Drug Interaction Probability Scale Research Articles

Significant Bleeding in Elderly Patient with Atrial Fibrillation Due to Probable Interaction between Dabigatran and Amiodarone

Objective: To present the case of an elderly patient who developed significant bleeding while receiving a standard dose of dabigatran with concomitant amiodarone therapy. Case Summary: A 77-year-old man was admitted for upper gastrointestinal bleeding that presented as coffee ground emesis. A coronary artery bypass graft had been performed 4 weeks earlier, which was well tolerated, except that his postoperative course was complicated by atrial fibrillation, for which amiodarone was initiated; dabigatran was added subsequently. Upon his admission to the hospital, dabigatran was stopped. The patient's bleeding was stabilized and dabigatran 150 mg twice daily was restarted after amiodarone was discontinued. The laboratory was not equipped to measure thrombin clotting time or ecarin clotting time; therefore, the team relied on the measurement of international normalized ratio (INR) and activated partial thromboplastin time to guide therapy based on pharmacokinetic and pharmacodynamic studies of therapeutic dabigatran concentrations. Based on laboratory values the following morning, the team maintained dabigatran 150 mg once daily. Subsequent INR and partial thromboplastin time values were within the desired range. He remained stable, without further evidence of bleeding even after anticoagulation with dabigatran was restarted for atrial fibrillation. Discussion: Dabigatran received FDA approval in October 2010 to reduce the risk of stroke and systemic embolization in patients with nonvalvular atrial fibrillation. It has a favorable monitoring profile compared to warfarin. The manufacturer acknowledges the potential for amiodarone to increase the effective concentration of dabigatran because of its inhibition of P-glycoprotein. An objective causality assessment using the Horn Drug Interaction Probability Scale revealed that the interaction was probable. Conclusions: A probable interaction suggests that providers should use caution with the coadministration of amiodarone with dabigatran; dose adjustment in the setting of concomitant administration in elderly patients with atrial fibrillation should be considered.

The combined use of edaravone, diuretics, and nonsteroidal anti-inflammatory drugs caused acute kidney injury in an elderly patient with chronic kidney disease.

The purpose of this study was to draw attention to the fact that the combined use of edaravone, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) may lead to acute kidney injury. This study was a case report of acute kidney injury resulting from the combined use of the aforementioned types of drugs. A 77-year-old male patient with chronic kidney disease (third stage) who was treated with a combination of edaravone, diuretics, and NSAIDs showed significantly increased blood urea nitrogen and creatinine. Interestingly, the blood urea nitrogen and creatinine levels returned to pretreatment levels after the medications were stopped. The patient's score on the Naranjo Adverse Drug Reaction Probability Scale was a nine, and the score on the Drug Interaction Probability Scale was a five. For elderly patients with chronic kidney disease, the combined use of edaravone, diuretics, and NSAIDs should be avoided.

Enhanced anticoagulant effect of warfarin in a patient treated with cloxacillin

To present the case of warfarin-cloxacillin interaction that resulted in an increased international normalized ratio (INR). A 70-year-old man had been treated with warfarin for atrial fibrillation. He was hospitalized because of superficial thrombophlebitis of the left median cubital vein, which developed after venipuncture. An antibiotic therapy with cloxacillin was initiated immediately after the admission. Two days later, INR value increased from baseline 1.9 to 4.6. Anticoagulation therapy was discontinued and INR value was measured daily. His INR remained high for the entire duration of antibiotic therapy. Three days after the cloxacillin therapy was discontinued, the INR decreased to the baseline value. In the presented case, the temporal relationship between the administration of cloxacillin and increased INR suggests that the cloxacillin was responsible for the enhanced warfarin activity. According to the Drug Interaction Probability Scale, a causal relationship between the warfarin-cloxacillin interaction and increased INR value was rated "probable". Interactions between warfarin and cloxacillin can result in serious adverse reactions. INR value should be closely monitored when patients are prescribed this combination of drugs.

