Drug Interaction Probability Scale Research Articles

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.

Increased Aripiprazole Concentrations in an HIV-Positive Male Concurrently Taking Duloxetine, Darunavir, and Ritonavir

To report a case of increased aripiprazole concentrations during coadministration with darunavir, ritonavir, and duloxetine. A 43-year-old HIV-positive Hispanic man received darunavir/ritonavir-based antiretroviral therapy (ART) in addition to aripiprazole and duloxetine for depression and anxiety. A month after the aripiprazole dosage was increased to 50 mg daily, the patient developed confusion and loss of coordination. Weeks later, he presented to the emergency department with fever, cough, headache, neck stiffness, back pain, and blurred vision and was admitted for possible meningitis. Because symptoms improved with pain control and intravenous fluids during hospitalization, he was discharged within a couple days after admission. One month later he was readmitted for worsening symptoms, and the resulting diagnostic workup showed unremarkable findings except for lymphadenopathy (LAD). This finding was attributed to discontinuing ARTs after his first admission. He was discharged on aripiprazole 50 mg daily, darunavir 800 mg daily, ritonavir 100 mg daily, and duloxetine 60 mg daily. A random steady-state concentration of aripiprazole was 1100 ng/mL (therapeutic concentration 100-200 ng/mL) obtained 49 days after discharge. The Horn Drug Interaction Probability Scale demonstrated a possible relationship between the increased aripiprazole concentration and coadministration of darunavir/ritonavir and duloxetine, which inhibit CYP3A4 and 2D6. Potential confounders to the increased concentration include duloxetine inhibition of CYP2D6 polymorphism, possible 2D6 polymorphism, and exceeding aripiprazole's maximum dose. The initial presentation of confusion and loss of coordination may have been early signs of aripiprazole toxicity, which relapsed as shown by his symptoms prior to admission. The interaction between aripiprazole and darunavir, ritonavir, and duloxetine may be significant. Clinicians should be cognizant of increased risk of aripiprazole toxicity in HIV-positive patients concurrently taking ritonavir-boosted ART and other cytochrome P450 inhibitors like duloxetine. Dose adjustments or monitoring parameters should be an area of research and discussion.

Decreased plasma efavirenz concentrations in a patient receiving rifabutin

The case of a patient with decreased plasma efavirenz concentrations during concomitant rifabutin therapy is reported. A 42-year-old Hispanic man newly diagnosed with acquired immune deficiency syndrome (AIDS) and coinfected with aseptic meningitis and disseminated Mycobacterium avium complex (MAC) received efavirenz-based highly active antiretroviral therapy (HAART). When the patient was admitted to the hospital, his medications included enoxaparin, metformin, ganciclovir, clarithromycin, ethambutol, rifampin, pyrazinamide, isoniazid, pyridoxine, trimethoprim-sulfamethoxazole, dexamethasone, and tenofovir-emtricitabine- efavirenz. Rifampin was changed to rifabutin 450 mg daily due to the potential interaction with rifampin and efavirenz. Clarithromycin was replaced with azithromycin for the treatment of MAC infection, and dexamethasone was gradually decreased over three months. The established therapeutic plasma concentration of efavirenz is 1-4 μg/mL. After receiving the standard efavirenz dosage of 600 mg daily, the patient had subtherapeutic plasma efavirenz concentrations. To correct these low concentrations, the patient's efavirenz dosage was increased to 800 mg daily; however, his efavirenz concentrations continued to remain subtherapeutic (two concentrations of 0.58 μg/mL). The patient's viral load decreased slowly while on HAART; however, it only became undetectable 12 days after rifabutin was discontinued. The Drug Interaction Probability Scale demonstrated a probable relationship between the coadministration of rifabutin and the decreased efavirenz concentrations due to the possible induction of efavirenz metabolism by rifabutin. A 42-year-old Hispanic man newly diagnosed with AIDS had subtherapeutic efavirenz levels during concomitant treatment with rifabutin.

