Elmer ress

Case Report J Med Cases. 2017;8(3):90-92

Ranolazine and Hallucinations

Saminder Singh Kalraa, c, Zubin Arorab, Craig Nielsena

Abstract while having minimum effect on blood pressure or heart rate

[1, 2]. The beneficial effect of ranolazine in the management of
Ranolazine is a piperazine derivative which produces its anti-ischem- chronic angina has been demonstrated in several trials [2, 3].
ic effect by decreasing myocardial oxygen demand and enhancing However, there are limited data on the effectiveness of ranola-
myocardial perfusion without having any effect on heart rate or blood zine in the elderly population, especially those with multiple
pressure. Many trials have proved its benefits in the management of comorbidities and taking multiple other medications.
chronic stable angina; however, some rare neurological side effects In this report, we describe a case of a 75-year-old female
have been seen in elderly population. In this case report, we describe a who suffered a rare and debilitating neurologic adverse effect
case of a 75-year-old female with underlying coronary artery disease, after initiation of ranolazine.
chronic kidney disease and mild cognitive impairment who was ad-
mitted for a new onset auditory and visual hallucinations along with
Case Report
new onset tremors in both upper and lower extremity after she was
started on ranolazine for management of her chronic stable angina.
Her workup was negative for any source of infection and no metabol- A 75-year-old Hispanic female was admitted to the hospital
ic derangements, drugs or stroke were found. Her symptoms resolved with complaints of new onset visual and auditory hallucina-
after the ranolazine was discontinued. We recommend starting ranola- tions, and upper and lower extremity tremors for 5 days. Her
zine in elderly population only when other anti-ischemic therapies past medical history included coronary artery disease treated
have been exhausted and starting with the lowest therapeutic dose with four-vessel coronary artery bypass graft surgery 15 years
possible. Ranolazine should be discontinued immediately if any signs ago and a bare metal stent placed 5 years ago, congestive heart
of neurological adverse effect appear. We also recommend monitor- disease with last recorded ejection fraction of 30%, stage 4
ing renal functions in these patients and withholding ranolazine if any chronic kidney disease with baseline serum creatinine of 2 mg/
signs of worsening renal functions appear. dL, mild cognitive impairment and hypertension.
Her home medications included metoprolol 100 mg twice
Keywords: Ranolazine; Hallucinations; Tremors; Elderly; Neuro- daily, aspirin 325 mg daily, hydralazine 50 mg three times dai-
logical complications ly, isosorbide dinitrate 20 mg three times daily, furosemide 20
mg daily, amlodipine 5 mg daily, atorvastatin 40 mg daily and
ranolazine 1,000 mg twice daily.
She had been started on ranolazine 6 days prior to admis-
Introduction sion by her cardiologist for the management of intractable an-
gina.
Upon admission, patient was hemodynamically stable
Ranolazine is a piperazine derivative which was approved with blood pressure of 92/63 mm Hg, HR of 64/min, tempera-
by FDA in 2006 for the treatment of chronic stable angina ture 98.6 F, and oxygen saturation 95% on room air. She was
refractory to beta and alpha/beta adrenergic blocking agents, alert but disoriented to time, place and person and had some
calcium channel blockers (CCB) and oral nitrates. Ranolazine difficulty in following commands. Neurological examination
produces its anti-ischemic effects by decreasing myocardial revealed coarse resting tremors in her both upper and lower
oxygen demand and enhancing myocardial oxygen perfusion extremities (1 - 2 Hz) with no change in tremors with activity.
She had normal and equal muscle strength in bilateral upper
Manuscript accepted for publication February 13, 2017 and lower extremities. She also had normal and equal sensory
perception in bilateral upper and lower extremities with no fo-
aDepartment of Internal Medicine, The Cleveland Clinic Foundation, Cleve- cal neurological deficits.
land, OH 44195, USA Initial investigations revealed mild stable anemia with a
bDepartment of Gastroenterology and Hepatology, The Cleveland Clinic
hemoglobin 10.7 mg/dL and mean capsular volume (MCV)
Foundation, Cleveland, OH 44195, USA
cCorresponding Author: Saminder Singh Kalra, Department of Internal Medi- 91 fL but otherwise normal cell counts including white blood
cine, Cleveland Clinic, 9500 Euclid Ave., G10, Cleveland, OH 44195, USA. cells 7,620/L and platelets 251,000/L. Serum chemistry
Email: [email protected] showed acute kidney injury with blood urea nitrogen 50 mg/dL
and serum creatinine 2.84 mg/dL. Other chemistries including
doi: https://doi.org/10.14740/jmc2774w blood glucose, serum electrolytes, liver function tests, thyroid