Shortening of Donepezil-induced QTc Prolongation with a Change in the Interacting Drug, after Electrocardiograph Monitoring by Community Pharmacists: A Case Report

We used a mobile electrocardiograph to manage the adverse effects and interactions of drugs, especially QT-prolonging drugs, in a community pharmacy setting. We report the case of a patient in whom the risk of drug-induced torsades de pointes (TdP) was lowered, after monitoring by community pharmacists. An 80-year-old woman was under donepezil (5 mg/d) therapy for Alzheimer's disease and also taking other drugs that interact with donepezil, namely, benidipine (8 mg/d) and atorvastatin (10 mg/d). The patient was visited almost every month, and an electrocardiogram was usually obtained. QTc prolongation (avg. 470±9 ms) was observed in the first to third tests. Her doctor was informed about these results and the risk factors (advanced age, gender, and drugs interactions (benidipine and atorvastatin)) associated with TdP and asked to respond promptly since several cases of donepezil-induced TdP have been reported. As a result, benidipine was replaced with amlodipine, while the remaining drugs were continued. After the change, a significant decrease in QTc values were observed in the fourth to seventh tests (avg. 441±9 ms, p=0.010), thereby indicating a decrease in TdP risk. The Drug Interaction Probability Scale (object drug, donepezil; precipitant drug, benidipine) score was +6 (probable). Thus, QTc shortening was a result of differences in donepezil-benidipine and donepezil-amlodipine interactions.

Drug Interactions between Common Illicit Drugs and Prescription Therapies

Objective: The aim was to summarize the clinical literature on interactions between common illicit drugs and prescription therapies. Methods: Medline, Iowa Drug Information Service, International Pharmaceutical s, EBSCO Academic Search Premier, and Google Scholar were searched from date of origin of database to March 2011. Search terms were cocaine, marijuana, cannabis, methamphetamine, amphetamine, ecstasy, N-methyl-3,4-methylenedioxymethamphetamine, methylenedioxymethamphetamine, heroin, gamma-hydroxybutyrate, sodium oxybate, and combined with interactions, drug interactions, and drug–drug interactions. This review focuses on established clinical evidence. All applicable full-text English language articles and abstracts found were evaluated and included in the review as appropriate. Results: The interactions of illicit drugs with prescription therapies have the ability to potentiate or attenuate the effects of both the illicit agent and/or the prescription therapeutic agent, which can lead to toxic effects or a reduction in the prescription agent’s therapeutic activity. Most texts and databases focus on theoretical or probable interactions due to the kinetic properties of the drugs and do not fully explore the pharmacodynamic and clinical implications of these interactions. Clinical trials with coadministration of illicit drugs and prescription drugs are discussed along with case reports that demonstrate a potential interaction between agents. The illicit drugs discussed are cocaine, marijuana, amphetamines, methylenedioxymethamphetamine, heroin, and sodium oxybate. Conclusion: Although the use of illicit drugs is widespread, there are little experimental or clinical data regarding the effects of these agents on common prescription therapies. Scientific Significance: Potential drug interactions between illicit drugs and prescription drugs are described and evaluated on the Drug Interaction Probability Scale by Horn and Hansten.

Individual differences in prothrombin timeinternational normalized ratio variation following coadministration of the anticancer agents S-1 and warfarin: 3 case reports

We report three cases of elevated prothrombin time-international normalized ratios (PT-INR) following the initiation of coadministration of warfarin and S-1, a preparation containing tegafur (FT), gimeracil (CDHP), and oteracil potassium (Oxo). The three cases included 2 men and 1 woman aged 79, 71, and 54 y, respectively. PT-INRs were in the range of 2.0 - 3.0 before therapy but were elevated to values in the range of 3.79 - 4.92 within 8 - 17 days after initiating the coadministration of warfarin (1.5 - 3.5 mg/d) and S-1 (80 - 120 mg/d). When the drug interactions in Cases 1 - 3 were evaluated using the Drug Interaction Probability Scale, each of these cases was assessed as "probable". The drug interaction between warfarin and S-1 presumably leads to elevated PT-INR because the 5-fluorouracil (5-FU), which is metabolite of FT in S-1, inhibits the metabolic processing of S-warfarin by cytochrome P450 (CYP) 2C9. However, individual differences in the metabolic production of 5-FU from FT because of genetic polymorphisms in CYP2A6 and individual variation in the levels of renal function may lead to complications when 5-FU is coadministered with warfarin as compared to when 5-FU is administered alone. It is essential that the dosage level of warfarin is appropriately adjusted by frequent PT-INR measurements when warfarin and S-1 are coadministered.

