Horn Drug Interaction Probability Scale Research Articles

Natural Health Product-Drug Interaction Causality Assessment in Pediatric Adverse Event Reports Associated with Attention-Deficit/Hyperactivity Disorder Medication.

Background: Some pediatric patients with attention-deficit/hyperactivity disorder (ADHD) use natural health products (NHPs) such as herbal remedies. Although herbal remedies are generally considered to be safe when they are used appropriately, they may contain active components that can interact with medications being used concurrently, with potential for NHP-drug interactions leading to adverse events. Objectives: The objectives of this study were (1) to identify adverse event reports (AERs) involving commonly used herbal remedies and ADHD prescription medicines in children and adolescents; (2) to evaluate the quality of collected AERs; and (3) to assess whether NHP-drug interactions can be causally linked to reported adverse events. Methods: We systematically searched the FDAble database (FDAble.com) for herbal remedies commonly used by patients (4-18 years old) also taking ADHD drugs from 1997 to 2015. We assessed the completeness of the AERs and used three causality assessment tools modified for NHPs (Naranjo Adverse Drug Reaction Probability Scale, HORN Drug Interaction Probability Scale, and World Health Organization Uppsala Monitoring Centre Scale). Results: Of the 23 identified AERs involving both an herbal remedy and an ADHD prescription medication, most involved multiple (>3) substances with inadequate detail to assess multiple potential interactions. Following data extraction and evaluation of completeness, five AERs involving only one herbal remedy and one ADHD medication were evaluated for causality. An NHP-drug interaction was assessed to be probable in one case and to be possible in another. Both these reports involved a methylphenidate formulation and St. John's wort. Conclusions: Eighteen of the 23 identified AERs involving both an herbal remedy and an ADHD drug also involved other multiple ingredient products. The reporting quality was poor for the five AERs examined. Further research is needed to study the interaction between St. John's wort and methylphenidate.

Interaction between Levothyroxine and Phenprocoumon: a case report

Abstract Several case reports have associated the combined use of thyroid drugs and oral anticoagulants, like coumarin, with overanticoagulation. However, this effect has never been described for phenprocoumon, a coumarin derivate that is widely prescribed in continental European countries and in Latin America. We describe a 62-year-old female who had an unexpectedly labile anticoagulation profile when levothyroxine (Puran T4®) was added to her drug therapy regimen, which included phenprocoumon (Marcoumar®). This resulted in an elevated international normalized ratio (INR) that was unrecordable and bleeding (macroscopic hematuria) that required hospitalization and treatment with vitamin K. The patient had been taking phenprocoumon for almost ten years for systemic embolism prophylaxis because of her history of mechanical bileaflet mitral valve prosthesis. One month before the events described, the patient was prescribed sodium levothyroxine (50 mcg daily) to treat hypothyroidism (TSH = 40 µU/mL; reference range, 0.40–4.0 µU/mL). Approximately 3 weeks prior to initiation of levothyroxine treatment, her INR was 2.8. A drug interaction was therefore suspected. The Horn Drug Interaction Probability Scale (DIPS) indicated a probable interaction between oral phenprocoumon and levothyroxine in this case. Clinicians should be aware that levothyroxine may interact with oral phenprocoumon, resulting in overanticoagulation.

Rhabdomyolysis after Concomitant Use of Simvastatin and Voriconazole in an Allogeneic Stem Cell Transplant Patient

