A Comprehensive Monograph on Ranolazine

Executive Summary

Ranolazine is a piperazine derivative classified as an antianginal agent, occupying a unique position in the therapeutic landscape for cardiovascular disease.[1] First approved by the U.S. Food and Drug Administration (FDA) in 2006, it is indicated for the treatment of chronic stable angina, a condition affecting millions worldwide and causing significant disability.[1] Marketed under brand names such as Ranexa and Aspruzyo Sprinkle, Ranolazine can be used as monotherapy or as an adjunctive treatment with traditional antianginal agents like beta-blockers, calcium channel blockers, and nitrates.[1]

The primary mechanism of action that distinguishes Ranolazine from conventional therapies is its selective inhibition of the late inward sodium current (INaL​) in cardiac myocytes.[5] During myocardial ischemia, this aberrant current leads to intracellular sodium and subsequent calcium overload, causing diastolic dysfunction and increased myocardial oxygen consumption. By blocking

INaL​, Ranolazine mitigates this ionic imbalance, thereby exerting its anti-ischemic effects without significantly altering heart rate or blood pressure—a key point of differentiation from hemodynamically active agents.[1] Ancillary mechanisms, including the partial inhibition of fatty acid oxidation, further contribute to its metabolic-modulating profile by shifting the heart towards more oxygen-efficient glucose utilization.[8]

The pharmacokinetic profile of Ranolazine is complex and clinically significant. It is administered as an extended-release formulation to achieve twice-daily dosing and is extensively metabolized, primarily by the cytochrome P450 3A4 (CYP3A4) enzyme and to a lesser extent by CYP2D6.[5] This metabolic pathway renders Ranolazine highly susceptible to drug-drug interactions. Its use is contraindicated with strong CYP3A4 inhibitors and inducers, and dose adjustments are required with moderate inhibitors, necessitating meticulous review of a patient's medication regimen before and during therapy.[11]

The safety profile of Ranolazine is notable for a well-documented paradox. The drug blocks the IKr​ potassium channel, leading to a dose-dependent prolongation of the QT interval on the electrocardiogram.[1] While this effect typically raises concerns for proarrhythmia, large clinical trials have consistently shown that Ranolazine does not increase, and may even decrease, the risk of ventricular tachyarrhythmias like Torsades de Pointes.[12] This protective effect is attributed to its primary

INaL​-blocking activity, which suppresses the triggers for such arrhythmias. Common adverse effects are generally mild to moderate and include dizziness, headache, constipation, and nausea.[5]

In conclusion, Ranolazine represents a valuable therapeutic option for the management of chronic angina, particularly in patients who remain symptomatic on traditional therapies or in whom hemodynamic side effects limit treatment intensification. Its unique mechanism provides a complementary approach to ischemia management. However, its complex pharmacokinetic and drug interaction profile demands a high level of clinical vigilance and a thorough understanding of its properties for safe and effective use.

Identification and Physicochemical Properties

Precise identification and a thorough understanding of the physicochemical properties of a drug are fundamental to its development, formulation, and clinical application. This section provides a comprehensive dossier on Ranolazine.

Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory documents, and chemical databases, Ranolazine is cataloged under a variety of names and identifiers.

• Generic Name: Ranolazine [1]
• IUPAC Name: (RS)-N-(2,6-Dimethylphenyl)-2-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide [5]
• Synonyms and Brand Names: Common synonyms include Ranolazina, CVT 303, and RS 43285-003.[1] It is marketed under several brand names, most notably Ranexa, Aspruzyo Sprinkle, and Corzyna (Canada).[1]
• Database Identifiers: Key identifiers for cross-referencing in major databases include:
• DrugBank ID: DB00243 [1]
• CAS Number: 95635-55-5 [1]
• PubChem CID: 56959 [5]
• UNII: A6IEZ5M406 [2]
• ChEMBL ID: CHEMBL1404 [2]
• ATC Code: C01EB18 [15]

Chemical Structure and Formula

Ranolazine is a small molecule belonging to the piperazine class of compounds.[1]