Critically Elevated INR in a Patient on Warfarin After Increase in Extended-Release Niacin Dose

To report a case of a probable interaction between warfarin and extended-release niacin that may have led to synergistic coagulopathy and to inform health care providers of a need for more frequent monitoring of international normalized ratio (INR) in patients taking these drugs concomitantly. A 69-year-old white female whose anticoagulation treatment had been stable for 18 months with warfarin 2.5 mg daily (17.5 mg/wk) presented to an anticoagulation clinic with a critically elevated INR of greater than 12.3 after a dose increase in extended-release niacin (Niaspan) from 500 mg to 1000 mg daily the previous week. Extended-release niacin 500 mg daily had not affected the patient's INR for the previous 3 months; the most recent INR before this episode was 2.4. Warfarin was withheld and extended-release niacin was discontinued. The INR 2 days later was 4.8 and, with titration of warfarin to the previous maintenance dose of 2.5 mg daily, the INR was 2.3. Common drug interaction resources do not consistently list an interaction between warfarin and extended-release niacin. The mechanism of niacin-induced coagulopathy is theorized to be related to diminished coagulation factors, and limited data suggest that this may be more pronounced with extended-release niacin. Because of the described effects of niacin on the coagulation cascade and the possibility for pharmacokinetic interactions, there is a potential for synergistic coagulopathy when combined with warfarin therapy. For patients taking both medications, more frequent INR monitoring than that which drug interaction references suggest may be advised. An objective causality assessment (Horn Drug Interaction Probability Scale) revealed that the interaction was probable. An interaction between niacin and warfarin likely elevated the INR in this patient because of synergistic coagulopathy and pharmacokinetic effects of niacin. Increased frequency of INR monitoring may be advised for patients taking these drugs concomitantly.

Transient Elevation of International Normalized Ratio During Cisplatin-Based Chemotherapy in Patients Who are Taking Warfarin

To report 2 cases of a probable interaction between cisplatin and warfarin. Two cases of transient elevation of international normalized ratio (INR) during irinotecan (60 mg/m2 on days 1, 8, and 15) plus cisplatin (60 mg/m2 on day 1) chemotherapy with concomitant warfarin are presented. In both cases, warfarin dosages were stable at the therapeutic target range prior to initiation of chemotherapy. Granisetron hydrochloride (3 mg on days 1, 8, and 15) and dexamethasone (13.2 mg on day 1 and 6.6 mg on days 2, 3, 8, and 15) were used prior to irinotecan administration in both patients. In addition, aprepitant was administered to both patients for 3-5 days with cisplatin. One of these patients also received aprepitant with irinotecan on days 8 and 15. During chemotherapy, INR was transiently elevated almost 1.5-fold over baseline level on day 3. This variation did not occur in subsequent irinotecan cycles on days 8 and 15. The timing of these increases was similar in each of the cycles. Cisplatin was the common drug in the cases presented and therefore could be related to the INR elevations. To our knowledge, these are the first reports of an interaction between warfarin and irinotecan-cisplatin chemotherapy, but reports of a similar interaction with chemotherapy including platinum derivatives exist. Use of the Horn Drug Interaction Probability Scale indicated a probable interaction between warfarin and cisplatin. Cisplatin might affect the anticoagulation function of warfarin. Careful INR monitoring is necessary during antineoplastic chemotherapy with cisplatin in patients taking warfarin.

