Fatal Drug Interaction Research Articles

Lesson of the month 1: A rare adverse reaction between flucloxacillin and paracetamol

Flucloxacillin, a beta-lactam antibiotic, is a commonly prescribed antibiotic for the treatment of infections caused by staphylococci and streptococci, most notably Staphylococcus aureus Paracetamol is one of the most dispensed medications by NHS England and is used for the treatment of fever and pain.1 However most doctors are unaware that concurrent use of these drugs can cause a potentially fatal drug interaction due to pyroglutamic acidosis (PGA), also known as 5-oxoprolinaemia. PGA is a rare cause of raised anion gap metabolic acidosis due to disruption of the γ-glutamyl cycle. We report the case of a patient with multiple comorbidities who developed PGA due to coadministration of paracetamol and flucloxacillin.

A fatal drug interaction

The consumption of caffeine in response to insufficient sleep may impair the onset and maintenance of subsequent sleep. This systematic review and meta-analysis investigated the effect of caffeine on the characteristics of night-time sleep, with the intent to identify the time after which caffeine should not be consumed prior to bedtime. A systematic search of the literature was undertaken with 24 studies included in the analysis. Caffeine consumption reduced total sleep time by 45 min and sleep efficiency by 7%, with an increase in sleep onset latency of 9 min and wake after sleep onset of 12 min. Duration (+6.1 min) and proportion (+1.7%) of light sleep (N1) increased with caffeine intake and the duration (−11.4 min) and proportion (−1.4%) of deep sleep (N3 and N4) decreased with caffeine intake. To avoid reductions in total sleep time, coffee (107 mg per 250 mL) should be consumed at least 8.8 h prior to bedtime and a standard serve of pre-workout supplement (217.5 mg) should be consumed at least 13.2 h prior to bedtime. The results of the present study provide evidence-based guidance for the appropriate consumption of caffeine to mitigate the deleterious effects on sleep.

Interacción farmacológica letal

Interacción farmacológica letal

Fatal warfarin drug interactions reported

Fatal warfarin drug interactions reported

Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study

BackgroundPatients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.Case presentationOn Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.ConclusionsAfter extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.

Drug interaction presenting as acute abdomen

Warfarin is the most common oral anticoagulant prescribed around the world. Adverse drug interactions with warfarin are a huge problem especially in the elderly and in patients who take multiple medications. Most adverse drug interactions involve concomitantly prescribed oral or intravenous medications. Occasionally, topical or mucosally absorbed drugs can interact, leading to fluctuations in warfarin levels with adverse consequences. In this case report, we describe a case of intestinal intramural hematoma, a rare but known consequence of a supra therapeutic international normalized ratio (INR). The supra therapeutic INR was a consequence of mucosally absorbed miconazole, prescribed for vaginal candidiasis. We wish to highlight this rare and potentially fatal drug interaction, along with the need for frequent INR monitoring when new drugs are added or removed in patients taking warfarin.

Eine tödliche Arzneimittelinteraktion

b Klinische Pharmakologie und Toxikologie, Universitatsspital Basel Summary A fatal drug interaction After intake of only two 125 mg tablets of brivudine (Zostex ® ) fatal toxicity of the 5-FU-prodrug capecitabine (Xeloda ® ) occurred due to irreversible inhibition of the catalytic enzyme dihydropyrimidine dehydrogenase (DPD). Despite im- mediate withdrawal of capecitabine and appropriate supportive measures in the intensive care unit, the tissue concentration was sufficient to cause death within twelve days from cutaneous and mucosal toxicity, sepsis and circula- tory failure.

EVIDENCE FOR CONTAMINATION OF HERBAL ERECTILE DYSFUNCTION PRODUCTS WITH PHOSPHODIESTERASE TYPE 5 INHIBITORS

We determined if pharmacological dosages of phosphodiesterase type 5 inhibitors (PDE5) inhibitors were present within a group of natural products marketed for the treatment of erectile dysfunction. Seven herbal products marketed for the treatment of erectile dysfunction were purchased via the Internet or at local health food stores. Specimens were batched, relabeled and blindly analyzed for contamination with PDE5 inhibitors. High performance liquid chromatography and mass spectrometry were used to detect evidence of contamination with sildenafil, tadalafil or vardenafil. Of the 7 tested products 2 contained pharmacological dosages of sildenafil and tadalafil. Contamination with vardenafil was not identified. Mean dosages of sildenafil and tadalafil were 30.2 and 19.7 mg, respectively. A significant proportion of natural products marketed for erectile dysfunction contains PDE5 inhibitors. Although marketed as natural products devoid of adverse effects, these agents are known to have potentially fatal drug interactions with nitrates. Better regulation of the natural health products industry is urged.