• Chemical Formula: C24​H33​N3​O4​ [1]
• Structural Identifiers: For computational and cheminformatics applications, its structure is defined by:
• SMILES: O=C(NC1=C(C)C=CC=C1C)CN2CCN(CC(O)COC3=CC=CC=C3OC)CC2 [5]
• InChIKey: XKLMZUWKNUAPSZ-UHFFFAOYSA-N [5]
• Chirality: The molecule contains one stereocenter and is commercially supplied as a racemic mixture of its (R) and (S) enantiomers.[5]
• Chemical Classification: It is structurally characterized as a monocarboxylic acid amide, an aromatic amide, an N-alkylpiperazine, a secondary alcohol, and a monomethoxybenzene.[2]

Physical and Chemical Properties

The physical and chemical properties of Ranolazine dictate its behavior in biological systems and are crucial for its formulation as a pharmaceutical product. It exists as a white to off-white solid or crystalline powder.[2] A summary of its key properties is presented in Table 1.

One of the most clinically relevant physicochemical properties is its pH-dependent solubility.[10] Ranolazine is freely soluble in the highly acidic environment of the stomach (below pH 4.40) but becomes very slightly soluble in the more neutral to alkaline environment of the small and large intestines (above pH 6.99).[10] This characteristic presents a significant formulation challenge. If administered in an immediate-release form, the drug would dissolve rapidly in the stomach, leading to a sudden surge in plasma concentration (dose dumping) and potential toxicity, while providing poor sustained absorption in the lower gastrointestinal tract. This solubility profile is the primary driver behind the development of the extended-release (ER) tablet formulation. The ER technology is specifically designed to control the rate of drug release as the tablet transits through the varying pH environments of the gut, thereby preventing initial dose dumping and ensuring a prolonged absorption phase. This controlled release is what enables the convenient twice-daily dosing regimen and the maintenance of therapeutic plasma concentrations over a 12-hour period.[11] It also underscores the critical patient instruction to swallow the tablets whole and not to crush, break, or chew them, as doing so would destroy the ER matrix and negate its protective and sustained-release functions.[11]

Table 1: Summary of Physicochemical Properties of Ranolazine

Property	Value(s)	Source(s)
Molecular Formula	C24​H33​N3​O4​	1
Average Molecular Weight	427.54 g/mol	1
CAS Number	95635-55-5	1
Physical Description	White to off-white solid/crystal	2
Melting Point	117–124 °C	2
Boiling Point (Predicted)	624.1 °C	2
Water Solubility	Very slightly soluble; pH-dependent	2
Partition Coefficient (log P)	2.07	10
pKa (Predicted)	14.06	15

Pharmacodynamics: Mechanisms of Action

The therapeutic effects of Ranolazine stem from a novel and complex set of pharmacodynamic actions that distinguish it from all other classes of antianginal medications. While early literature and regulatory documents sometimes describe the mechanism as "not fully understood," this reflects the drug's unique profile compared to traditional agents and the cautious language of initial approvals.[1] Extensive subsequent research has elucidated a clear primary mechanism supplemented by important secondary actions.

Primary Mechanism: Selective Inhibition of the Late Inward Sodium Current (INaL​)

The cornerstone of Ranolazine's anti-ischemic effect is its potent and selective inhibition of the late component of the inward sodium current (INaL​).[5] This mechanism targets a key pathological process that occurs specifically in ischemic cardiac cells.

The Pathophysiology of Sodium and Calcium Overload in Ischemia

Under normal physiological conditions, the rapid influx of sodium ions through voltage-gated sodium channels (Nav​1.5) generates the fast upstroke (Phase 0) of the cardiac action potential. These channels inactivate almost instantaneously, and the current is very brief.[7] However, in the setting of myocardial ischemia, a small fraction of these sodium channels fail to inactivate properly or reopen during the plateau phase of the action potential. This malfunction generates a small but persistent inward sodium current, known as the late sodium current or

INaL​.[5]

Although small in amplitude compared to the peak current, the prolonged duration of INaL​ leads to a significant and pathological accumulation of sodium ions inside the myocyte, elevating the intracellular sodium concentration ([Na+]i​).[7] This rise in

[Na+]i​ has a critical downstream consequence: it disrupts the electrochemical gradient that drives the normal forward-mode operation of the sodium-calcium exchanger (NCX). The NCX, which typically expels one calcium ion in exchange for importing three sodium ions, begins to operate in a "reverse mode," exporting sodium and importing excess calcium into the cell.[6]

