Hence, it is possible that the chemotherapy was of a type that stimulated immune response (against the cancer) or that the chemotherapy was of a type that does not involve immune response, such as paclitaxel or cisplatin. In addition to choices from the perspective of the individual patient and physician, it may be important to take a broader view. Limitations of Pre-Approval Clinical Trials • Trial population ... • Other serious medical conditions • Use of concomitant medications ... • Case definition included AV block within one As prescription medication, over-the-counter drug, and supplement use by the general population continues to increase, the potential impact of con-meds on the validity of clinical trial data is becoming more apparent. With sponsors facing tremendous financial pressures to run their trials on-time and on-budget, we need to recognize the importance of concomitant medications in meeting patient enrollment timelines. The actions of hydroxylated tricyclic metabolites are however complex and difficult to study, especially for the tertiary amines. Demethylation of the side-chain converts tertiary compounds to secondary amines, and these to primary amines. Minimisation of unwanted effects. clinical studies. If a patient is taking a medication PRN, do not use a separate line for each time the medication is taken, instead report the first and last dates taken. For instance, some clinical trial protocols require the use of medicinal products such as concomitant or rescue/escape medication for preventive, diagnostic or therapeutic reasons and/or to ensure that adequate medical care in infections, hypertension and in cancer, when several drugs are given separately. Protriptyline (withdrawn in the UK), with t1/2 values in the region of 75–80 hours, is exceptional and, with daily dosing regimes, accumulation is possible. As such practices vary across sites, study teams are often left with inconsistent con-med data, making it difficult and time-consuming to analyze. Other common drugs that diminish theophylline clearance include the macrolide antibiotics (e.g., erythromycin or clarithromycin) and the quinolone antibiotics (e.g., ciprofloxacin or norfloxacin). 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. As outlined in preamble 54 concomitant medications is unrelated to the clinical trial and not relevant for the design of the clinical trial. In general, the data suggest that physicians should be cautious in using NSAIDs in patients with known cardiovascular disease. Pentazocine Low doses of the mixed agonist–antagonist pentazocine produce euphoria, sedation, impotence, and anhidrosis; higher doses cause headache, nausea, blurred vision, diplopia, tachycardia, hypertension, urinary retention, depressed respiration, dysphoria, delusions, hallucinations, and seizures.5 Subcutaneous or intramuscular injections of pentazocine cause severe focal skin and muscle fibrosis, the result of precipitation of the acidic drug.25. Consequently, the cost of NSAIDs as a proportion of total drug costs can be high when drugs are expensive. In contrast, azathioprine and mycophenolic acid (MPA), the active metabolite of mycophenolic mofetil (MMF), or enteric-coated mycophenolate sodium (EC-MPS), are not associated with an adverse effect on lipid profile in transplant recipients.59 The incidence of hypercholesterolemia is significantly higher in patients treated with cyclosporine and prednisolone versus cyclosporine and MMF,60 and converting renal transplant recipients from cyclosporine/azathioprine to MMF leads to an improvement in levels of total cholesterol and triglycerides.61, David Cunningham Owens, in Companion to Psychiatric Studies (Eighth Edition), 2010. Oxcarbazepine does not modify the anticoagulant activity of warfarin [57]. Concomitant medications (a.k.a., con-meds) are other prescription medications, over-the-counter (OTC) drugs or dietary supplements that a study participant takes in addition to the drug under investigation. In a retrospective study, in which 376 samples from 222 patients were analysed, oxcarbazepine induced the metabolism of lamotrigine and reduced lamotrigine concentrations by about 29% [62]. Absence of anti-inflammatory activity reduces the effectiveness of acetaminophen for diseases accompanied by a significant component of inflammation (e.g., RA and gout). Statin (or placebo) is the drug of interest in the study. Sujay started as employee #6 and was instrumental in the growth of Model N to 600 employees, over $100M in revenue, and its eventual IPO (NYSE: MODN). Amoxapine, with an average half-life in the region of 8 hours, may be better suited to split-dosing. fit this definition of a clinical trial. No dosage adjustment of EPCLUSA is required for patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C) … hepatic laboratory monitoring (including direct bilirubin) … is recommended for patients with decompensated cirrhosis receiving treatment with EPCLUSA.88, The relatedness analysis attributed the AEs to concomitant drugs (chemotherapy). Concomitant medications are used by nearly 100% of subjects involved in Phase 1 cancer clinical trials, for example, but the topic of con-meds is not given much attention in medical literature. Part of the resistance to tracking con-meds may simply be lack of technology adoption. Purpose. 