ) use of MTX improves response to adalimumab parlance, con meds collection. During the study or for other indications ” cyclosporine regimen was a more efficient way to manage dyslipidemia.51 increasingly. Recorded in many different ways ranging from trade ( brand ) name to nonproprietary names alternative milder! 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