Elevated International Normalized Ratio Associated with Use of Dronedarone and Warfarin

To describe a case of elevated international normalized ratio (INR) after addition of dronedarone to warfarin therapy. A 72-year-old white female with a history of tinnitus, gastroesophageal reflux disease, and permanent pacemaker implantation was taking warfarin (target INR 2-3) and sotalol for chronic atrial fibrillation; atorvastatin for hyperlipidemia; and risedronate for osteopenia. Her warfarin therapy had been managed by a nurse-run anticoagulation clinic for several years. During the prior year, her INR had been stable with a weekly dose of warfarin 25 mg. After persistent episodes of atrial fibrillation, the antiarrhythmic agent was changed from sotalol to dronedarone 400 mg twice daily. Approximately 10 days after starting dronedarone, the INR was 4.8; she stated that there was no bleeding. The warfarin dose was decreased to 20 mg/wk, and the INR remained stable with that dosage for the next 11 months. Postmarketing surveillance has revealed cases of increased INR values with or without bleeding in patients taking warfarin who were started on dronedarone. In this case, the Horn Drug Interaction Probability Scale suggested a probable causality for an interaction between dronedarone and warfarin. Based on current knowledge, this interaction may involve an indirect gastrointestinal mechanism and/or a direct pharmacokinetic mechanism. Clinicians should monitor patients who are taking warfarin and dronedarone for INR changes and bleeding episodes about 1 week after initiation of dronedarone. If a significant interaction is noted, the warfarin dosage should be decreased and the patient should be monitored within 2 weeks to assess the need for further adjustments.

Rapid Onset of Iatrogenic Adrenal Insufficiency in a Patient with Cystic Fibrosis–Related Liver Disease Treated with Inhaled Corticosteroids and a Moderate CYP3A4 Inhibitor

To report the rapid onset of adrenal insufficiency and subsequent development of Cushing syndrome precipitated by a CYP3A4-mediated drug-drug interaction that may have been enhanced by the presence of cystic fibrosis (CF)-related liver disease. A 9-year-old girl with CF and cirrhosis experienced a decline in lung function that led to a diagnosis of asthma. After initiation of asthma therapy with inhaled fluticasone 110 μg/actuation, the patient experienced improvement in lung function to baseline. Seven weeks after the initiation of inhaled fluticasone, she developed vaginal candidiasis and was prescribed fluconazole 100 mg/day, a CYP3A4 inhibitor. Three days after starting fluconazole, she developed polyuria and polydipsia and was found to have severe hyperglycemia, which led to the diagnosis of Cushing syndrome. Fluticasone was discontinued, and the patient's adrenal function normalized. Patients with CF are commonly prescribed complex medication regimens that may affect drug metabolism. CYP3A4 inhibitors may significantly decrease metabolic clearance in patients using chronic inhaled corticosteroids. Iatrogenic Cushing syndrome has been reported in patients with CF treated concomitantly, and for extended duration, with inhaled corticosteroids and CYP3A4 inhibitors. This case highlights rapid onset of adrenal insufficiency in a patient with CF-related liver disease treated briefly with a moderate CYP3A4 inhibitor. Use of the Horn drug interaction probability scale indicates that the interaction between fluticasone and fluconazole was probable. CYP3A4-mediated drug interactions represent a significant risk in patients treated with long-term inhaled corticosteroids. The presence of clinically significant CF-related liver disease may enhance this risk.

Methadone Toxicity Due to Smoking Cessation—A Case Report on the Drug-Drug Interaction Involving Cytochrome P450 Isoenzyme IA2