Ranolazine-Tacrolimus Interaction

To report the case of a kidney allograft recipient on a stable regimen of tacrolimus who exhibited increased tacrolimus concentrations within 24 hours of initiating ranolazine. A 64-year-old kidney allograft recipient on a stable dose of tacrolimus (10 mg twice daily) was admitted for recent worsening of her chronic anginal pain. The patient was initiated on ranolazine 500 mg twice daily on hospital day 2. Tacrolimus concentrations rose from 7.0-10.1 ng/mL preadmission to 17.8 ng/mL within 24 hours of ranolazine initiation. Ranolazine therapy was continued due to the patient's beneficial response; therefore, the tacrolimus dose was eventually decreased by 70% to 3 mg twice daily to maintain steady-state trough concentrations between 6.6 and 7.9 ng/mL with ranolazine therapy. Ranolazine dechallenge on a subsequent admission produced subtherapeutic tacrolimus concentrations requiring dosage increases. Ranolazine, an antianginal agent, is both a substrate and a weak inhibitor of CYP3A as well as a substrate and moderate inhibitor of the P-glycoprotein (P-GP) efflux transport system. Tacrolimus, an immunosuppressant, is also a substrate of CYP3A and P-GP. Through possible inhibition of both P-GP- and CYP3A-mediated first-pass metabolism and CYP3A systemic metabolism, ranolazine may have significantly increased serum concentrations of tacrolimus necessitating an eventual 70% decrease in the tacrolimus dose. Based on the Horn Drug Interaction Probability Scale, this interaction is possible. We suggest that the eventual 70% decrease in tacrolimus dose after ranolazine initiation may indicate that ranolazine decreases the metabolism and clearance of tacrolimus, causing an elevation in tacrolimus concentrations and the potential for tacrolimus toxicity. Clinicians should be aware of this possible interaction when initiating ranolazine in patients on tacrolimus.

Simvastatin-induced myopathy, the role of interaction with diltiazem and genetic predisposition

Diltiazem shows a pharmacokinetic interaction with statins that are CYP3A substrates but this may not result in myopathy unless additional genetic or clinical factors are present. Subsequent changes in treatment or underlying disease may result in a delayed onset of this adverse affect. Our objective is to report on two cases of statin-induced myopathy associated with concomitant use of diltiazem and other contributing factors, and to briefly review the related literature. A 63-year-old Chinese woman with hypertension and familial hypercholesterolaemia (FH) taking diltiazem 90 mg twice daily had elevation of creatine kinase (CK) to 4016 U/L and alanine aminotransferase (ALT) to 165 IU/L 4 weeks after increasing the dose of simvastatin from 40 to 80 mg daily. Another 80-year-old Chinese woman with FH, mild vascular dementia and hypertension was hospitalized with bilateral lower limb weakness associated with raised CK (8869 IU/L), lactate dehydrogenase (1384 IU/L) and ALT (288 IU/L) after taking diltiazem 60 mg twice daily with simvastatin 40 mg for 11 months. Statin-associated myopathy was suspected and simvastatin was stopped in both cases, and symptoms resolved and all laboratory parameters returned to normal in 2 weeks. The myopathy in both cases is likely to have resulted from an interaction of higher doses of simvastatin with diltiazem through inhibition of CYP3A enzymes and drug transporters. The strength of simvastatin-diltiazem interactions in the two cases estimated by the Drug Interaction Probability Scale (DIPS) indicated a possible association. The two cases reported here and the brief literature review emphasize the potential interaction between two drugs frequently coadministered, simvastatin and diltiazem and we suggest that diltiazem should not be used with higher doses of those statins metabolized by CYP3A such as simvastatin or atorvastatin and even with lower doses caution should be exercised in patients who may have cause for impaired metabolism.

Probable tacrolimus toxicity from tibolone co-administration in a woman: a case report

IntroductionTibolone is a synthetic steroid, used with increasing frequency to treat symptoms of menopause, including patients with solid-organ transplants who are taking concurrent immune suppression. To the best of our knowledge, there are no reported drug interactions between tibolone and tacrolimus, one of the principal immune suppressants used in kidney transplantation.Case presentationWe report the case of a 49-year-old Caucasian woman who had received a kidney transplant and who developed acute kidney injury secondary to tacrolimus toxicity 10 days after starting tibolone therapy. No alternative causes were found. Tibolone is known to be a weak competitive inhibitor of CYP3A4, which is involved in tacrolimus metabolism.ConclusionsDespite a careful evaluation, no alternative reason was found for the acute kidney injury, and her kidney function returned to the previous baseline within several days of cessation of the medication, and with no other specific treatment. Using the Drug Interaction Probability Scale we conclude that she experienced a probable drug interaction. We believe that transplant clinicians should utilise frequent therapeutic drug monitoring of tacrolimus in patients starting or stopping tibolone therapy.

Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma

Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other agents to CYP3A4 drug-drug interactions. This report discusses a clinically relevant pharmacokinetic CYP3A4 drug-drug interaction between sorafenib and felodipine in an 80-year-old Caucasian patient with HCC. On day 15, after the introduction of sorafenib (400mg bid), sorafenib plasma concentration was at 3.6mg/L. Felodipine (5mg bid), an anti-hypertensive agent that is exclusively CYP3A4 substrate, was then introduced due to grade 2 sorafenib-related hypertension. On day 30, hypertension was well controlled. However, sorafenib plasma concentration was 3-fold greater (11.4mg/L) and the patient experienced grade-3 anorexia. Since neither diarrhea nor cutaneous side effects were noticed at this time, sorafenib treatment was continued at the same daily dosage. On day 45, sorafenib plasma concentration was stable (10.8mg/L) before declining on days 60 and 75 (7.0mg/L and 7.4mg/L, respectively), which was probably related to an occurrence of grade-2 diarrhea. This observation suggests a pharmacokinetic interaction involving CYP3A4 inhibition by felodipine. According to the Drug Interaction Probability Scale, this interaction was possible. Since hypertension is a common toxicity of sorafenib, clinicians should be aware of this possible interaction. The clinical relevance of pharmacokinetic interactions involving CYP3A4 inhibition in HCC patients receiving sorafenib is analyzed in this case report.

An Interaction Between Levodopa and Enteral Nutrition Resulting in Neuroleptic Malignant-Like Syndrome and Prolonged ICU Stay

To describe a probable interaction between enteral feeds and levodopa leading to neuroleptic malignant-like syndrome (NMLS) in a polytrauma patient with Parkinson's disease (PD). A 63-year-old morbidly obese male polytrauma patient with PD and type 2 diabetes mellitus was admitted to our intensive care unit postoperatively. Enteral feeds were administered per nasogastric tube and provided 0.88 g /kg/day of protein based on ideal body weight (IBW). His PD medications (pramipexole, entacapone, and immediate-release levodopa/carbidopa 100 mg/25 mg, 1.5 tablets 4 times daily) were administered via nasogastric tube. To achieve better glycemic control, his enteral feeds were changed to a formula that provided 1.8 g/kg/day of protein based on IBW. In the following 24 hours, the patient's mental status deteriorated and he was reintubated. He developed a high fever (40.5 degrees C), leukocytosis, elevated serum creatine kinase (CK) (480-1801 units/L), and acute renal impairment. His enteral nutrition was changed to decrease protein intake to 1.0 g/kg/day based on IBW and he was given bromocriptine 5 mg 3 times daily via nasogastric tube. Within 24 hours, the patient's mental status improved, his temperature and CK decreased, and his renal function began to improve; the values returned to baseline levels on the 18th day of admission. Withdrawal or dose reduction of levodopa in patients with PD has been reported to precipitate NMLS, which is potentially fatal. Because dietary protein can decrease the absorp0tion of levodopa, a potential for an interaction between levodopa and enteral feedings exists, although published reports of such an interaction are limited. In this patient, the likelihood that a drug-nutrient interaction occurred between levodopa and enteral feedings is considered to be probable based on the Naranjo probability scale and the Horn Drug Interaction Probability Scale. Health-care professionals should be aware of the interaction between levodopa and protein content of enteral nutrition to avoid the occurrence of NMLS in patients with PD.

