Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives

BackgroundEnzyme-inducing antibacterial drugs can impair the efficacy of hormonal contraceptives. Suspicion that other antibiotics might do likewise led to advice that extra contraceptive precautions should be taken during a course of antibiotics. However, current advice is that the purported interaction does not occur, based on small studies observing few pregnancies, assuming that all women are susceptible, and without measuring unbound hormone concentrations.ObjectiveTo test the null hypothesis that antibiotics do not impair the effectiveness of oral contraceptives.DesignA database review of Yellow Card reports to the UK’s Medicines and Healthcare products Regulatory Agency.DataSpontaneous reports of suspected adverse drug reactions in people taking antibacterial drugs (n=74 623), enzyme-inducing medicines (n=32 872), or control medicines (n=65 578).Main outcome measuresReports of the primary outcome—unintended pregnancies; reports of cardiac arrhythmias and headaches (control events); reports of congenital abnormalities (positive control events); and reports of diarrhoea (a possible confounding factor).ResultsCompared with control medicines, unintended pregnancies were seven times more commonly reported with antibiotics and 13 times more commonly reported with enzyme inducers (the positive controls). Congenital abnormalities were reported seven times more often with enzyme inducers but were not more common with antibiotics. Diarrhoea was not a confounding factor.ConclusionThis study provides a signal that antibacterial drugs may reduce the efficacy of hormonal contraceptives. Women taking hormonal contraceptives should be warned that antibiotics may impair their effectiveness. Extra precautions can be taken during a course of antibiotics; an unintended pregnancy is a life-changing event.

Oral Anticancer Therapy: Management of Drug Interactions

Oral anticancer therapy is increasingly integrated into the care of patients with cancer. Recognition and management of drug-drug interactions (DDIs) is critical to providing efficacious and safe anticancer treatment. DDIs with QTc-prolonging agents, anticoagulants, enzyme inducers and inhibitors, antidepressants, and acid suppressants are commonly encountered with anticancer therapies. Here, we review frequently observed DDIs and outline literature-supported suggestions for their management.

Clozapine toxicity in a CYP2D6 poor metaboliser: Additive effects of haloperidol and valproate on clozapine metabolism

Objective: To illustrate the complexities of clozapine metabolism with the use of therapeutic drug monitoring. Methods: We describe a case of clozapine toxicity in a patient with schizophrenia treated with the combination of clozapine, valproate and haloperidol. Results: A 24-year-old CYP2D6 poor metaboliser developed clozapine toxicity corresponding to the additive effects of haloperidol, and increasing clozapine and valproate doses. Saturation of metabolism, evidenced by a high clozapine/norclozapine ratio, was present at this time. Conclusions: Clozapine metabolism is complex and influenced by multiple factors, including interactions with hepatic P450 enzyme inducers/inhibitors, genetic polymorphisms and the potential for saturation of the N-demethylation metabolic pathway.

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust

Background: The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. Methods: All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. Results: During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5–800 mg) and the mean plasma level 5.9 mg/l (range 0.8–18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug ( n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [ n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug ( n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [ n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one ( p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any ( p = 0.574). Conclusions: Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

New hybrid bromopyridine-chalcones as in vivo phase II enzyme inducers: potential chemopreventive agents

We report the synthesis of eighteen new potential cancer chemopreventive agents, structurally designed to combine (naphtho)chalcone and (bromo)pyridine skeletons.