To report the potential clinically significant pharmacokinetic interaction that may result from smoking cessation in patients on methadone maintenance therapy. A 46-year-old white man was admitted to the step-down intensive care unit with decreased respirations and altered mental status related to methadone toxicity. The patient had been on a stable dose of methadone for chronic back pain, and he reported a 1 pack per day, 33-year history of cigarette smoking. After methadone was held for 3 days, his mental status improved. It was later revealed that he had initiated smoking cessation. He was discharged home on a reduced dose of methadone with no further complications. While the potential for toxicity exists for patients who are maintained on methadone and decrease the number of cigarettes they smoke, to our knowledge, there is no recent peer-reviewed literature on this interaction. Methadone is a synthetic opioid primarily metabolized by CYP3A4 and, to a lesser degree, by other isoenzymes, including CYP1A2. Polycyclic aromatic hydrocarbons found in tobacco smoke are known CYP1A2 inducers. Decreased intake of cigarette smoke can lead to a reduction in methadone metabolism, resulting in higher serum concentrations. Our case is an example of methadone toxicity secondary to smoking cessation in a patient on methadone maintenance therapy. An objective causality assessment based on the Horn Drug Interaction Probability Scale revealed the interaction to be probable. Patients on methadone should be monitored for signs of methadone toxicity upon the start of smoking cessation, and the dose of methadone should be adjusted accordingly. Additional information and reports cautioning clinicians and patients about this potential interaction would be beneficial.

Moxifloxacin–acetaminophen–warfarin interaction during bacille Calmette-Guérin treatment for bladder cancer

The case of a patient receiving long-term anticoagulation with warfarin who had supratherapeutic International Normalized Ratios (INRs) after receiving concomitant acetaminophen and moxifloxacin as prophylaxis with bacille Calmette-Guérin (BCG) therapy for bladder cancer is reported. An 89-year-old man receiving long-term anticoagulation with warfarin sodium (total weekly dosage of 19 mg) arrived at the anticoagulation clinic for his monthly visit. On the day before this visit, he had received the third of six serial weekly BCG bladder instillations for the treatment of bladder cancer. He did not report that acetaminophen 1000 mg four times daily and one dose of moxifloxacin 400 mg had been prescribed before these instillations. An INR check revealed a value of 6.7. He was instructed to take 2.5 mg of oral phytonadione and to withhold his warfarin dose that night. On the next day, his INR was 3.2. Each time he arrived at the anticoagulation clinic after his BCG therapy, his INR was supratherapeutic, except after his fourth treatment (INR of 2.5), which can be explained by residual effects from the phytonadione he received a week earlier. After completion of his BCG therapy, he was instructed to resume his usual warfarin sodium dosage of 19 mg weekly, and his INR remained in the desired therapeutic range. According to the Drug Interaction Probability Scale, the development of supratherapeutic INRs was probably associated with concomitant acetaminophen and moxifloxacin use. An 89-year-old man receiving long-term anticoagulation with warfarin had supratherapeutic INRs after receiving acetaminophen and moxifloxacin as prophylaxis during BCG therapy for bladder cancer.

Olanzapine-induced parkinsonism associated with smoking cessation

The case of a patient taking high-dosage olanzapine who experienced parkinsonism after smoking cessation is reported. A 73-year-old Caucasian woman with a recent diagnosis of Parkinson disease and a history of chronic obstructive pulmonary disease, hyperlipidemia, chronic osteoarthritis, and hypothyroidism was hospitalized for altered mental status, weakness, and ambulatory dysfunction. The diagnosis of Parkinson disease was made approximately four months prior. Despite initiation of carbidopa-levodopa, the patient's symptoms did not improve, and her mental and physical status declined. The patient was taking olanzapine 30 mg daily for bipolar disorder and had a 40-pack-year history of smoking, but she quit smoking approximately four months before this hospitalization. The results of a neurologic evaluation suggested that the patient did not have Parkinson disease but was possibly experiencing olanzapine toxicity secondary to smoking cessation. Carbidopa-levodopa was discontinued. Psychiatry was consulted, and a monthlong cross-taper to discontinue olanzapine and initiate aripiprazole with a target dosage of 20 mg daily was recommended. During the course of therapy, the patient's level of alertness and bradykinesia improved. Overall, it was noted that her extrapyramidal symptoms were gradually improving; two days before hospital discharge, she was noted to have no definite remaining evidence of parkinsonism. In this case, use of the Naranjo et al. adverse-drug-reaction probability scale and the drug interaction probability scale indicated that the adverse effects were probably related to the interaction between smoking and olanzapine. A 73-year-old woman receiving high-dosage olanzapine for bipolar disorder developed parkinsonism after smoking cessation.