Drug Interaction Between Itraconazole and Bortezomib: Exacerbation of Peripheral Neuropathy and Thrombocytopenia Induced by Bortezomib

To investigate whether a drug interaction exists between bortezomib and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole and/or the CYP2C19 inhibitor lansoprazole that results in increased severity of bortezomib-induced peripheral neuropathy and thrombocytopenia. Retrospective medical record review. Hematology-oncology ward of a university-affiliated hospital in Japan. Six adults with relapsed multiple myeloma who received intravenous bortezomib plus oral dexamethasone as the first course of a 21-day cycle between July 2007 and December 2008. Four of the six patients were treated concomitantly with itraconazole or lansoprazole: two with itraconazole, one with lansoprazole, and one with both itraconazole and lansoprazole. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, we identified the presence and graded the severity of peripheral neuropathy and thrombocytopenia before and during each patient's first 21-day course of bortezomib plus dexamethasone therapy. All three patients who received itraconazole experienced new or worsening peripheral neuropathy; they also experienced grade 4 thrombocytopenia. The patient who received lansoprazole alone, as well as the two patients who did not receive itraconazole or lansoprazole, had no changes in either adverse effect. We also evaluated the relationship between peripheral neuropathy and bortezomib plus dexamethasone therapy by using the Naranjo adverse drug reaction probability scale, and a probable relationship was found. We further assessed whether a drug interaction between bortezomib and itraconazole and/or lansoprazole had occurred involving the CYP3A4 and/or the CYP2C19 pathways, respectively-resulting in increased severity of the bortezomib-induced peripheral neuropathy and thrombocytopenia-by using the Horn drug interaction probability scale. We found that the occurrence of this drug interaction was strongly supported. Itraconazole appears to exacerbate peripheral neuropathy and thrombocytopenia induced by bortezomib; however, the mechanism of this drug interaction is unknown. Clinicians should closely monitor for bortezomib-induced adverse effects when itraconazole, or any other potent CYP3A4 inhibitor, is administered concomitantly with bortezomib.

Analysis of purported erythromycin–warfarin interaction

In their article about a potential interaction between warfarin and erythromycin ointment, Parker et al.[1][1] applied the Drug Interaction Probability Scale (DIPS)[2][2] to assess the probability of a causal relationship between the purported drug interaction and changes in the International

Interaction between Warfarin and Transdermal Selegiline: First Case Report and Literature Review

Abstract A procoagulant effect may occur when enzymatic inhibitors of CYP2C9, 1A2, or 3A4 are therapeutically coadministered with warfarin. To our knowledge, there have been no case reports of such an interaction between warfarin and selegiline. We describe a case of a 49-year-old female who was taking warfarin for prevention of a venous thromboembolism after orthopedic surgery. During routine follow-up, the patient's international normalized ratio (INR) suddenly elevated to 9.0. Her INR had been subtherapeutic for 2 months prior despite escalating doses of warfarin. The only identifiable change to the patient's lifestyle or medications was the initiation of transdermal selegiline 5 days prior to this supratherapeutic INR. Recent laboratory tests revealed no significant abnormalities, with the exception of slightly depressed serum albumin. Her warfarin was held for 2 days, oral phytonadione 2.5 mg was given, and selegiline was held. The Drug Interaction Probability Scale revealed a probable drug-drug interaction between warfarin and selegiline. The likely mechanism of this interaction is selegiline-mediated moderate inhibition of CYP1A2 and weak or competitive inhibition of 2C9 and 3A4. Clinicians should be hypervigilant to this probable drug-drug interaction when initiating either therapy in a patient maintained on the opposing drug.

Interaction between tacrolimus and clindamycin.

