Ranolazine

An Overview and
Toxicology
Angina
• Atherosclerosis is the most common cause
• Paroxysmal attacks of retrosternal chest discomfort, tightness, or pressure
due to myocardial ischemia.
• Most commonly occurs in individuals with coronary heart disease.
• Triggers include exertion or stress, which results in increased myocardial
oxygen demand.
• Angina is the cardinal symptom of CAD.
• Patients with CAD usually become symptomatic when the degree of
coronary stenosis reaches ≥ 70%.
• Typically retrosternal chest pain or pressure
Antianginal drugs

• Goal: reduction of myocardial oxygen demand

• First-line agent: beta blockers
• Second-line agents: CCBs, nitrates, Consider as initial monotherapy for patients with
contraindications to beta blockers (e.g., vasospastic angina).
• Consider as combination therapy with beta blockers to improve symptom control , e.g.,
a beta blocker PLUS a nitrate, dihydropyridine CCB
• CCB (nondihydropyridine) PLUS a nitrate (nondihydropyridine CCBs such
as verapamil have a similar effect to beta blockers on cardiac conduction)
• Third-line agent: Consider ranolazine if beta-blockers, CCBs, and nitrates are ineffective or
not tolerated.
History
• Ranolazine is a piperazine derivative
• With a mechanism of action different from drugs used
to treat the same condition, ranolazine is a promising
anti-anginal therapy.
• Patented in 1986 and is available in an oral and
intravenous form. It was originally approved by the
FDA in 2006 for use in patients with chronic angina
who continue to be symptomatic on β-blockers,
calcium antagonists, or nitrates
• Ranexa, Aspruzyo Sprinkle, Corzyna
Indications
• Treatment of chronic angina
• Ventricular tachycardia
Cardiac Action Potential Phases
Late phase of Na channel (in)
Late INa in contractility
Dosages for Antianginal therapy

• Available as 500 mg and 1000 mg extended-release tablets. OR Granules

• Begin at 500 mg twice daily and be titrated to 1000 mg twice daily as
tolerated
• Maximum recommended dose is 1000 mg twice a day
Off label use for
Ventricular
tachycardia
• 500 to 1,000 mg every 12
hours
Metabolism
• Peak plasma concentrations are reached between 2 to 5 hours
• Half-life is 7 hours
• Steady-state is achieved within three days of twice-daily dosing
• Ranolazine plasma concentrations that are therapeutically effective for chronic angina are in the range of
therapeutic level 0.4-6.1 mg/L
• Cytochrome P450 (CYP) 3A4–mediated pathway accounts for the majority of ranolazine biotransformation
• Excretion: Primarily urine (75% mostly as active and inactive metabolites; <5% as unchanged drug); feces (25%
mostly as active and inactive metabolites; <5% as unchanged drug).
 • Ranolazine is metabolized in the liver mainly by CYP3A4 and
CYP2D6 enzymes.
• Potent CYP3A4 inhibitors like ketoconazole, clarithromycin,
and ritonavir increase ranolazine levels, and concomitant use is
contraindicated.
• Dose adjustment is required when ranolazine is taken with
moderate CYP3A inhibitors like verapamil, diltiazem, and
Contraindications erythromycin. The dose should not exceed 500 mg twice a day.
• CY3A4 inducers such as rifampin, carbamazepine, phenytoin,
and St. John’s Wort decrease ranolazine plasma levels
• Patients with a family history of long QT syndrome and patients
with known prolonged QT intervals
• Dialysis patients & Renal Failure
• Liver cirrhosis
Monitoring

Monitor QT in patients on Monitor serum creatinine, BUN,

ranolazine and other QT-prolonging and urine output in patients with
drugs. CrCl less than 60 ml per minute.