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Kalra et al J Med Cases. 2017;8(3):90-92

function tests, vitamin B12 levels and urine toxicology screen primarily through urine (75% as metabolites and < 5% un-
were all within normal limits. changed drug) [8]. The most common adverse effects reported
Workup to evaluate the cause of her neurological symp- in clinical trials include dizziness, constipation, nausea, hypo-
toms was performed as follows. Acute coronary syndrome was tension and headache [2, 3, 6, 7] along with post-marketing
ruled by three sets of normal cardiac enzymes taken 8 h apart. reports of angioedema, ataxia, paresthesia, increased serum
Occult infectious etiology was felt unlikely based on normal creatinine and blood urea nitrogen, and torsade de pointes [9].
results of urinalysis, negative urine and blood cultures, and an Case reports of neurological adverse effects from ranola-
unremarkable chest X-ray. A computed tomography of brain zine have been reported previously. Porhomayon et al reported
without contrast showed chronic microvascular white matter a case of an elderly lady developing myoclonus after initia-
changes but with no acute intracranial process. Electroenceph- tion of ranolazine. Myoclonus, in that case, was thought to be
alography performed was found to be within normal limits of as a result of ranolazines interaction with neuronal sodium
patients age with no epileptiform activity. A lumbar puncture channels leading to increased neural sensitivity [10]. Mishra
was not done given the low clinical suspicion for meningitis et al described a case of new onset dysarthria, dysmetria and
(absence of fever, neck rigidity, headache and absence of leu- ataxia after initiation of ranolazine therapy in a patient who
kocytosis). was being treated with clarithromycin for a lobar pneumonia.
Given the negative results of testing mentioned above, The side effect developed due to concomitant use of strong
her neurological symptoms were deemed to be secondary to CYP3A inhibitor clarithromycin which increased plasma con-
ranolazine toxicity in the setting of acute kidney injury. There- centration of ranolazine [11]. Southard et al reported a case of
fore, ranolazine was held and her acute kidney injury was new onset tremors, hallucinations and paresthesia in an elderly
treated with careful intravenous hydration. With these meas- female with chronic kidney disease after she was initiated on
ures, her symptoms gradually improved and resolved by day 8 ranolazine therapy for her chronic angina. The side effect was
of her hospital stay. Her mental status was noted to be back to thought to be from impaired urinary excretion of the drug [12].
baseline following which she was discharged home. She con- In our patient, the time course of initiation of ranolazine
tinued to do well and followed up as outpatient 12 weeks after and appearance of symptoms, especially in the setting of acute
discharge without any recurrence of symptoms. kidney injury, was highly suggestive that the symptoms were
related to ranolazine. Also, symptoms improved once ranola-
zine was held. Additionally, no other causes such as infec-
Discussion tion, metabolic derangements, drugs, or stroke were found.
Although ranolazine has been shown to play a promising role
Chronic stable angina (CSA) or chronic angina pectoris is in the management of chronic stable angina, most of the trials
described as chest pain that occurs during physical exertion excluded the patients with end-stage renal disease on dialysis
or mental/emotional stress and is usually reproducible. Anti- or patients with glomerular filtration rate of < 30 mL/min/1.73
ischemic therapy has an important role in management of CSA m2. These trials showed no significance difference in safety in
and includes four pharmacological subcategories: beta and al- patients > 65 years compared to younger patients, but patients
pha/beta adrenergic blocking agents, calcium channel blockers with > 75 years on ranolazine had a higher incidence of ad-
(CCB), oral nitrates and ranolazine [4]. verse effects [2, 3].
Ranolazine acts by inhibiting the late inward sodium cur- To our knowledge, this is the fourth reported case of de-
rent that is increased in ischemic cardiomyocytes which in turn bilitating neurological symptoms developing after initiation
decreases intracellular calcium load, thus decreasing diastolic of ranolazine therapy and second reported case of ranolazine
tension and oxygen demand [5]. Combination assessment of causing visual and auditory hallucinations. We recommend that
ranolazine in stable angina (CARISA) trial studied the role of ranolazine be initiated in elderly patients and in patients with
ranolazine on angina frequency and demonstrated a significant chronic kidney disease only after all other medical therapies
higher reduction of mean angina attacks per week and a de- have been exhausted and at the lowest possible dose of ranola-
crease in average weekly consumption of nitroglycerine by us- zine especially if the patient is taking other CYP3A inhibitors.
ing ranolazine dosage of 750 - 1,000 mg twice a day compared Given reports of acute renal failure after initiation of ranola-
to placebo [2]. The same results were reproduced by type 2 zine, it would be prudent to closely monitor serum creatinine
diabetes evaluation of ranolazine in subjects with chronic sta- and blood urea nitrogen in these patients so that the medication
ble angina (TERISA) study which evaluated the role of ranola- can be discontinued early if renal function worsens.
zine in CSA who also had concomitant diabetes [6], Effect of
ranolazine in chronic angina (ERIKA) study [3] and metabolic
Conflicts of Interest
efficiency with ranolazine for less ischemia in non-ST seg-
ment elevation acute coronary syndromes (MERLIN-TIMI
36) study [7]. None.
After oral administration, ranolazine reaches its peak
plasma concentration between 2 and 5 h. It is primarily me-
tabolized in liver and gut by cytochrome P450 (CYP) 3A4 and Source of Funding
to a lesser extent by CYP2D6. Ranolazine reaches its plasma
steady state within 3 days of twice daily dosing and is excreted None.

