A rare debilitating neurological adverse effect of ranolazine due to drug interaction with clarithromycin.

Medication errors may occur at any point during patient care in the health care system. Drug interaction in known with macrolide antibiotics and ranolazine and is primarily related to effects on the cytochrome P4503A (CYP3A) metabolic pathway. This case highlights medication errors that resulted in rare debilitating neurological adverse effects of ranolazine in an elderly due to drug interaction with clarithromycin.

Introduction

Medication errors may occur at any point during patient care in the health care system. Errors can occur at any step of patient care, including diagnosis, treatment, and prevention. Obtaining a true estimate of the number of errors is difficult, but preventable medication errors are known to increase patient harm and total health care costs.[1] Macrolide antibiotics are known to interact with ranolazine and are primarily related to effects on the CYP3A metabolic pathway. This case highlights rare neurological adverse effects of ranolazine due to medication error.

Case Report

A 74-year-old man presented with the history of breathlessness, cough with expectoration, and fever for two days. His past medical history was significant for coronary artery disease and chronic angina. His other active medical comorbidities include obstructive airway disease (OAD), hypertension, and benign prostate hypertrophy.

His drug therapy at home included carvedilol 3.125 mg twice a day, aspirin 75 mg, clopidogrel 75 mg, atorvastatin 20 mg, torsemide 5 mg, ivabradine 5mg, isosorbide mononitrate 30 mg, all once day. Digoxin 0.25 mg was prescribed once a day (5 days a week).

On arrival, he was febrile, pulse rate was 48/min (irregular), blood pressure 144/90 mm Hg with postural fall of 30 mm Hg, and respiratory rate 26/min. There were bilateral rhonchi and coarse crepitations in right interscapular region on chest auscultation. On neurological examination: Glasgow Coma Scale (GCS) 15/15, mini–mental state examination (MMSE) 26/30, frontal assessment battery (FAB) score 13/18 with no focal neurological deficit. Examination of the abdomen and cardiovascular system were unremarkable.

His initial investigations showed white blood cells 10,900/mm3, hemoglobin 13.7 mg/dL, platelets 169000/mm3, random blood sugar 182 mg/dL, and serum creatinine 1.16 mg/dL. An arterial blood gas analysis (ABG) showed mixed disorder metabolic and respiratory alkalosis with hypoxia: pH 7.5, PaCO2 31, PaO2 67, HCO3 26, and Po2/Fio2 2.4 on 28% Fio2 (Normal ABG values: pH 7.35–7.45, PaCO2 35-45 mm Hg, PaO2 80-100 mm Hg, HCO3 21-28 mEq/L). He had normal urine analysis, serum transaminases, serum electrolytes, troponin T, and thyroid function test. Electrocardiogram (ECG) showed 1st degree atrioventricular block with multiple ventricular premature contractions. 2D transthoracic echocardiography showed 20% ejection fraction with regional wall motion abnormalities. Chest X-ray revealed cardiomegaly with right lower zone consolidation.

A diagnosis of acute exacerbation of OAD due to lobar pneumonia was made by chest physician and he was treated with antibiotics (piperacillin-tazobactum, clarithromycin), and bronchodilators. Cardiologist was consulted for postural fall in blood pressure and ECG changes. On cardiologist advice, digoxin was omitted due to possibility of digoxin toxicity. Beta-blocker, ivabradine, diuretic, and nitrate were put on hold due to bradycardia and orthostatic hypotension. Ranolazine 500 mg twice/day was started as an antianginal agent.

During 48 hours after admission, his chest condition improved. The white blood cell count dropped to 7,300/mm3 and arterial blood gas analysis showed metabolic alkalosis: pH 7.45, PaCO2 40, PaO2 94, HCO3 28, Po2/Fio2 3.3 on 28% Fio2. On day 3, the patient started developing mild confusion and visual hallucinations and by the day 7 of hospitalization, he developed dysarthria, dysmetria, and difficulty in ambulation due to ataxia. Neurological examination revealed GCS 15/15, MMSE 26/30, FAB 8/18 with no focal neurological deficit. Neurologist was consulted and magnetic resonance imaging with angiography was performed to rule out acute stroke. The imaging showed chronic small vessel ischemic changes with normal angiography. Cerebrospinal fluid examination and antithyroid antibodies test performed thereafter were within normal limits.

Keeping the possibility of drug-induced toxicity, recently added drug ranolazine was stopped. Within 2 days, his neurological signs and symptoms improved markedly and returned to baseline. The presumed correlation between the adverse reaction and the administration of ranolazine was not reinforced by rechallenge. The patient was discharged on clopidogrel 75mg once/day, atorvastatin 20mg once/day, and isosorbide mononitrate 30 mg once/day. On discharge and follow-up visits, there was no recurrence of symptoms.

Discussion

Ranolazine is a new compound that has been approved by the FDA for use in patients who have chronic stable angina refractory to conventional antianginal medications. Its mechanism of action does not depend on lowering determinants of myocardial O2 demand, which is the mechanism used by conventional anti-ischemic medications, but instead it prevents the pathologic persistent opening of the late INa current, which occurs when the myocardium is exposed to ischemia, heart failure, and oxidative stress.[2]

In most cases, metabolic biotransformation of ranolazine occurs through the cytochrome P4503A4-mediated pathway. Drug-drug interactions primarily are related to effects on the CYP3A metabolic pathway. Diltiazem, ketoconazole, verapamil, macrolide antibiotics, human immunodeficiency virus (HIV) protease inhibitors, and grapefruit juice inhibit the CYP3A enzyme system, and their concomitant use with ranolazine should be done with caution.[3] Commonly reported adverse effects in clinical trials included dizziness, nausea, constipation, asthenia, and minor changes in Bazett's QTc interval; it appears that adverse effects are dose related.[456] Post-marketing reports of adverse effects include tremor, paresthesia, hypoesthesia, and hallucinations.[7]

A review of the literature revealed few case reports of debilitating neurological complications due to ranolazine. Southard RA et al., reported new onset dysarthia, dysmetria, hallucinations, worse tremors, and difficulty with word finding in an elderly with renal impairment. They suggested that elderly patients with age-related decreases in renal and hepatic function are at increased risk of elevated ranolazine serum concentrations and, thus, adverse effects.[8] Porhomayon J et al., reported myoclonus in an elderly female on ranolazine after cardiac catheterization for angina.[9] The exact mechanism by which ranolazine exerts these neurologic effects is unknown. It is well-known, however, that congenital loss of function and gain of function mutations to neuronal sodium channel alpha subunits have been identified in patients with epilepsy, ataxia, and increased or decreased sensitivity to pain.[10]

In our patient, rare neurological adverse effects of ranolazine developed due to concomitant use of strong CYP3A inhibitors clarithromycin because of oversight in drug prescription and multiple specialist consultations. Other concurrent administered drugs, aspirin, clopidogrel, and atorvastatin are less likely to cause drug–drug interaction with ranolazine. The pharmacokinetics of ranolazine are considerably affected by age and hepatic and renal impairment. Pharmacokinetic models predict that an 80-year-old subject at steady state with clinically relevant doses will achieve peak and trough concentrations that are, on average, 10-30% higher than those for a subject aged 45 years.[11] Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient's neurologic adverse events and ranolazine therapy as the causal drug.

Many of the medication errors occur due to oversight or negligence during the process of prescribing, dispensing, storage and administration of drug. This case highlights medication errors that resulted in rare debilitating neurological adverse effects and increase in health care cost due to drug interaction. It is important to take a thorough medication history and consider all medications when a new drug is prescribed. Also important is understanding drug interactions that may result from induction or inhibition of the CYP enzyme system.