Sir, Tacrolimus is widely used in organ transplantation to prevent allograft rejection. Its hepatic metabolism via cytochrome P450 (CYP) 3A4 represents the major eliminating process. In addition, its bioavailability depends on intestinal P-glycoproteins (PGP) and CYP3A5 activities. Due to its potential toxicity, tacrolimus usage requires a close drug monitoring, as well as the early identification of any pharmacological interaction. Here, we report on a novel interaction between tacrolimus and clindamycin in a renal transplant recipient with Pneumocystis jirovecii pneumonia (PJP). A 61-year-old woman underwent kidney transplantation from a deceased donor for end-stage renal disease secondary to chronic glomerulonephritis with IgA deposits. Two months later, she presented with grade IV dyspnoea. Maintenance immunosuppression included modified-release (MR) tacrolimus 15 mg/day, mycophenolate mofetil (MMF) 720 mg/day and prednisolone 4 mg/day. Thorax computed tomography showed bilateral ground-glass opacities compatible with PJP, as confirmed by bronchoalveolar lavage analyses. MMF was interrupted, and sulphamethoxazole–trimethoprim (4 × 1280 mg/day) was initiated with methylprednisolone (32 mg/day). The patient's condition declined, requiring mechanical ventilation. From that time, medications were given through a nasogastric tube, and tacrolimus trough level remained stable ∼10 ng/mL while receiving 7 mg/day (Figure 1). Because sulphamethoxazole–trimethoprim treatment induced type IV renal tubular acidosis, antimicrobial therapy was substituted for atovaquone (1500 mg/day) and clindamycin (2400 mg/day IV) on Day 8. Tacrolimus trough level progressively decreased, while its dosage was accordingly increased (Figure 1). Six days later, both atovaquone and clindamycin were interrupted with a progressive return of tacrolimus trough level to baseline. Since the administration of MR tacrolimus through a nasogastric tube may decrease its disposition, the twice-a-day form was initiated (Figure 1). Fibroscopy was performed 10 days after antibiotic withdrawal and disclosed PJP recurrence. Both atovaquone and clindamycin were resumed for 6 days. Again, tacrolimus trough level significantly decreased (Figure 1) though no other medication was initiated. Renal graft function remained stable. Fig. 1 Changes in tacrolimus blood trough level (nanogram per millilitre) and tacrolimus dose (milligram per day) according to atovaquone/clindamycin therapy from Day 4 at the intensive care unit. Advagraf® and Prograft® represent the modified-release ... Because of its extensive metabolism, tacrolimus disposition tightly depends on CYP3A4/5 and PGP activities. Here, a significant decrease of tacrolimus trough level was repeatedly observed when co-administered with atovaquone and clindamycin. Atovaquone is 94% excreted unchanged in faeces, with a modest inhibition of CYP2C19 which is not implicated in tacrolimus metabolism [1]. Conversely, clindamycin metabolism primarily requires its oxidation by CYP3A4/5 and exhibits a clear propensity to induce CYP3A4 activity [2,3]. Thus, similarly to former cases reported under cyclosporine [4], clindamycin may accelerate tacrolimus catabolism. Here, the co-administration of clindamycin and tacrolimus led twice to a significant decrease in tacrolimus trough level. Such temporal relationship is highly suggestive of pharmacological interactions, as supported by a significant Drug Interaction Probability Scale (DIPS) score [5]. In conclusion, the present observation emphasizes the need for a close monitoring of tacrolimus trough level when co-administered with high-dose clindamycin. Conflict of interest statement. None declared.

Significant Sirolimus and Dronedarone Interaction in a Kidney Transplant Recipient

To report the potential clinically significant pharmacokinetic interaction between sirolimus and dronedarone. A 67-year-old man status post-kidney transplant in 2004 was maintained on an immunosuppressive regimen consisting of sirolimus, mycophenolate mofetil, and prednisone. He had been maintained for more than 1 year on a stable dose of sirolimus (5 mg/day), with concentrations ranging between 5 and 13.5 ng/mL. The patient was admitted to the hospital with a complaint of bloody diarrhea; shortly after admission, he developed atrial fibrillation for which dronedarone 400 mg twice daily was initiated. Sirolimus concentrations obtained 3 days after initiation of dronedarone revealed a trough concentration that was increased by more than 3-fold (38.6 ng/mL) from his baseline trough concentration. After sirolimus was held for 6 days, the trough concentration was 7.8 ng/mL. The dosage was reduced to 1 mg/day; there was no need for further adjustment. While the potential for an interaction between sirolimus and dronedarone is listed in the package insert of dronedarone, there are no documented reports of this interaction in the peer-reviewed literature. Since sirolimus is a narrow therapeutic index medication, information about the severity and magnitude of the interaction with dronedarone may help clinicians avoid therapeutic misadventures when this combination is employed. Our case clearly demonstrates a significant pharmacokinetic interaction between sirolimus and dronedarone. The Horn Drug Interaction Probability Scale indicates that the occurrence of an interaction between sirolimus and dronedarone in our case is probable. Due to the potential for sirolimus toxicity and excessive immunosuppression, the concurrent use of dronedarone and sirolimus should be avoided when possible. If concurrent administration cannot be avoided, we suggest close monitoring and a 50-75% dose reduction of sirolimus prior to dronedarone initiation.