Rhabdomyolysis in a Prostate Cancer Patient Taking Ketoconazole and Simvastatin: Case Report and Review of the Literature

To report a case of severe rhabdomyolysis resulting in acute renal failure caused by an interaction between ketoconazole and simvastatin in a patient with prostate cancer. A 64-year-old man who received ketoconazole for prostate cancer, along with simvastatin and fenofibrate for dyslipidemia, presented to our ambulatory clinic with complaints of blood in his urine and weakness following an increase in his ketoconazole dose. Two days after presentation, the patient was admitted with rhabdomyolysis and acute renal failure, as evidenced by elevated serum creatine kinase (>32,000 IU/L), serum myoglobin (20.6 ng/mL), and serum creatinine (4.2 mg/dL) as well as abnormal bone scintigraphy findings. Ketoconazole, fenofibrate, and simvastatin were discontinued. Renal function did not normalize with hydration, and intermittent hemodialysis was initiated; 10 days of hemodialysis resulted in normalization of electrolytes and creatine kinase. Symptom improvement and normalization of laboratory parameters were observed after prolonged hospitalization (24 days). Prostate cancer is the most common malignancy among men in the US. Androgen deprivation therapy is the standard initial treatment for biochemical recurrence or metastatic disease. Most patients experience progression to a castrate-resistant disease state, requiring the use of additional therapies. Ketoconazole is considered a secondary hormonal treatment option. We describe an interaction in a patient with prostate cancer between a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and ketoconazole resulting in rhabdomyolysis, requiring hemodialysis. An objective causality assessment using the Horn Drug Interaction Probability Scale revealed that the adverse drug reaction was a possible result of the interaction. The temporal fashion in which the episode occurred suggests that a possible simvastatin-ketoconazole interaction precipitated rhabdomyolysis in this patient. The use of ketoconazole for castrate-resistant prostate cancer can lead to drug-drug interactions in patients taking simvastatin or other HMG-CoA reductase inhibitors. Clinicians should be aware of this severe adverse event and take steps to minimize its occurrence.

Probable Drug Interaction Between Intravenous Ciprofloxacin and Mycophenolate Mofetil in a Bone Marrow Transplant Recipient

Several studies have reported that oral antibacterials, including ciprofloxacin, administered during mycophenolate mofetil therapy may reduce mycophenolic acid (the active drug moiety) exposure. To our knowledge, however, this effect has never been described with antibiotics administered by the parenteral route. We describe a 17‐year‐old female who received intravenous mycophenolate mofetil after bone marrow transplantation, with therapeutic drug monitoring performed during therapy. On day 2 of mycophenolate mofetil therapy, the mycophenolic acid area under the plasma concentration‐time curve was 30.3 mg•hour/L. On day 8, although her mycophenolate mofetil dosage had remained unchanged, the mycophenolic acid area under the plasma concentration‐time curve was unexpectedly lower at 10.7 mg•hour/L. A drug interaction was suspected. Three intravenous antiinfective drugs had been introduced after initial therapeutic drug monitoring had been performed—ciprofloxacin, trimethoprim‐sulfamethoxazole, and caspofungin. The patient subsequently developed severe graft‐versus‐host disease during mycophenolate mofetil therapy and died. Use of the Horn drug interaction probability scale indicated a probable interaction between intravenous mycophenolate mofetil and intravenous ciprofloxacin in this patient. The available literature does not support the role of either trimethoprim‐sulfamethoxazole or caspofungin in a drug interaction with mycophenolate mofetil. Published studies have shown that ciprofloxacin is partially excreted by transintestinal elimination after intravenous administration and that it may greatly reduce the levels of enterobacteria of gastrointestinal flora, which are responsible for mycophenolic acid enterohepatic recirculation. Clinicians should be aware that ciprofloxacin, even administered intravenously, may modify the pharmacokinetics of mycophenolate mofetil. Ciprofloxacin should be used with caution in patients receiving mycophenolate mofetil; if this antiinfective must be used, therapeutic drug monitoring should be performed to guide dosage adjustments.

