Concomitant Use Of Phenytoin Research Articles

Association Between Use of Pharmacokinetic-Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case-Control Study.

Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition/induction effect on P‐gp/CYP3A might increase risk of bleeding/treatment failure, respectively. We designed a nested case‐control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow‐up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient‐years of follow‐up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P‐gp/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran‐verapamil, rivaroxaban‐verapamil, and rivaroxaban‐amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13–4.60), 2.18 (1.07–4.40), and 1.68 (1.14–2.49), respectively. There were 1,116 events of stroke/SE, in 79,302 DOAC‐treated patients with AF and 118,124 patient‐years of follow‐up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke/SE: adjusted OR 2.18 (1.55–3.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.

Changing incidence of hyperammonemia in Japan from 2006 to 2013: expansion of new antiepileptic drugs reduces the risk of hyperammonemia.

The purpose of the present study was to examine the relationship between the incidence of hyperammonemia and changes in the prescribing of concomitant antiepileptic drugs (AEDs) in patients receiving valproic acid. We evaluated 40,363 plasma samples from 6009 epilepsy patients obtained from 2006 to 2013. Hyperammonemia was defined as a plasma ammonia level exceeding 100μg/dL. In 2006, 32.6% of the plasma samples were from patients with concomitant use of phenytoin but this decreased to 16.0% in 2013. Lamotrigine and levetiracetam were approved in 2008 and 2010, respectively, and were prescribed for patients who provided 27.8 and 14.9% of the plasma samples in 2013. The incidence rate of hyperammonemia (per 100 person years) decreased markedly from 40.8(95% confidence interval (CI), 37.7-43.9) in 2006 to 14.2 (95% CI, 12.5-15.9) in 2013. In any year reviewed, concomitant use of phenytoin, phenobarbital, carbamazepine, or carbonic anhydrase inhibitors was a risk factor for hyperammonemia. Among enzyme-inducing AEDs, concomitant use of phenytoin was associated with the highest risk of hyperammonemia. Drug interactions caused by enzyme-inducing AEDs, especially phenytoin, are closely related to the development of hyperammonemia. This study demonstrated that introduction of new AEDs changed the co-prescribing pattern in patients receiving valproic acid, resulting in a marked decrease of hyperammonemia. Although their higher cost may be problematic, new AEDs are beneficial for reducing the risk of drug interactions.

Risk factors for hyperammonemia in pediatric patients with epilepsy

To identify risk factors for hyperammonemia in pediatric patients with epilepsy. A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dl with reference to the standard range and previous reports. The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 μg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide. A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia.

Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients

Hyperammonemia is one of the side effects of treatment with valproic acid (VPA), but the risk factors and mechanisms involved remain obscure. This study analyzed the risk factors for hyperammonemia associated with VPA therapy in adult epilepsy patients. A retrospective analysis of 2724 Japanese patients (1217 males and 1507 females aged from 16 to 76years) treated with VPA between January 2006 and December 2010 were analyzed. The ammonia level increased markedly in a VPA dose-dependent manner, and was significantly elevated in patients who also used hepatic enzyme inducers such as phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ), and combinations of these drugs. When a blood ammonia level exceeding 200μg/dl was defined as hyperammonemia, the risk factors for hyperammonemia according to multiple regression analysis were a VPA dose >20mg/kg/day (odds ratio (OR): 4.1; 95% confidence interval (CI): 1.6-10.8) and concomitant use of PHT (OR: 11.0; 95% CI: 3.1-38.7), concomitant PB (OR: 4.3; 95% CI: 1.0-17.9), concomitant CBZ (OR: 2.8; 95% CI: 0.6-11.9), and concomitant topiramate (OR: 2.8; 95% CI: 1.2-6.5). Regimens containing multiple inducers were associated with an increased risk of hyperammonemia. Identification of risk factors for hyperammonemia associated with VPA therapy can help to minimize side effects during its clinical use.