Concomitant use of ranolazine and

metformin increases
metformin levels. Monitor blood Monitor for neurologic side effects.
glucose and for side effects of
metformin in these patients
Pregnancy and Breast Feeding

There are no available data on RANEXA use in pregnant women to inform any drug-associated
risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 times the
maximum recommended human dose

There are no data on the presence of ranolazine in human milk, the effects on the breastfed
infant, or the effects on milk production. However, ranolazine is present in rat milk

The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for ranolazine and any potential adverse effects on the breastfed infant
from ranolazine or from the underlying maternal condition.
 • 1% to 10%:
• Cardiovascular: Bradycardia (≤4%), hypotension
(≤4%), orthostatic hypotension (≤4%), palpitations
(≤4%), peripheral edema (≤4%), syncope (≤4%)
• Dermatologic: Hyperhidrosis (≤4%)
• Gastrointestinal: Abdominal pain (≤4%), anorexia
Adverse (≤4%), constipation (5%), dyspepsia (≤4%), nausea
(4%), vomiting (≤4%), xerostomia (≤4%)
Effects • Genitourinary: Hematuria (≤4%)
• Nervous system: Asthenia (≤4%), confusion (≤4%),
dizziness (6%; may be dose-related), headache
(6%), vertigo (≤4%)
• Ophthalmic: Blurred vision (≤4%)
• Otic: Tinnitus (≤4%)
• Respiratory: Dyspnea (≤4%)
 • <1%:
• Genitourinary: Urine discoloration
• Hematologic & oncologic: Eosinophilia, leukopenia, pancytopenia,
thrombocytopenia
• Hypersensitivity: Angioedema
• Nervous system: Hypoesthesia, paresthesia, tremor
• Renal: Increased blood urea nitrogen, renal failure syndrome
Adverse • Respiratory: Pulmonary fibrosis

Effects • There have been a few cases of ranolazine-induced myopathy, but this is
very rare
• Ranolazine prolongs the cardiac action potential duration and QT interval
by 2 to 6 ms.
• Torsades de pointes was not reported as a side effect in clinical trials, but
the risk may increase in patients also taking other QT-prolonging
medications. Hepatic impairment may also lead to increased plasma
concentrations, and hence, prolonged QTc interval.
65-year old woman with Turner’s syndrome and schizoaffective
disorder reported ingestion of fifty 1000 mg ranolazine tablets (her
brother’s) and seven pills of quetiapine, valproate, and mirtazapine
 High oral doses of ranolazine have led to dizziness,
nausea, and vomiting. These effects have been shown
to be dose related. High intravenous doses can cause
diplopia, confusion, paresthesia, in addition to syncope.

Overdose Provide supportive therapy accompanied by continuous

ECG monitoring for QT interval prolongation
Management
Since ranolazine is about 62% bound to plasma
proteins, hemodialysis is unlikely to be effective in
clearing ranolazine.
Other Potential Effects of Ranolazine

• Ranolazine has been associated with significant reductions in glycosylated hemoglobin

(HbA1C)
• One study showed ranolazine treatment leads to improvement in beta-cell function of the
islets.
• One study showed that Ranolazine and a more selective sodium channel blocker reduced
postprandial and basal glucagon levels, leading to a reduction in hyperglycemia,
suggesting that glucose-lowering effects of ranolazine may be due to the blockade of
sodium channels leading to a reduction in glucagon secretion
• There are only a small number of trials currently available as the glycemic benefits of
ranolazine have not been evaluated in all clinical trials and there is no clinical trial that has
specifically investigated glucose lowering as its primary outcome.
Bibliography
• https://en.wikipedia.org/wiki/Cardiac_action_potential
• https://www.ncbi.nlm.nih.gov/books/NBK507828/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454281/
• chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://
www.accessdata.fda.gov/drugsatfda_docs/label/2019/021526s035lbl.pdf
• https://www.ahajournals.org/doi/full/10.1161/circulationaha.105.597500
• https://www.ahajournals.org/doi/10.1161/JAHA.116.003196#:~:text=Ran
olazine%20prolongs%20the%20cardiac%20action,by%202%20to%206%20
ms
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• https://pubmed.ncbi.nlm.nih.gov/18221101/
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• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307613/
• https://www.ahajournals.org/doi/10.1161/JAHA.116.003196#d3e940
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