Objective: To report a case of rhabdomyolysis after concomitant use of simvastatin and voriconazole. Case Summary: A 65-year-old white male, weight 66 kg, 79 months post allogeneic stem cell transplant for chronic lymphocytic leukemia, was on a stable medication regimen that included voriconazole. He was hospitalized with weakness and elevated creatine kinase a few weeks after initiation of simvastatin for treatment of hyperlipidemia. His symptoms resolved and creatine kinase level returned to within the normal range after fluid administration and discontinuation of simvastatin. Discussion: The use of statins has become a standard in the treatment and prevention of atherosclerotic disease. Most statins are metabolized via the cytochrome P450 enzyme system. For simvastatin, metabolism occurs specifically via the CYP3A4 isoenzyme. Drugs known to inhibit this isoenzyme, such as voriconazole, can increase the risk for toxicities, including rhabdomyolysis, when used concomitantly with simvastatin. This case represents a probable drug-drug interaction, based on the Horn Drug Interaction Probability Scale. Conclusions: Due to the broad use of statins for the treatment and prevention of atherosclerotic disease, as well as the need for azole antifungals in the stem cell transplant population, interactions between these agents are becoming an increasing possibility. Care should be taken to minimize these interactions and, when feasible, a change to an alternative agent may be warranted to avoid adverse effects.

Serotonergic and Adrenergic Drug Interactions Associated with Linezolid: A Critical Review and Practical Management Approach

To describe the evidence for serotonergic and adrenergic drug interactions with linezolid and discuss clinical management strategies. A literature search of PubMed (1947-November 2012), MEDLINE (1946-November 2012), EMBASE (1974-November 2012), and International Pharmaceutical Abstracts (1970-November 2012) was conducted using the terms linezolid, drug interaction, serotonin syndrome, serotonin toxicity, sympathomimetic, serotonergic agents, and adrenergic agents. Citations of retrieved articles were also reviewed. English-language articles describing coadministration of serotonergic or adrenergic agents with linezolid to humans were included. Studies published only in abstract form were excluded. One prospective study, 6 retrospective studies, and 24 case reports were identified describing a serotonergic or adrenergic drug interaction. Incidence of serotonin syndrome in patients on linezolid and serotonergic agents ranged between 0.24% and 4%. Serotonergic agents determined to have probable (according to the Horn Drug Interaction Probability Scale) linezolid interactions in case reports included meperidine, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, and venlafaxine. Serotonergic agent dose and duration of coadministration with linezolid did not appear to influence the occurrence of serotonin syndrome. Adrenergic medication coadministration was associated with a possible drug interaction as determined by the Horn Drug Interaction Probability Scale but did not appear to result in clinically significant drug interactions with linezolid. Linezolid-associated serotonergic drug interactions occur more commonly than adrenergic interactions. Serotonergic interactions considered probable according to the Horn Drug Interaction Probability Scale do not appear to correlate with drug dosage; time of onset ranges from <1 to 20 days, and effect resolves in <1 to 5 days after discontinuation of offending agents. If coadministration of linezolid and a serotonergic agent cannot be avoided, clinicians should be aware of the symptoms and management of serotonergic toxicity; close monitoring is recommended and additional serotonergic agents should not be used. While adrenergic drug interactions with linezolid are less common in clinical practice, monitoring for signs of hypertension remains important.

Antidepressant-Selective Gynecomastia

To describe what we believe is the first reported case of synergistic gynecomastia during treatment of depressive and anxiety disorders when sertraline was added to a stable medication regimen including duloxetine, rosuvastatin, and amlodipine. A 67-year-old male with major depression, dysthymia, obsessive-compulsive disorder, social anxiety, hypertension, diabetes, and hyperlipidemia presented with new-onset gynecomastia and breast tenderness. Mammography revealed bilateral gynecomastia (fibroglandular tissue posterior to the nipples bilaterally) without suspicious mass, calcification, or other abnormalities. These new symptoms developed after sertraline was added to his stable medication regimen (duloxetine, alprazolam, rosuvastatin, metoprolol, amlodipine, hydrochlorothiazide/triamterene, metformin, and sitagliptin). These symptoms were dose-dependent, with gynecomastia and breast tenderness more severe as sertraline was titrated from 25 mg/day to 50 mg/day and then to 75 mg/day. When sertraline was discontinued, gynecomastia and breast tenderness rapidly resolved. Mammoplasia and gynecomastia are associated with altered dopamine neurotransmission and/or perturbations in sexual hormones. These adverse effects may be medication induced. Selective serotonin reuptake inhibitors (sertraline), serotonin-norepinephrine reuptake inhibitors (duloxetine), rosuvastatin, and amlodipine have been reported to cause these adverse effects. This case was unique, since the patient had been on both sertraline and duloxetine previously as independent psychotropics without the development of gynecomastia. In the context of an additive drug adverse effect, the probability of sertraline as the precipitant drug was determined by both the Naranjo probability scale and the Horn drug interaction probability scale as probable. Gynecomastia is associated with antidepressants and other medications but is rarely addressed. Gynecomastia may be antidepressant selective or may be the result of additive adverse effects. Clinicians are advised to question patients regarding this potential adverse effect. Further education of clinicians is indicated.