A Potential Interaction between Warfarin and Atovaquone

To report a case of increased international normalized ratio (INR) in a patient established on warfarin therapy who was then initiated on atovaquone therapy. A 53-year-old African American male with HIV was prescribed warfarin 5 mg/day for 12 months after diagnosis of idiopathic deep vein thrombosis and bilateral pulmonary emboli (target INR 2.5 [range 2.0-3.0]). The patient required Pneumocystis jiroveci pneumonia prophylaxis and was prescribed atovaquone instead of trimethoprim/sulfamethoxazole therapy because of the latter drug's known interaction with warfarin. The patient's INR rose by greater than 50% (from 2.3 to 3.5) after 7 days of concomitant warfarin and atovaquone. In response, the patient's total weekly warfarin dose was decreased by 5%. Eight days later, the patient's INR was still supratherapeutic at 3.1. Approximately 4 weeks later, his INR was 4.2. One dose of warfarin was withheld and then the total weekly warfarin dosage was decreased by another 10%. Eight days later, the patient discontinued atovaquone therapy but continued on warfarin as prescribed. One day after atovaquone discontinuation, his INR decreased to 1.7. Due to this subtherapeutic INR level, 8 days later the total weekly warfarin dose was increased by 5%. Although a follow-up appointment was scheduled, no further INR values were obtained because the patient's 12-month course of anticoagulation therapy was completed and warfarin was discontinued. The patient did not report any adverse effects or signs or symptoms of hemorrhage while his INR values were supratherapeutic. Warfarin's potential for interactions with other highly protein-bound drugs, such as atovaquone, can result in displacement from protein binding sites and increased serum concentrations of warfarin. Based on a search of MEDLINE/PubMed, International Pharmaceutical Abstracts, and the Food and Drug Administration MedWatch Adverse Event Reporting Program (all through July 31, 2010), no cases were found of an interaction between atovaquone and warfarin. The Horn Drug Interaction Probability Scale calculated this to be a probable interaction between warfarin and atovaquone. Although current medication references do not report an interaction between atovaquone and warfarin, knowledge of their pharmacodynamic properties can enable practitioners to anticipate the consequences of a possible transient increase in warfarin serum concentration, such as that seen in our patient, when given concomitantly.

Myoclonus After Dextromethorphan Administration in Peritoneal Dialysis

To report a case of myoclonus that developed after administration of dextromethorphan. A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

Probable interaction between warfarin and bee pollen

A probable interaction between warfarin and honeybee-collected pollen is reported. A 71-year-old Caucasian man arrived at an anticoagulation clinic for routine warfarin monitoring with an International Normalized Ratio (INR) value of 7.1 (therapeutic range, 2.0-3.0). His medical history included atrial flutter, hypertension, hyperlipidemia, diabetes mellitus, erectile dysfunction, obesity, and hypothyroidism. His medication regimen included warfarin, hydrochlorothiazide, lisinopril, levothyroxine, simvastatin, glyburide, metformin, vardenafil, aspirin, a multivitamin, and the herbal products Cataplex E2, Cataplex B, and Cyruta. The dosages of all medications and herbal products had been stable for the previous nine months, including warfarin (INR, 1.9-3.3). The patient began taking bee pollen granules (one teaspoon orally twice daily) for a perceived general health benefit one month before this clinic visit. He denied use of alcohol and tobacco, changes in dietary phytonadione intake, missed or extra doses of warfarin, any other medication changes, and acute illness and diarrhea. Warfarin was withheld, and the patient was seen at the anticoagulation clinic three days later with an INR of 3.7. Warfarin was held for a fourth day and then restarted with the weekly dose decreased by 11%. The patient continued to take bee pollen, and all INR values during the next seven months were within or near the therapeutic range. Use of the Drug Interaction Probability Scale indicated that there was a probable interaction between bee pollen and warfarin. Consumption of bee pollen led to increased INR values in a patient taking warfarin.