The first case of phenytoin intoxication associated with the concomitant use of phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium

We reported the first case of phenytoin intoxication due to the concomitant use of phenytoin and TS-1, together with a review of the literature regarding the occurrence of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs such as fluorouracil (5-FU) and tegafur (FT). We showed the clinical course of our patient. Reports of phenytoin intoxication due to the concomitant use of phenytoin and fluoropyrimidine antitumor drugs in the English and Japanese language literature up to 2007 were identified by searching Medline and ICHUSHI Web (Japana Centra Revuo Medicina). A patient taking phenytoin and TS-1, a combination preparation of tegafur, gimeracil, and oteracil potassium, experienced lightheadedness and repeated falls associated with an increase in serum phenytoin concentration (32.8 mug/ml) at 1 month after the start of TS-1 treatment. The time lag between initiation of combined treatment and onset of adverse symptoms suggests the presence of an indirect mechanism, rather than direct inhibition of drug-metabolizing enzymes by drugs in TS-1 or their active metabolites. Plasma phenytoin concentration should be closely monitored in patients receiving TS-1 and phenytoin concomitantly.

A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC)

15527 Background: ACC is a rare malignancy with a very poor prognosis. Surgery is the only potential curative option. Gefitinib is an oral EGFR inhibitor that may have activity in solid tumors that express EGFR. ACC over expresses EGFR in a high proportion of cases. Methods: From April 2004 through December 2006, the ACC Working Group conducted a phase II trial of Gefitinib as second line, monotherapy in patients with pathologically confirmed unresectable ACC who had progressed on mitotane or chemotherapy. All prior systemic therapy was discontinued 28 days prior to starting gefitinib. Patients were ineligible if: had received prior therapy with any EGFR inhibitor, pregnant or breast feeding, had other co-existing malignancies (other than basal cell carcinoma or cervical cancer in situ), had an ECOG PS > 2, absolute neutrophil counts < 1,500, or platelets < 20,000. Patients were not allowed concomitant use of phenytoin, carbamazepine, rifampicin, barbiturates, or St John’s Wort. Patients took gefitinib 250 mg orally once a day. Each cycle was 21 days with radiological assessment every 6 weeks.Response rate as determined by RECIST criteria was the primary endpoint. Results: 19 patients accrued to the study (18 with measurable disease and 1 without). Pt Characteristics: Female 79% (15/19); Median age 48 (range 26–74); 84% (12 female and 4 male =15/19) of the patients had steroid secreting tumors. Grade 3 toxicity was noted in 2 patients and included, hypertension and lower extremity edema and elevated liver transaminases. No grade 4 toxicities occurred. Of 19 patients evaluable, there were no complete responders, partial responders or patients with stable disease (0% response rate; 95% CI: 0%-18%). Conclusions: Gefitinib demonstrated no activity in patients with unresectable ACC. This study is now closed. This study demonstrated the ability to successfully accrue to a trial of novel agents in rare tumors in a multicenter setting. [Table: see text]

Neuropsychology/Language/Behavior: All Ages

Neuropsychology/Language/Behavior: All Ages

Drug Therapy in the Heart Transplant Recipient

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. With improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs.1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug–drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug–drug interactions and guidelines for avoiding these interactions. The risk for drug–drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors.2 Patient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism.2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess >40% homology, they are grouped together into families designated by an Arabic numeral (eg, the …