Imatinib and Panax Ginseng: A Potential Interaction Resulting in Liver Toxicity

To report a case of imatinib-induced hepatotoxicity after concurrent ginseng ingestion in a patient with chronic myelogenous leukemia (CML). A 26-year-old man with CML who had taken imatinib 400 mg daily for 7 years with no complications presented with right upper quadrant pain. Laboratory test results included alanine aminotransferase 1069 U/L, aspartate aminotransferase 481 U/L, alkaline phosphatase 124 IU/L, total bilirubin 1.4 mg/dL, albumin 4.0 g/dL, and international normalized ratio 1.08. Liver biopsy showed acute lobular hepatitis favoring a drug-induced etiology, and a diagnosis of imatinib-induced hepatotoxicity was made. The patient's only lifestyle modification prior to the diagnosis of hepatotoxicity was daily ingestion of Panax ginseng via energy drinks for the past 3 months. Both imatinib and ginseng were discontinued, and the patient was treated with a short course of corticosteroids. Imatinib was later restarted at the same dose with no recurrent elevations in his liver enzyme levels. Imatinib-associated hepatotoxicity usually presents within 1-2 years of therapy initiation, with the median time to hepatotoxicity being 100 days. Ginseng is an herb that is not known to be hepatotoxic. In vivo, ginseng is known to inhibit CYP3A4, the primary enzyme involved in the metabolism of imatinib. We propose that our patient's late-onset imatinib-associated hepatotoxicity was due to an interaction between ginseng and imatinib through CYP3A4. Based on the Naranjo probability scale, it is probable that imatinib caused this patient's hepatotoxicity, and the Horn drug interaction probability scale also indicates a probable interaction between imatinib and ginseng. This case emphasizes the importance of continuous monitoring of liver function tests even after several years of imatinib therapy and the importance of advising patients to avoid ginseng and any other over-the-counter herbal supplements that may interact with imatinib.

Symptomatic Hypoglycemia Associated with Trimethoprim/Sulfamethoxazole and Repaglinide in a Diabetic Patient

To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient. A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale). This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia. This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

Warfarin-flucloxacillin interaction presenting as cardioembolic ischemic stroke

Both warfarin and flucloxacillin are frequently prescribed medications which have the potential to have life threatening interactions. We describe a case of sub-therapeutic anticoagulation following a course of oral flucloxacillin, resulting in an ischemic stroke. A 68-year-old female on long term anti-coagulation for atrial fibrillation presented with an acute left hemiparesis. International normalised ratio (INR) was 1.4 in the emergency department. She had commenced a 14-day course of oral flucloxacillin 500 mg qid and oral phenoxymethylpenicillin 999 mg qid for a soft tissue infection of her foot 17 days prior to admission. The most recent INR taken 19 days prior to admission was 3.5. The patient’s anti-coagulation regimen had been managed by a hospital based clinic. A target INR of 2–3 had been maintained with doses of 4 and 3 mg on alternate days for a period of over 6 months with monthly INR checks. Past medical history included diabetes mellitus type 2, tissue mitral valve replacement, myocardial infarction and hypercholesterolaemia. Her concomitant medications were quinapril, atorvastatin, metoprolol, lercardipine, spironolactone, bumetanide, digoxin, metformin, gliclazide and biphasic isophane insulin. The patient did not report any other recent change in medication, any change in diet or alcohol intake and no change in warfarin brand. She had not experienced any gastrointestinal illness and reported good compliance with her medication regimen. No alternative stroke mechanism was identified following extensive investigation including carotid duplex, magnetic resonance brain imaging (MRI), magnetic resonance angiography (MRA), and trans-thoracic echocardiography. Using the Drug Interaction Probability Scale, a rating of 7 in this case indicates a probable causative interaction [1]. On review of the patient’s pharmacy, medical and anticoagulation clinic records, it was noted that oral flucloxacillin and phenoxymethylpenicillin had previously been prescribed for the patient 6 weeks prior to admission. On that occasion an INR of 1.8 was recorded 5 days after completing the course of antibiotics. A case of suspected interaction between oral flucloxacillin and warfarin has been recently reported [2]. Review of the literature reveals one further description of subtherapeutic anti-coagulation when flucloxacillin and a coumarin were prescribed concurrently. The authors in that case attributed the fall in INR to concomitant rifampicin, however the role of flucloxacillin may have been underestimated [3]. Flucloxacillin has the potential to induce expression of cytochrome P450 3A4 which is the enzyme which catalyzes the 10-hydroxylation of R-warfarin [4, 5]. The inflammatory response to infection and individual genetic variation may influence warfarin metabolism by pharmacokinetic or pharmacodynamic mechanisms [1, 6]. In this case the infection treated was a localised skin infection with no evidence of a systemic inflammatory response or underlying osteomyelitis. Sub-therapeutic anticoagulation has been reported previously with warfarin and This work has not been published or presented previously.