Phenobarbital/Lamotrigine Coadministration–Induced Blood Dyscrasia in a Patient with Epilepsy

To report on a patient with epilepsy who developed leukopenia and thrombocytopenia during phenobarbital/lamotrigine treatment. A 45-year-old woman with a 10-year history of complex partial seizures being treated with phenobarbital 100 mg/day presented due to the development of complex partial seizure episodes (8 episodes/month in the last 6 months). Results of laboratory tests on admission showed normal platelets (250 x 10³/μL) and white blood cells (8.2 x 10³/μL). After clinical evaluation, lamotrigine titrated to a final dose of 100 mg twice daily was added to the phenobarbital. About 2 months later no epileptic manifestations were reported, but hematologic tests revealed a decrease in both platelets (36 x 10³/μL) and white blood cells (2.0 x 10³/μL). One day later, phenobarbital was discontinued and the patient developed 2 episodes of complex partial seizure. Levetiracetam titrated to 1500 mg/day was added to lamotrigine, with a normalization of platelets (260 x 10³/μL) and white blood cell (7.9 x 10³/μL) counts about 20 days later. After a few days, levetiracetam was discontinued and phenobarbital rechallenge during lamotrigine treatment induced a new blood dyscrasia in about 2 weeks (platelets 80 x 10³/μL; white blood cells 3.2 x 10³/μL). Phenobarbital was discontinued and levetiracetam was restarted, with a recovery of normal hematopoiesis in 25 days. The patient is presently receiving treatment with both lamotrigine 200 mg/day and levetiracetam 1500 mg/day and shows no seizure symptoms, blood abnormalities, or other adverse effects. Using the Horn Drug Interaction Probability Scale, we estimated a probable relationship between the drug-drug interaction and blood dyscrasia. The underlying mechanism of this interaction has not been well characterized. Cytochrome P450 enzyme induction by phenobarbital could be responsible for the production of reactive metabolites of lamotrigine that might be causative for the observed hematologic effects. A pharmacodynamic interaction between the 2 drugs is also a possible mechanism of this interaction. Our patient with epilepsy developed blood dyscrasia during lamotrigine/phenobarbital treatment. Clinicians should carefully monitor hematologic parameters during lamotrigine/phenobarbital treatment.

Rhabdomyolysis in a Patient Receiving High-Dose Simvastatin After the Induction of Therapeutic Hypothermia

To report a case of rhabdomyolysis in a patient receiving high-dose simvastatin after the induction of therapeutic hypothermia. A 45-year-old African American male was brought to the emergency department for a witnessed cardiac arrest. He was placed on a therapeutic hypothermia protocol and his simvastatin dose was increased from 40 to 80 mg at bedtime. Target core temperature (34 °C) was reached within 8 hours and was maintained for 24 hours. His admission creatine kinase was 965 units/L, which decreased to 153 units/L by day 4. On day 5, the patient voided a large quantity of orange-brown urine and had a dramatically increased creatine kinase (8523 unit/L) level and myoglobinuria. Statin therapy was subsequently discontinued. Creatine kinase remained elevated for 2 days, then gradually declined toward normal levels over the following week. Simvastatin undergoes extensive first-pass metabolism mediated by CYP3A4, making it susceptible to significant drug interactions. Therapeutic hypothermia has been shown to significantly reduce the clearance of CYP3A4 substrates. We attribute this patient's rhabdomyolysis to a therapy-drug interaction between the therapeutic hypothermia and the administration of high-dose simvastatin. We believe that the induced hypothermia caused a reduction in simvastatin clearance, leading to toxic plasma concentrations. According to the Naranjo probability scale, it was probable that the rhabdomyolysis was related to simvastatin use. The Horn Drug Interaction Probability Scale likewise classified the probability of a causal relationship between the potential therapy-drug interaction and the event as probable. Clinicians must be aware of the pharmacokinetic effects of therapeutic hypothermia to prevent potential drug-therapy interactions. It may be prudent to avoid the use of CYP3A4 substrates that are not essential treatments in patients undergoing therapeutic hypothermia until more information is known about their safety in this patient population.