A Complex Interaction between Clozapine and Phenytoin

Objective: As of July 9, 2004, to report the first case of potential pharmacodynamic and pharmacokinetic interactions between clozapine and phenytoin occurring simultaneously in a patient. Case Summary: A 60-year-old African American female treated with clozapine and phenytoin developed neutropenia after the clozapine dose was increased from 650 to 900 mg/day. The neutropenia resolved after phenytoin was discontinued, and the clozapine dose was decreased from 900 to 300 mg/day without any significant change in clozapine levels. Discussion: Neutropenia can be explained on the basis of a potential pharmacodynamic interaction between clozapine and phenytoin. However, neutropenia did not occur until the clozapine dose was increased from 650 to 900 mg/day, corresponding to an increase in clozapine levels from 90 to 114 ng/mL. Neutropenia resolved after phenytoin was discontinued, even though the clozapine concentrations achieved after phenytoin discontinuation (137 ng/mL) were almost the same as those when phenytoin was coadministered (114 ng/mL). This finding suggests that neutropenia was precipitated not only by an increase in the clozapine dose, but also by the concomitant use of phenytoin. On the other hand, the decrease in clozapine concentrations can be explained on the basis of a pharmacokinetic interaction between clozapine and phenytoin. Phenytoin has the potential to decrease clozapine concentrations by inducing the activity of CYP1A2, which provides a primary metabolic pathway for clozapine. Conclusions: Concomitant use of phenytoin may not only decrease clozapine concentrations and compromise its efficacy, but can also precipitate neutropenia. Although based on a single case report, these findings warrant caution when coadministering clozapine and phenytoin.

Thrombolytic therapy of a left-sided prosthetic valve thrombosis without hemodynamic obstruction: A case report

We report a case of a 38-year-old woman with a prosthetic mitral valve who presented with multiple embolic events. Transesophageal echocardiography was used to diagnose nonobstructive thrombi on the prosthetic valve. She underwent successful thrombolytic therapy. The patient was discovered to be in a hypercoagulable state, which probably was caused by the concomitant use of phenytoin. We review the literature for diagnosis and treatment of nonobstructive prosthetic valve thrombosis. (J Am Soc Echocardiogr 2001;14:1230-4.)

免疫抑制薬の中枢毒性モニタリング

Cyclosporine-or tacrolimus-induced neurotoxicity was retrospectively evaluated in five patients. Symptoms ranging from mild (tremor, insomnia, visual disturbance) to severe events (convulsion, leukoencephalopathy) were observed. The predisposing risk factors in these patients included hypomagnesemia, liver dysfunction and transient high blood concentrations of the immunosuppressants. Besed on our findings as well as those from other reports, the initial signs and symptoms of immunosuppressant-induced neurotoxicity were as follows ; tremor, headache, anorexia, nausea, vomiting, lethargy, insomnia, anxiety, amnesia, visual disturbance. However, not all of these events correlated with the blood concentrations of the immunosuppressants. The blood cyclosporine concentrations decreased by concomitant use of phenytoin. The blood tacrolimus concentrations varied markedly during the two-week-period after liver transplantation. To prevent patientsfrom developing serious events under immunosuppressant therapy, pharmacists should thus recognize the predisposing risk factors in patients, and carefully monitor the initial signs related to neurotoxicity and the blood concentrations of the patients receiving immunosuppressants.

Emergence of Motor and Vocal Tics During Imipramine Administration in Two Children

ABSTRACT Two children with major depression experienced the emergence of motor and vocal tics after 2-3 weeks on imipramine at doses of 75-100 mg daily. The tics did not show any sign of subsiding for 9-10 days following the discontinuation of imipramine, but subsequently responded to treatment with haloperidol. Case 1 involved an 8-year-old child with depression, attention-deficit hyperactivity disorder (ADHD), other behavioral problems, and a history of a single febrile seizure. His family history was positive for tics, depression, anxiety, and seizures. He was found to have a toxic plasma level of the tricyclic antidepressant. Case 2 involved a 13-year-old child with depression, ADHD, behavioral problems, obsessive compulsive symptoms, intellectual deficit, developmental delays, grand mal seizures, and concomitant use of phenytoin. The child had previously developed tics while receiving methylphenidate. The family history was positive for tics, depression, obsessive compulsive symptoms, suicide, and alcohol abuse. The child had a subtherapeutic plasma level of the antidepressant. It is suggested that tricyclic antidepressants may precipitate tics consistent with the symptoms of Tourette's syndrome in genetically vulnerable children. Although this possibility has been suggested in the literature, these are the first two documented cases of this phenomenon. Speculating from these two cases, ADHD may be a risk factor for the appearance of imipramine-induced tic symptoms in depressed children.