Interaction between Warfarin and the Herbal Product Shengmai-Yin: A Case Report of Intracerebral Hematoma

A 71-year-old man was stable on warfarin (2.25 mg daily) therapy with an international normalized ratio (INR) of 1.8-2.2 after a heart valve replacement surgery. Recently, he consumed the liquid-like herbal product called shengmai-yin (10 mL daily) against medical advice. Seven days after the daily consumption of shengmai-yin, he was admitted to the intensive care unit because of consciousness disturbance [Glasgow Coma Scale (GCS) score 7] with an INR of 5.08. Head computed topography revealed intracerebral hematoma in the left temporoparietal region. Both warfarin therapy and the herbal product were withdrawn. At the same time, therapy with intravenous vitamin K1 40 mg was started. On the second day of admission, craniectomy was performed to remove the intacerebral hematoma under general anesthesia. He remained confused and restless for 2 days, but then showed progressive recovery in the consciousness level as well as motor and verbal functions. Shengmai-yin contains herbal ingredients that can interact with warfarin. The Drug Interaction Probability Scale (DIPS) indicated that warfarin and shengmai-yin were highly probable causes of intracerebral hematoma. Patients on warfarin therapy should be discouraged from taking herbal medicines, especially preparations that are already known to have antiplatelet and antithrombotic effects.

Severe toxicity related to a pharmacokinetic interaction between docetaxel and ritonavir in HIV‐infected patients

The treatment of AIDS-related malignancies raises specific pharmacological issues in patients receiving highly active antiretroviral therapy (HAART), particularly when the regimen includes a ritonavir-boosted protease inhibitor. Ritonavir potently inhibits CYP3A4, the main enzyme involved in the metabolism of a number of anticancer agents, including docetaxel [1–3]. We have recently treated three patients receiving ritonavir-based HAART, who experienced severe haematological and skin toxicity shortly after the first infusion of docetaxel. We believe that this toxicity was directly triggered by ritonavir. Hence, despite normal baseline liver function and blood cell counts, our patients experienced early febrile neutropenia, grade 3 mucositis, skin rash and hand-foot syndrome (Table 1). None of the patients had other recognized risk factors for docetaxel-induced febrile neutropenia: albuminaemia and C-reactive protein were normal, and baseline lymphocyte count was >700 g l−1[2, 4]. Table 1 Severe toxicity following co-administration of docetaxel and ritonavir-based highly active antiretroviral therapy (HAART) Docetaxel is approved in the treatment of non-AIDS-defining malignancies such as breast, prostate and lung cancers, but also displays clinical activity in Kaposi's sarcoma [5]. In a Phase II study, docetaxel administered weekly was active and well tolerated in Kaposi's sarcoma patients, with moderate haematological toxicity [5]. However, patients included in this study received HAART without ritonavir pharmacoenhancement, and therefore did not experience toxicity in the same range as that observed in our case series. Preclinical reports indicate that ritonavir-induced inhibition of CYP3A4 causes a significant increase in exposure to docetaxel [6]. In a similar way, concomitant administration of docetaxel and ketoconazole, another potent inhibitor of CYP3A4, resulted in a major reduction in plasma clearance of docetaxel [7]. Therefore, we assume that ritonavir-induced inhibition of CYP3A4 may decrease the plasma clearance of docetaxel, and subsequently lead to severe docetaxel-related toxicity (mainly haematological and cutaneous). Another three cases [8, 9] of severe toxicity following co-administration of docetaxel and ritonavir were found in the literature (Table 1). As well, toxicity occurred after the first cycle of treatment, even with moderate doses of docetaxel (25–60 mg m–2). According to the drug interaction probability scale, the event–drug relationship was probable [10]. Among the above-described cases, paclitaxel was substituted for docetaxel in two patients, without recurrence of severe toxicity in the following cycles. However, two cases of severe haematological toxicity (including one fatal outcome) have been reported after the concomitant administration of paclitaxel and ritonavir [11]. Of note, paclitaxel is mainly metabolized by CYP2C8, and to a lesser extent by CYP3A4 [12]. Hence, it remains unclear whether inhibition of CYP3A4 by ritonavir could significantly decrease the plasma clearance of paclitaxel and cause severe haematological toxicity. In conclusion, these cases strongly support our hypothesis of a pharmacokinetic drug–drug interaction between ritonavir and docetaxel, even in patients treated with low doses of docetaxel. Clinicians should be aware that human immunodeficiency virus-infected patients receiving ritonavir-based HAART must receive anticancer drugs that are not metabolized by CYP3A4 instead of docetaxel.