Commentary on: Borrows DL, Hagardorn AN, Harlan GC, Wallen EDB, Ferslew KE. A fatal drug interaction between oxycodone and clonazepam. J Forensic Sci 2003;48(3):683-86.

Abstract Sir: This letter is in response to information published within a case report written by David L. Burrows et al. in the May 2003 issue of J Forensic Sci (1). We credit the authors for bringing to light the potentially fatal consequence of the concomitant abuse of two central nervous system (CNS) depressant drugs, such as oxycodone and clonazepam, as there may be an under-appreciation of such a risk. The risk of fatal overdose is indeed substantially increased when opioids are abused in combination with other CNS active drugs (2). However, in the article, titled “A fatal drug interaction between oxycodone and clonazepam,” the authors provide a table with OxyContin® (oxycodone HCl controlled-release) pharmacokinetic and dosage information (Table 1) that is inaccurate and potentially misleading.

Author's Response

Abstract Sir: Thank you for the comments regarding our article A fatal drug interaction between oxycodone and clonazepam. The commentary states that the authors seem to base their statement of a fatal drug interaction on a metabolic interaction between oxycodone and clonazepam. The second paragraph of the introductory section postulates not only mechanisms of metabolic hindrance by competitive substrates (clonazepam and oxycodone), but also by other drugs (cannabinoids) and pathologies present in this particular subject. In our conclusions, we also state the concentrations of oxycodone and clonazepam observed may have resulted from either an acute administration of a particular dosage and/or an attenuated metabolism.

Author's Response

Abstract Sir: Thank you for the comments regarding our article “A fatal drug interaction between oxycodone and clonazepam.” First, it should be noted that the dosages and concentrations in Table 1 are all referenced from previously published literature and are considered typical initial dosages and concentrations (1–3). There is a typographical error presented in Table 1 of our article. The maximum daily dose should have been printed as 20–320 mg/day. We appreciate the correction.

Subdural Hematoma Due to Probable Warfarin–Fluorouracil Interaction

Objective: To describe the occurrence of a subdural hematoma in a woman undergoing chemotherapy with cyclophosphamide, methotrexate, and fluorouracil combined with warfarin therapy. Case Summary: A 60-year-old white woman with atrial fibrillation underwent radical mastectomy for primary breast cancer with histologically positive axillary lymph nodes. Following surgery, the patient received adjuvant chemotherapy with a CMF 1–8 regimen consisting of cyclophosphamide 100 mg/m2 orally on days 1–14, methotrexate 40 mg/m2 intravenously, and fluorouracil 600 mg/m2 by intravenous bolus on days 1 and 8 every 4 weeks. Warfarin 5 mg/day was administered concomitantly due to atrial fibrillation. Following the second course of concomitant therapy, the patient developed a headache, hemiparesis, and an international normalized ratio (INR) of 7.6, which was highly suggestive of a drug interaction between fluorouracil and warfarin. A computed tomography scan of the brain revealed a left parieto-occipital subdural hematoma. Discussion: This case emphasizes the importance of the potentially fatal drug interaction involving warfarin and fluorouracil. Conclusions: Several adverse interactions between warfarin and fluorouracil have been reported. Considering the severity of this interaction, close monitoring of the INR is recommended in patients receiving these agents concomitantly.