This sodium-dependent calcium overload is a central driver of ischemic myocardial dysfunction. The excess intracellular calcium ([Ca2+]i​) impairs the ability of the heart muscle to relax during diastole, leading to increased diastolic stiffness and elevated left ventricular end-diastolic pressure (LVEDP).[6] This heightened diastolic wall tension has two detrimental effects: it increases the energy (ATP) and oxygen consumption of the heart muscle, and it physically compresses the small intramural coronary blood vessels, which perfuse the myocardium primarily during diastole. This compression reduces coronary blood flow, particularly to the vulnerable subendocardial region, thereby worsening the oxygen supply-demand imbalance and perpetuating a vicious cycle of ischemia.[6]

Ranolazine's Targeted Intervention

Ranolazine directly interrupts this pathological cascade. As a selective inhibitor of INaL​, it blocks the initial aberrant entry of sodium into ischemic cells.[6] By preventing the rise in

[Na+]i​, Ranolazine averts the subsequent reverse-mode operation of the NCX and the resulting calcium overload.[7] This preservation of ionic homeostasis leads to a reduction in diastolic wall tension and LVEDP. The beneficial consequences are twofold:

1. Reduced Oxygen Demand: By decreasing wall tension, Ranolazine reduces the energy required for contractile work, thus lowering myocardial oxygen demand (MVO2​).[7]
2. Improved Oxygen Supply: By reducing wall tension, it alleviates the compression of intramural vessels, which can improve nutritive blood flow and oxygen supply to the myocardium during diastole.[7]

Crucially, these antianginal and anti-ischemic effects are achieved without any clinically significant impact on heart rate or blood pressure.[1] This hemodynamic neutrality is the fundamental feature that distinguishes Ranolazine from beta-blockers and most calcium channel blockers, which exert their effects primarily by reducing heart rate and/or blood pressure.

Secondary and Ancillary Mechanisms

In addition to its primary action on INaL​, Ranolazine possesses other pharmacodynamic properties that contribute to its overall therapeutic profile.

Partial Inhibition of Fatty Acid Oxidation (FAO)

The heart can metabolize both fatty acids and glucose to produce ATP. Under normal conditions, fatty acid oxidation (FAO) is the predominant energy source. However, during ischemia, the reliance on FAO becomes metabolically inefficient, as it requires more oxygen per unit of ATP produced compared to glucose oxidation.[9] Ranolazine is a partial inhibitor of FAO.[1] By partially blocking this pathway, it promotes a metabolic shift, encouraging the ischemic myocardium to utilize the more oxygen-efficient glucose oxidation pathway.[8] This metabolic modulation results in more efficient ATP production from the limited available oxygen, reduces the accumulation of harmful byproducts like lactate and protons, and helps preserve cardiac function under ischemic stress.[8]

The dual mechanisms of Ranolazine—targeting both ionic imbalance and metabolic inefficiency—represent a complementary, multi-pronged strategy against the pathophysiology of myocardial ischemia. The inhibition of INaL​ directly addresses the electromechanical consequences of ischemia by reducing sodium and calcium overload, thereby alleviating diastolic tension and improving the myocardial oxygen supply/demand balance.[7] Concurrently, the partial inhibition of FAO addresses the underlying energy crisis by optimizing how the heart uses its limited oxygen supply to generate ATP.[8] This multifaceted approach provides a more comprehensive anti-ischemic effect than an agent acting on only one of these pathways. It explains the documented efficacy of Ranolazine when added to traditional hemodynamic agents, as it provides a distinct and synergistic mode of action.[1]

Inhibition of the Delayed Rectifier Potassium Current (IKr​)

Ranolazine also blocks the rapid component of the delayed rectifier potassium current (IKr​), an outward current crucial for cardiac repolarization.[1] This channel is encoded by the hERG gene. Inhibition of

IKr​ slows the repolarization process, which manifests on the surface electrocardiogram (ECG) as a dose-dependent prolongation of the QT interval.[1] While QT prolongation is often associated with a risk of life-threatening arrhythmias, Ranolazine presents a unique safety profile in this regard, which is discussed in detail in the Safety and Tolerability section.