Elevated International Normalized Ratio associated with concurrent use of sorafenib and warfarin

The case of a patient who experienced elevated International Normalized Ratio (INR) values and hemorrhage after sorafenib was added to his warfarin regimen is presented. A 70-year-old Caucasian man with a history of hypertension, congestive heart failure, gastroesophageal reflux disease, chronic obstructive pulmonary disease, and chronic hepatitis C was treated with warfarin for anticoagulation subsequent to atrial fibrillation. He began anticoagulation management by a clinical pharmacist in April 2007 and was stabilized on warfarin 36 mg weekly. He was diagnosed with hepatocellular carcinoma in June 2007 and began treatment with sorafenib 200 mg daily in September 2007. The patient arrived at the emergency room one month later with a prothrombin time (PT) of 84.8 and an INR value of 39.5. He was admitted for lower-extremity hemorrhage and diagnosed with warfarin toxicity. Sorafenib was discontinued, and warfarin was held during this hospital stay. The patient was discharged on warfarin 3 mg daily. In November, warfarin was increased to 36 mg weekly, and his INR values stabilized. In late November, he was restarted on sorafenib 200 mg daily presumably due to multiple new hepatic hypodense lesions indicating progression of the metastatic disease. Approximately two weeks later, the patient's INR value increased to 4.7. Sorafenib was discontinued permanently. Both the Naranjo et al. probability scale score and the drug interaction probability scale score suggest that there was a probable interaction between warfarin and sorafenib. A 70-year-old man diagnosed with hepatocellular carcinoma experienced an increase in INR values after the addition of sorafenib to his warfarin regimen.

Potential Interaction Between Pomegranate Juice and Warfarin

To my knowledge, no published reports have described an interaction between pomegranate juice and warfarin. Investigators from previous animal and in vitro studies have reported a potential for pomegranate juice to inhibit metabolism involving the cytochrome P450 system, an effect that could translate into a clinical drug-diet interaction with warfarin. This case report describes a 64-year-old Caucasian woman who was treated with warfarin for recurrent deep vein thrombosis. She had been receiving a relatively stable dosage of warfarin 4 mg/day for several months, with stable international normalized ratios (INRs). During that time, the patient was consuming pomegranate juice 2-3 times/week. She stopped drinking the juice, and her INRs became subtherapeutic. Her dosage of warfarin was increased to maintain therapeutic anticoagulation. No rechallenge with pomegranate juice was performed. Use of the Drug Interaction Probability Scale indicated a possible relationship between the patient's subtherapeutic INR and the pomegranate juice. Although this potential interaction needs to be explored further, clinicians should be aware of the interaction and thoroughly interview and closely monitor their patients who are receiving warfarin.