Articles The authors | Journal compilation J Med Cases and Elmer Press Inc | www.journalmc.org 91
Ranolazine and Hallucinations J Med Cases. 2017;8(3):90-92

Disclosures zine. Heart. 2006;92(Suppl 4):iv6-iv14.

6. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li
Y, Yue P, Ben-Yehuda O, et al. Evaluation of ranolazine
None.
in patients with type 2 diabetes mellitus and chronic sta-
ble angina: results from the TERISA randomized clinical
References trial (Type 2 Diabetes Evaluation of Ranolazine in Sub-
jects With Chronic Stable Angina). J Am Coll Cardiol.
1. Chaitman BR, Skettino SL, Parker JO, Hanley P, Me- 2013;61(20):2038-2045.
luzin J, Kuch J, Pepine CJ, et al. Anti-ischemic effects 7. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E,
and long-term survival during ranolazine monotherapy in Murphy SA, Budaj A, Varshavsky S, Wolff AA, et al.
patients with chronic severe angina. J Am Coll Cardiol. Effects of ranolazine on recurrent cardiovascular events
2004;43(8):1375-1382. in patients with non-ST-elevation acute coronary syn-
2. Pepine CJ, Parker JO, Wang W, Wolff AA. Amlodipine, dromes: the MERLIN-TIMI 36 randomized trial. JAMA.
or Diltiazem on Exercise. Cardiology. 2004;291(3):309- 2007;297(16):1775-1783.
316. 8. Jerling M. Clinical pharmacokinetics of ranolazine. Clin
3. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng Pharmacokinet. 2006;45(5):469-491.
L. Antianginal efficacy of ranolazine when added to 9. Gilead Sciences. RANEXA - Prescribing Information.
treatment with amlodipine: the ERICA (Efficacy of 2016. http://www.gilead.com/~/media/Files/pdfs/medi-
Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. cines/cardiovascular/ranexa/ranexa_pi.ashx.
2006;48(3):566-575. 10. Porhomayon J, Zadeii G, Yarahmadi A, Report C. Case
4. Fox K, Garcia MA, Ardissino D, Buszman P, Camici Report A Rare Neurological Complication of Ranolazine.
PG, Crea F, Daly C, et al. Guidelines on the manage- 2013;2013:10-12.
ment of stable angina pectoris: executive summary: The 11. Mishra A, Pandya HV, Dave N, Mathew M, Sapre CM,
Task Force on the Management of Stable Angina Pecto- Chaudhary S. A rare debilitating neurological adverse ef-
ris of the European Society of Cardiology. Eur Heart J. fect of ranolazine due to drug interaction with clarithro-
2006;27(11):1341-1381. mycin. Indian J Pharmacol. 2014;46(5):547-548.
5. Belardinelli L, Shryock JC, Fraser H. Inhibition of the 12. Southard RA, R MB, Bui AH, Blankstein R. Neurologic
late sodium current as a potential cardioprotective prin- adverse effects of ranolazine in an elderly patient with
ciple: effects of the late sodium current inhibitor ranola- renal impairment. Pharmacotherapy. 2013;33(1):e9-13.

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