Drug interactions and the anesthesiologist

ZusammenfassungEines der Grundprinzipien der modernen Anästhesie ist die Kombination unterschiedlicher Pharmaka aus verschiedenen Substanzgruppen. Zusätzlich sehen sich Anästhesisten häufig mit der umfangreichen medikamentösen Dauertherapie chronisch kranker Patienten konfrontiert. Werden zwei oder mehrere Medikamente gleichzeitig appliziert, kann sich der pharmakologische Effekt von der Summe der einzeln verabreichten Substanzen unterscheiden. Das kann erwünscht, aber für den Patienten auch potenziell gefährlich sein. Die Wahrscheinlichkeit einer unerwünschten Arzneimittelwechselwirkung steigt exponentiell mit der Anzahl der verabreichten Medikamente und kann sowohl auf pharmazeutischer, pharmakodynamischer wie pharmakokinetischer Ebene entstehen. Obwohl die Fülle der Interaktionsmöglichkeiten enorm und die Komplexität der Arzneimittelwechselwirkungen schwer greifbar und zu identifizieren sind, gelten ernsthafte Medikamenteninteraktionen in der Anästhesie allgemein als vorhersehbar. Neben der Erkennung der Risikofaktoren wie Leber- und Niereninsuffizienz, ASA-Status sowie metabolische und endokrine Veränderungen des Patienten sind grundlegende Kenntnisse und ein Verständnis der allgemeinen und speziellen Pharmakologie notwendig, um unerwünschte Arzneimittelwechselwirkungen zu verhindern.

A Fatal Drug Interaction Between Oxycodone and Clonazepam

A case is presented of a fatal drug interaction caused by ingestion of oxycodone (Oxycontin) and clonazepam (Klonapin). Oxycodone is an opium alkaloid used in long-term pain management therapy. Clonazepam is a benzodiazepine used for the treatment of seizures and panic disorders. The Drug Abuse Warning Network (DAWN) has reported an increase of 108% in the last two years of emergency department episodes related to Oxycontin. Six billion prescriptions were written for Oxycontin in the year 2000, an 18-fold increase from four years previous (1). Oxycontin has recently gained enormous notoriety at the local and national levels; however, there are very few previously documented cases of lethal drug interactions between oxycodone and clonazepam. Synergistic effects between these two drugs are postulated to arise from different agonistic mechanisms producing similar physiological changes. It is also theorized that clonazepam may inhibit the metabolism of oxycodone. A 38-year-old white female was found dead in Jefferson County, Tennessee in March of 2001. The deceased had physical evidence of previous drug abuse and positive serological findings of hepatitis B and C. Prescription pill bottles filled under the name of the deceased, as well as another name, were found with the body. Serum, urine and gastric contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatography and immunoassay techniques (EMIT and FPIA). Analysis of biological specimens from the deceased revealed the presence of: benzodiazepines, opiates (oxycodone), and trazodone metabolites in the serum; cannabinoids, benzodiazepines, opiates (oxycodone), trazodone, trazodone metabolites, nicotine, and nicotine metabolite in the urine; and benzodiazepines, opiates (oxycodone), nicotine, and nicotine metabolite in the gastric contents. Quantitative analyses for clonazepam was performed by high performance liquid chromatography (HPLC) and revealed a plasma concentration of 1.41 microg/mL. Plasma oxycodone and urine 11-nor-carboxy-delta-9-tetrahydrocannabinol concentrations were determined by gas chromatography/mass spectrometry and revealed concentrations of 0.60 microg/mL and 27.9 ng/mL, respectively. The deceased had pathologies consistent with severe central nervous system (CNS) and respiratory depression produced by high concentrations of clonazepam and oxycodone including collapsed lungs, aspirated mucus, and heart failure. The pathologies were sufficient to cause death, which was officially attributed to a drug overdose; however, the manner of death was unknown.

Phenelzine–Opiate–Induced Delirium Complicated by Phenelzine Withdrawal

Objective: To report a case of delirium involving a drug interaction of the antidepressant phenelzine in combination with an opiate and to discuss the exacerbation of delirium secondary to a withdrawal syndrome caused by the abrupt discontinuation of phenelzine. Case Summary: A 67-year-old white woman with a history of major depression and chronic anxiety developed delirium shortly after the postsurgical administration of opioid analgesics. In addition, she was taking the antidepressant phenelzine and had been maintained on this medication for approximately 20 years. Her presenting symptoms included combativeness, auditory and visual hallucinations, and persecutory delusions. After development of the delirium, the patient's phenelzine medication was abruptly discontinued, introducing a withdrawal syndrome that further aggravated her condition. Discussion: This case emphasizes the importance of the potentially fatal drug interaction involving phenelzine and opiates and addresses the adverse consequences of abruptly discontinuing phenelzine during phenelzine–opiate–induced delirium. Phenelzine–opiate interactions and phenelzine withdrawal should be considered as possible etiologies of delirium in patients with a history of phenelzine use. Conclusions: Less widely prescribed antidepressants such as phenelzine may be unfamiliar to contemporary clinicians, resulting in adverse consequences for patients, such as phenelzine–opiate drug interactions and phenelzine withdrawal.