A Probable Interaction between Warfarin and the Antiretroviral TRIO Study Regimen

To report a probable drug interaction between the antiretroviral TRIO regimen (ritonavir-boosted darunavir, etravirine, and raltegravir) and warfarin in an HIV-infected patient. In January 2010, a 50-year-old transgender female with HIV infection and recurrent deep vein thrombosis began treatment with the TRIO study regimen. Treatment had been maintained with warfarin for the past 5 years and emtricitabine monotherapy for the preceding 22 months. Emtricitabine was discontinued when the TRIO regimen was started. The mean weekly warfarin dose while the patient was receiving emtricitabine monotherapy was 13.3 mg (95% CI 12.7 to 13.8), with a mean international normalized ratio (INR) of 2.8 (95% CI 2.5 to 3.1). Following the initiation of the TRIO regimen, the mean weekly warfarin dose was increased to 19.3 mg (95% CI 18.5 to 20.1) and was maintained over the ensuing 71 weeks with a mean INR of 2.6 (95% CI 2.2 to 3.0). Information on the effect of newer antiretrovirals on warfarin metabolism, as well as the collective contribution of combination antiretroviral therapy including multiple agents that may alter warfarin metabolism, is limited. We predicted that warfarin dose requirements would change upon initiation of the TRIO regimen. Given the variability in INR that can occur with chronic warfarin treatment, weekly warfarin doses were averaged during emtricitabine monotherapy (90 weeks) and TRIO regimen (71 weeks) periods. Mean weekly warfarin doses increased by 45% (p < 0.001) following initiation of the TRIO regimen. Mean INR results for the 2 time periods were not significantly different, demonstrating that stable anticoagulation was maintained. The Horn drug interaction probability scale score to assess causation indicated a probable interaction. An increased weekly warfarin dose requirement is predicted when warfarin is used concurrently with the antiretroviral TRIO regimen. Increased INR monitoring is prudent when the combination is administered.

Increased Warfarin Requirements during Concurrent Dicloxacillin Therapy

Objective: To report on a patient who required increased dosages of warfarin to achieve therapeutic anticoagulation while taking dicloxacillin. Case Summary: A 60-year-old woman was hospitalized for an infected lymphocele and cellulitis. Based on microbiology results, dicloxacillin 500 mg by mouth 4 times daily was initiated to complete 14 days of treatment. Concurrently, a deep vein thrombosis was diagnosed by computed tomography angiography. Enoxaparin 100 mg subcutaneously twice daily and warfarin 5 mg by mouth daily were initiated with an international normalized ratio (INR) goal of 2–3. The patient had a history of a supratherapeutic INR while on warfarin 5 mg daily. Throughout the 20-day hospitalization, her warfarin dose was steadily increased in an attempt to achieve a therapeutic INR. Required doses ranged from 7.5 to 15 mg daily. Two days after discontinuation of dicloxacillin and with administration of a 15-mg warfarin boost, the INR was therapeutic at 2.3. Enoxaparin was discontinued and the patient was discharged on warfarin 7.5 mg daily. Upon clinic follow-up 5 days after discharge, the INR was supratherapeutic at 3.3 and the warfarin dose was decreased. The patient was then lost to follow-up. Discussion: This interaction between warfarin and dicloxacillin has been described in the literature; however, the mechanism responsible remains unknown. In all cases reported, increased warfarin requirements appeared after several days of dicloxacillin therapy and slowly disappeared after dicloxacillin discontinuation. This case differs from previously reported cases because it demonstrates warfarin resistance associated with dicloxacillin and a subsequent new initiation of warfarin therapy. The Naranjo probability scale and the Horn Drug Interaction Probability Scale both rate this interaction as probable. Conclusions: Patients taking dicloxacillin who are initiated on warfarin may require a longer duration of concurrent low-molecular-weight heparin therapy, as well as higher doses of warfarin, and may take longer to achieve a therapeutic INR.