Other Minor Activities

Pharmacological studies have also identified weak antagonistic activity at alpha-1 and beta-1 adrenergic receptors and minimal inhibitory effects on L-type calcium channels.[1] These actions are generally considered to be of minor clinical significance but may contribute to its profile as a weak direct vasodilator.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical use of Ranolazine is profoundly influenced by its pharmacokinetic properties. Its absorption, distribution, extensive metabolism, and routes of elimination dictate its dosing regimen, potential for drug interactions, and use in special patient populations.

Absorption

• Formulation and Dosing: Ranolazine is administered orally in an extended-release (ER) tablet or as ER granules.[6] This formulation is essential for achieving a convenient twice-daily dosing schedule. The intrinsic elimination half-life of Ranolazine is short (approximately 2–3 hours), but the ER formulation creates an absorption-rate-limited elimination profile, often referred to as "flip-flop kinetics," which prolongs the apparent terminal half-life to about 7 hours at steady state.[10]
• Bioavailability and Tmax: After oral administration, the absolute bioavailability is highly variable between individuals, ranging from 35% to 50%.[10] Peak plasma concentrations ( Cmax​) are typically observed between 2 and 6 hours post-dose.[1] Steady-state concentrations are generally achieved within 3 days of initiating twice-daily dosing.[10]
• Food Effect: The absorption of Ranolazine from the ER formulation is not significantly affected by food, allowing it to be taken with or without meals.[20]
• Dose Proportionality: Ranolazine exhibits non-linear pharmacokinetics. Its exposure, as measured by the area under the curve (AUC), increases more than proportionally with the dose. A doubling of the dose from 500 mg to 1000 mg twice daily results in a 2.5- to 3-fold increase in steady-state AUC.[10] This non-proportionality suggests the saturation of one or more elimination pathways at higher doses.

Distribution

• Protein Binding: Ranolazine is moderately bound to plasma proteins, with approximately 62% of the drug bound in circulation.[5] It shows a slightly higher binding affinity for alpha-1 acid glycoprotein compared to albumin.[1]
• Volume of Distribution: The mean steady-state volume of distribution (Vss​) is large, approximately 180 L, indicating extensive distribution of the drug into peripheral tissues outside of the bloodstream.[15]

Metabolism

• Extent and Pathways: Ranolazine undergoes rapid and extensive metabolism in the liver and intestine. Less than 5% of an administered dose is excreted as unchanged drug.[10] Over 47 distinct metabolites have been identified in human plasma, highlighting the complexity of its biotransformation.[10] The key metabolic pathways are O-demethylation and N-dealkylation.[10]
• CYP450 Enzymes: The metabolism of Ranolazine is predominantly mediated by the cytochrome P450 enzyme system.
• CYP3A4: This is the major enzyme responsible for Ranolazine's metabolism.[3] Its location in both the liver and the gut wall contributes to the drug's significant first-pass effect and variable bioavailability.
• CYP2D6: This enzyme plays a lesser, but still significant, role in Ranolazine's metabolism.[5] Individuals who are genetically poor metabolizers of CYP2D6 exhibit higher exposure to Ranolazine; for instance, at the 500 mg twice-daily dose, the AUC is approximately 62% higher in poor metabolizers compared to extensive metabolizers.[10]
• Ranolazine as an Inhibitor: Ranolazine is not only a substrate but also an inhibitor of certain metabolic pathways. It is considered a weak inhibitor of CYP3A4 and a mild-to-moderate inhibitor of CYP2D6 and the efflux transporter P-glycoprotein (P-gp).[2] This inhibitory activity is the basis for several of its clinically important drug-drug interactions.