Fatal drug interaction between cholestyramine and phenprocoumon

We describe a patient with a prosthetic aortic valve who developed fatal valve thrombosis due to an interaction between phenprocoumon and cholestyramine. The general practitioner who had prescribed cholestyramine was aware of a potential interaction between these two drugs and the patient ingested cholestyramine exactly according to the rules of the manufacturer (>1 h before phenprocoumon). However, due to enterohepatic cycling and the long half-life of phenprocoumon, an interaction between these two drugs could not be avoided. We therefore recommend that cholestyramine not be administered to patients treated with drugs undergoing enterohepatic cycling, such as oral anticoagulants.

Sense and nonsense in the prediction of drug-drug interactions.

Drug interactions are always a major concern in medicine and within the pharmaceutical industry. Fatal drug interactions have been reported, and several prominent drugs have been withdrawn from the market because of serious adverse reactions related to drug interactions. Therefore, drug interactions represent not only a medical problem for clinicians, but also an economic loss for pharmaceutical companies. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates in an attempt to minimize such losses and to more effectively safeguard the welfare of patients. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? These are the fundamental questions that industrial drug metabolism scientists must confront daily. Prediction of in vivo drug interactions from in vitro metabolic data is highly controversial, because of the complexities of factors that are involved in drug interactions. Some scientists believe that quantitative prediction of drug interaction is possible, whereas others are less optimistic, and believe that quantitative prediction is extremely difficult, if not impossible. The purpose of this review is to present and discuss the technical problems inherent in estimating in vitro Ki values and in measuring inhibitor concentration at the active-site of enzymes. Theoretic considerations are briefly reviewed, and representative examples are drawn from literature to illustrate the sense and nonsense in predicting in vivo drug interactions.

Drug‐ and poison‐related deaths in Victoria during 1997

Abstract Objective: To audit deaths due to prescription or illicit drugs, alcohols or poisons (hereafter referred to as ‘drugs’) occurring in Victoria in 1997 and to examine the classes of drug causing death. Method: Retrospective review of all deaths reported to the Victorian State Coroner in 1997 in which toxicological investigation was undertaken and drugs were determined to have caused death. Deaths due to heroin and carbon monoxide were separately audited by the Victorian Institute of Forensic Pathology and are excluded from this paper. Results: One hundred and seventy‐three people died with an average age of 41 years. The most frequent cause of death was combined drug overdose (64 cases, 37%). Ethanol was the commonest single drug causing death (32 cases, 18%), followed by prescribed opiates (18 cases, 10%) and tricyclic antidepressants (15 cases, 9%). Four teenagers died while inhaling butane or propane. In 14 cases (8%), toxic levels of selective serotonin and noradrenaline re‐uptake inhibitor antidepressants were found in combination with drugs known to produce fatal drug interactions. Conclusions: Drug overdose remains a common cause of death. Prescribed opiates and ethanol are most frequently associated with death, followed by the older and more dangerous antidepressant medications. The newer selective serotonin and noradrenaline re‐uptake inhibitors may not be as safe as was initially proposed.

The Pharmacology of Moclobemide and its Fatal Drug Interactions in Overdose

ABSTRACTMoclobemide (Manerix™) is one of the first reversible inhibitors of monoamine-A (RIMA). It inhibits metabolism of norepinephrine, dopamine and, in particular, serotonin and as such is widely used as a second-line antidepressant. Alone it is usually benign in overdose, but in combination with other drugs that enhance synaptic concentrations of neurotransmitters there is the potential for fatal interactions.Medical Examiner's cases of moclobemide in combination with Serotonin Specific Reuptake Inhibitors (Case 1: moclobemide 9.4, paroxetine 1.1; Case 2: moclobemide 13.0, sertraline 1.5), with venlafaxine (Case 3: moclobemide 5.7, venlafaxine 1.1) and with cocaine (Case 4: moclobemide 2.1, benzoylecgonine 0.07) are presented (all levels are mg/L in postmortem blood).The combination of moclobemide overdose with reuptake blockers will sufficiently enhance neurotransmission to produce fatalities.

A Fatal Drug Interaction Between Clozapine and Fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.