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. This is essential to avoid adverse reactions between two drugs that are known to exist. The aim of this paper is to give an answer to the question: how to capture and encode concomitant therapies and medications in order to keep clinical trial data clean, complete and consistent. In well conducted clinical trials with an investigational pharmacist on staff, it should be uncommon for a patient to be excluded from a clinical trial due to concomitant medication use. Combining isoniazid with rifampicin (Rifinah, Rimactazid) ensures that single-drug treatment cannot occur; treatment has to be two drugs or no drug at all. The drug being evaluated in the trial; this definition is synonymous with “investigational new drug” or “investigational medicinal product.” Medication number A unique number on the label of each investigational drug package that is used in a trial to dispense and track medication. It is also notable that among drug classes, one member may inhibit clearance while others do not; for example, cimetidine, a histamine-2 (H2) antagonist, is a potent inhibitor of theophylline metabolism. Collecting concomitant medications taken during a study is also important for safety reasons. Behavioral clinical trials involving an intervention to modify behavior (diet, physical activity, cognitive therapy, etc.) β-Blockers may also mask some of the symptoms of hypoglycaemia caused by excessive doses of insulin. In order to avoid con-meds negatively impacting patient enrollment due to medication-related exclusion criteria, it is important for clinical trials to have an investigational pharmacist on hand to conduct a review of patient medications for potential investigational drug and concomitant medication interactions. This refers to combinations of drugs in a single pharmaceutical formulation. However, the same authors observed that addition of statin therapy to the cyclosporine regimen was a more efficient way to manage dyslipidemia.51. The reality is that almost every person participating in a clinical research study uses some form of concomitant medication, whether it be a multi-vitamin, dietary supplement, or common OTC medications used to treat pain or allergies. Immunosuppressive agents and, Companion to Psychiatric Studies (Eighth Edition). Intermittent dosing rather than continuous daily use reduces toxicity. Concomitant medications can be recorded in many different ways ranging from trade (brand) name to nonproprietary names. trials. As with antipsychotics, at therapeutic levels clearance is flow-dependent and decreased by hepatic disease or states that impede hepatic throughput. The protocol-defined period may be based on the elimination half-life of antimalarials that are locally available. The major metabolic steps involve hydroxylation of the ring structures and demethylation of the terminal nitrogen (Baldessarini 1985). Con-meds may be tracked as both a history item, as well as, during the study. Note that the study drug (certolizumab) dampens immune response. Patients who are selected for clinical trial participation may be more engaged in care, compliant, motivated or health-seeking, thereby also more likely to initiate and remain on a concomitant medication. Acute ingestion to intoxication in non-dependent individuals impairs metabolism by competition resulting in a two- to three-fold increase in the amount of unaltered drug reaching the systemic circulation. 76% of patients in a study of the pharmacokinetics of escitalopram, a drug used for treatment of major depression, were taking additional medications. Overall, however, half-lives are compatible with once daily dosing and steady state within 5–7 days. Phase 0 trials are the first clinical trials done among people. Such agents include phenobarbital, phenytoin, carbamazepine, and tobacco smoke. This finding was magnified in patients with more severe disease at baseline.148, Acetaminophen can be tried as the initial therapy in patients with mild to moderate pain for reasons of safety and cost. A case–control study found that heroin use, both past and present, was a risk factor for new onset seizures independent of overdose, head trauma, infection, ethanol, or other illicit drugs, and in none of the patients studied did a seizure occur in the setting of overdose.23. Con-meds may be used by study subjects for the same indication as the study or for other indications. They aim to learn how a drug is processed in the body and how it affects the body. There is evidence that with administration of secondary amine compounds, some 15% of patients develop detectable levels of tertiary drug in plasma, e.g. Oxcarbazepine metabolism is unaffected by several inhibitors of carbamazepine metabolism. The future of con-meds in clinical trials. The rate of absorption, and hence time to peak levels, is more rapid for tertiary amines (approximately 1–3 hours) than for secondary amines (approximately 4–8 hours) (Preskorn 1993). Hence, there is a point where a thorough concomitant medication analysis is absolutely appropriate and may ultimately act as a supporting piece of evidence. The requirements for recording concomitant medications should be specified in the study protocol. Theophylline is a drug whose metabolism is highly subject to alteration by concomitant drug use. Furthermore, patient preference for factors such as dosing regimen may be taken into account. Choosing anti-inflammatory analgesic therapy has become increasingly complex with the increased understanding of associated toxicities. The kidney is the major route for elimination of tricyclics and the most important source of alteration in pharmacokinetic parameters by age, illness or other incidental factors (Rudorfer & Potter 1987). The main purpose of clinical