The non-linear pharmacokinetic behavior of Ranolazine is a direct consequence of its metabolic profile and has significant clinical implications. The observation that doubling the dose leads to a nearly threefold increase in drug exposure indicates that at least one of its clearance pathways is becoming saturated within the therapeutic dosing range.[20] Evidence points to the saturation of the lower-capacity CYP2D6 pathway, which is also partially inhibited by Ranolazine itself.[20] At lower doses, both CYP3A4 and CYP2D6 contribute to clearance. As the dose increases toward 1000 mg, the CYP2D6 pathway becomes overwhelmed. This forces a greater reliance on the CYP3A4 pathway and means that any further increase in dose results in a disproportionately large increase in plasma concentration. Since the primary adverse effects of Ranolazine, such as dizziness and QT prolongation, are known to be dose- and concentration-dependent, this non-linearity creates a relatively narrow therapeutic window.[1] This pharmacokinetic characteristic provides the fundamental rationale for the strict maximum recommended daily dose of 1000 mg twice daily and explains why doses above this level are poorly tolerated.[11] It also reinforces the clinical importance of the "start low, go slow" titration strategy to ensure patient safety and tolerability.[11]

Excretion

• Primary Route: Ranolazine is eliminated almost entirely through metabolism.
• Recovery: Following a single oral radiolabeled dose, approximately 73% of the radioactivity is recovered in the urine and 25% is recovered in the feces, primarily in the form of metabolites.[5]

Pharmacokinetics in Special Populations

• Renal Impairment: Ranolazine exposure (AUC) is significantly increased in patients with renal impairment, with an average 1.7- to 2-fold higher AUC in subjects with mild, moderate, or severe impairment compared to those with normal renal function.[10] Due to this increased exposure and reports of acute renal failure in patients with severe impairment, careful dose titration is recommended, and the drug is contraindicated in some regions for patients with a creatinine clearance (CrCl) below 30 mL/min.[3]
• Hepatic Impairment: Ranolazine exposure is increased 1.8-fold in patients with moderate hepatic impairment and is expected to be even higher in severe impairment.[10] Due to the increased risk of adverse effects, particularly QT prolongation, Ranolazine is contraindicated in patients with moderate to severe hepatic impairment or established liver cirrhosis.[5]
• Elderly: Elderly patients may exhibit increased Ranolazine exposure, primarily due to an age-related decline in renal function.[27] The incidence of adverse events is also higher in this population.[27] Therefore, dose selection and titration should be performed with particular caution in elderly patients, often starting at the lower end of the dosage range.[33]

Clinical Efficacy and Therapeutic Applications

The clinical utility of Ranolazine is well-defined by a series of pivotal clinical trials that have established its role in the management of chronic angina and explored its potential in other cardiovascular conditions.

Approved Indication: Chronic Stable Angina

Ranolazine is approved by the FDA and other regulatory agencies for the treatment of chronic angina.[1] It can be used as monotherapy, but it is most frequently prescribed as an add-on therapy for patients who have an inadequate response to or are intolerant of other antianginal medications, such as beta-blockers, calcium channel blockers, and long-acting nitrates.[1] While initially approved as an add-on therapy, its indication was expanded by the FDA in 2008 to include first-line use.[35]

The evidence supporting its efficacy comes from three key randomized, double-blind, placebo-controlled trials:

• MARISA (Monotherapy Assessment of Ranolazine in Stable Angina): This trial established the dose-dependent efficacy of Ranolazine as monotherapy. It demonstrated that Ranolazine significantly increased exercise duration and time to angina onset compared to placebo.[29]
• CARISA (Combination Assessment of Ranolazine in Stable Angina): This landmark trial evaluated Ranolazine as an add-on therapy in patients who were already being treated with standard antianginals (atenolol, amlodipine, or diltiazem) but remained symptomatic. The results showed that adding Ranolazine (750 mg or 1000 mg twice daily) significantly improved exercise duration, time to angina, and time to 1-mm ST-segment depression. Furthermore, patients treated with Ranolazine experienced a statistically significant reduction in the frequency of weekly angina attacks and their use of short-acting nitroglycerin.[28]
• ERICA (Efficacy of Ranolazine in Chronic Angina): The ERICA trial further solidified Ranolazine's role as an add-on therapy. It enrolled patients with coronary artery disease who remained symptomatic despite treatment with the maximum recommended dose of amlodipine (10 mg daily). The addition of Ranolazine led to a significant reduction in angina frequency and nitroglycerin consumption compared to placebo, confirming its benefit in a difficult-to-treat patient population.[3]

The results from these pivotal trials, summarized in Table 2, provide quantitative evidence of Ranolazine's ability to improve ischemic symptoms and exercise capacity.