Risk of Spontaneous Bruising with Concomitant Use of Nonsteroidal Antiinflammatory Drugs and Citalopram

Objective: To report a case of spontaneous bruising with concomitant use of nonsteroidal antiinflammatory drugs (NSAIDs) and citalopram. Case Summary: A 34-year-old white woman with a history of chronic thrombocytopenia (baseline platelet count 120–130 × 103/μL) presented to the emergency department (ED) after noticing an increase in bruising on her upper and lower extremities. When the patient was interviewed, it was found that her dose of citalopram had been recently increased from 20 to 40 mg/day and she had started ibuprofen (dose unknown) on her own to manage rib pain approximately 1 month after the citalopram dosage increase. The patient was advised to discontinue ibuprofen and was discharged. Shortly thereafter, she was started on oxaprozin 600 mg twice daily for management of trochanteric bursitis. She returned to the ED stating that bruising occurred 1 week after she was given oxaprozin. At this visit, the patient was told to discontinue oxaprozin and naproxen 440 mg twice daily was prescribed. One week later, the patient again returned to the ED with complaints of spontaneous bruising. At this point citalopram and naproxen were discontinued and she was started on acetaminophen (dose not documented) and buspirone 10 mg twice daily. No other episodes of ecchymosis have occurred in the 8 months since this change to her drug regimen. Discussion: Medications that increase the risk of bleeding should be carefully administered in patients who have a low platelet count. This patient experienced bruising when her dose of citalopram was increased and an increase in bruising when she combined an NSAID with citalopram. Selective serotonin reuptake inhibitors (SSRIs) may increase antiplatelet activity of NSAIDs and could therefore increase the risk of bruising. Use of the Horn Drug Interaction Probability Scale indicated a possible interaction with concomitant use of NSAIDs and citalopram. Conclusions: Patients who experience NSAID- and/or SSRI-related bruising should consult their providers and alternative treatments should be considered.

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.

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.

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.

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.

Interaction Between Enfuvirtide, an Injectable Fusion Inhibitor, and Niacin in an HIV-Infected Patient

To report a potential drug-drug interaction between enfuvirtide, an injectable HIV fusion inhibitor, and niacin in an HIV-infected man with dilated cardiomyopathy. A 47-year-old HIV-infected man with dilated cardiomyopathy and prolonged QT syndrome with an automatic implantable cardiovascular defibrillator device was prescribed subcutaneous enfuvirtide 90 mg twice daily as part of his antiretroviral regimen and oral extended-release niacin 500 mg/day for a high-density lipoprotein level of 8 mg/dL. After 1 week of concomitant therapy, the patient began experiencing extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. This interfered with his daily activities, leading to self-discontinuation of both agents. As the patient had tolerated enfuvirtide therapy prior to the addition of niacin, we reinitiated enfuvirtide with close follow-up, and the patient has been maintained on this agent since then without consequence. Based on the Horn Drug Interaction Probability Scale, a probable interaction occurred between enfurvirtide and niacin. We hypothesize that a drug-drug interaction occurs between enfuvirtide and niacin related to prostaglandin synthesis and mobilization of inflammatory cells, specifically Langerhans cells. A theoretical mechanism for this interaction is that the Langerhans cells in the epidermis function improperly due to the presence of HIV and the attachment of enfuvirtide. When these cells are exposed to nicotinic acid, an exaggerated immune response is produced that may lead to pain, redness, and swelling at the injection site. Prostaglandins, cytokines, and other inflammatory molecules may all have a role in this interaction. Caution should be used when coadministering enfuvirtide and niacin to HIV-infected patients.