medication reviews targeting clinical trial participants is to identify prohibited or excluded concomitant medications and the potential for DDIs with use of investigational drugs; however, all medication-related issues should be addressed, including DDI threats within the patient’s current medication list, adverse effects, medication adherence, and effectiveness. In these trials, a very small dose of a drug is given to about 10 to 15 people. Oxcarbazepine is a weaker enzyme inducer than carbamazepine. clinical trials. In the eplerenone label … increases of ALT greater than 120 U/L and bilirubin greater than 1.2 mg/dL were reported 1/2259 patients administered eplerenone tablets and 0/351 placebo-treated patients.”86, The adjudication committee provided a strategy for assessing relatedness, for the situation where relatedness was confounded and unclear, “the … adjudication committee determined a more meaningful approach would be to categorize subjects as those for whom DILI could be excluded, those for whom DILI could not be excluded, and those with insufficient data to make a determination.”87. This is important for, not only reducing the overall cost of healthcare, but speeding the delivery and quality of life-saving therapies to patients. A growing list of drugs, when prescribed with theophylline, can result in either increased or decreased clearance. We use cookies to help provide and enhance our service and tailor content and ads. Tricyclic antidepressants are all well absorbed from the gastrointestinal tract, a process not prone to interference by, for example, concomitant drug administration. Concomitant medication (in parlance, con meds) collection is mandated by GCP for clinical trials. Few studies have examined the impact of CM use on trial eligibility. Copyright © 2021 Elsevier B.V. or its licensors or contributors. However, conmeds are frequently unanalyzed. If I take both aspirin and my heart medication, then these two drugs are concomitant. Plasma protein binding for tricyclics is high (90–95%) as is their lipophilicity, accounting for large distribution volumes. However, acetaminophen is a safe and effective alternative for milder pain conditions, including osteoarthritis. 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. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. NIH-FDA Clinical Trial Protocol Template – v1.027 Aug 20178 6 1.3 SCHEDULE OF ACTIVITIES (SOA) u Procedures ng 14--1 1 ne 2 +/-ay 4 3 28 44 +/-ay Informed consent X Demographics X Medical history X Randomization X Concomitant medication review X X----- The Concomitant Medications module was one of the group of variables included in the third round of the CRF Harmonization and Standardization Initiative. Concomitant medication (CM) use may result in Phase I cancer clinical trial ineligibility due to concern for potential CM-investigational drug interactions or alteration of investigational drug absorption. The Use in Specific Populations section of the package label acknowledged that it was acceptable to administer the drug to patients with even severe hepatic impairment, but warned that where the patient has cirrhosis then monitoring hepatic laboratory values is needed: USE IN SPECIFIC POPULATIONS … Hepatic Impairment. The list of agents that decrease theophylline clearance is extensive (Box 65-2). Almost every reported concomitant medication has a reason – and many, if not all of these reasons should be reported as adverse events. CONCOMITANT MEDICATIONS LOG. Subject’s Initials/ Randomization #: Study Title: Medication Total Daily Dose (Freq. On the other hand, adverse events can have important economic consequences, and improved safety may be cost-effective. Concomitant medications are collected to evaluate potential interactions with the study medication in terms of safety and efficacy. Commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics and β-blockers, are associated with glucose intolerance and increased insulin resistance (Sowers, 1991). His career has also included strategy consulting at Booz Allen Hamilton, product strategy at CommerceOne, and general management roles at Singapore Telecom. On the other hand, chronic alcohol ingestion without compromised hepatic blood flow increases the magnitude of first-pass metabolism via enzyme induction. Immunosuppressive agents and concomitant drugs such as diuretics and βblockers can have a negative effect on the lipid profile, while impaired renal function with or without proteinuria can also contribute.14–17 Known risk factors for raised total cholesterol and low-density lipoprotein (LDL) cholesterol following transplantation include obesity, male gender, and ethnicity.18,19, The lipoprotein profile following renal transplantation is characterized by an increase in both total cholesterol and LDL cholesterol levels.20–24 An increase of around 25% to 30% in total cholesterol is typical.20,25 The peak incidence of hypercholesterolemia occurs 3 to 6 months post-transplant and remains stable at an elevated level from 12 months after transplantation.26–28 It is estimated that 60% of the renal transplant population has a total cholesterol level above 240 mg/dL (6.2 mmol/L) and LDL cholesterol level above 132 mg/dL (3.4 mmol/L).29 Changes in high-density lipoprotein (HDL) cholesterol after transplantation are more variable, with studies reporting unchanged, increased, or decreased levels.17,30,31 These differences may be partly due to variations in the dose of corticosteroids used in each trial. 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