Table 2: Summary of Key Efficacy Outcomes from the CARISA Trial

Parameter	Placebo	Ranolazine 750 mg BID	Ranolazine 1000 mg BID
Change in Exercise Duration (Trough)	Reference	+24 sec (p≤0.05)	+24 sec (p≤0.05)
Change in Exercise Duration (Peak)	Reference	+34 sec (p≤0.005)	+26 sec (p≤0.05)
Angina Frequency (attacks/week)	3.3	2.5 (p=0.006)	2.1 (p<0.001)
Nitroglycerin Use (doses/week)	3.1	2.1 (p=0.016)	1.8 (p<0.001)
Data derived from the CARISA trial as presented in product labeling.28

Investigational and Off-Label Uses

Ranolazine's unique mechanism of action has prompted investigation into its use for other cardiovascular conditions, with varying degrees of success.

• Arrhythmias:
• Atrial Fibrillation (AF): Ranolazine's ability to modulate cardiac ion channels has suggested a potential role in managing AF. Some studies have shown it can be effective in preventing AF and may improve the success rate of pharmacological cardioversion when used in combination with amiodarone.[5] However, evidence is mixed; the large RAFFAELLO trial did not demonstrate a benefit in preventing AF recurrence following electrical cardioversion.[37] A clinical trial investigating Ranolazine for the prevention of new-onset AF was terminated, though the reason is not specified.[38]
• Ventricular Tachycardia (VT): While there is some off-label use for certain ventricular arrhythmias, this indication is not strongly supported by robust clinical evidence.[1]
• Long QT Syndrome (LQTS): A promising area of research is the use of Ranolazine for Long QT Syndrome Type 3 (LQT3). This genetic channelopathy is caused by a gain-of-function mutation in the SCN5A gene, which results in an pathologically enhanced late sodium current (INaL​)—the very current that Ranolazine selectively inhibits. Preclinical studies and computational modeling have shown that Ranolazine can shorten the action potential duration and correct the arrhythmic substrate in models of LQT3, suggesting it could be a targeted therapy for these patients, particularly when other agents are contraindicated.[40]
• Other Investigational Areas: Ranolazine has been studied for other conditions but is not approved for them. A major trial in patients with acute coronary syndrome (ACS), MERLIN-TIMI 36, failed to demonstrate a benefit on major adverse cardiovascular events (MACE), such as death or myocardial infarction.[11] It has also been explored for microvascular coronary dysfunction and glycemic control.[1] Ranolazine has been observed to cause small, statistically significant reductions in hemoglobin A1c in patients with diabetes, but it is not considered a treatment for diabetes.[11]

The collective clinical trial data for Ranolazine reveals a consistent and important pattern: the drug is highly effective for improving the symptoms and functional capacity of patients with stable ischemic conditions like chronic angina, but it has not been shown to improve hard clinical outcomes like mortality or MI in the setting of acute ischemic events like ACS. This distinction is rooted in its mechanism of action. In chronic angina, the primary challenge is a predictable mismatch between myocardial oxygen supply and demand during exertion. Ranolazine's ability to reduce calcium overload and optimize metabolic efficiency is perfectly suited to mitigate the consequences of this predictable ischemic burden, thus improving exercise tolerance and reducing symptoms.[7] In contrast, the pathophysiology of ACS is driven by acute plaque rupture and thrombus formation, leading to a sudden and severe occlusion of a coronary artery. Ranolazine's mechanism does not address this underlying thrombotic event; it cannot dissolve a clot or restore blood flow in the way that antiplatelet agents, anticoagulants, or revascularization procedures can. This understanding clearly defines Ranolazine's therapeutic niche: it is a powerful

symptom-modifying drug for chronic conditions, not a prognosis-modifying drug for acute events. The failure of the MERLIN-TIMI 36 trial to show a benefit on MACE was therefore not entirely surprising, but the trial did provide invaluable safety data by demonstrating no apparent proarrhythmic risk in this high-risk population, further reinforcing the drug's unique safety profile.[11]

Safety, Tolerability, and Risk Management

The safety profile of Ranolazine is well-characterized and is central to its appropriate clinical use. It is generally well-tolerated, but it carries specific warnings and contraindications related to its metabolism and pharmacodynamic effects, particularly on cardiac repolarization.

Adverse Drug Reactions (ADRs)

The most commonly reported adverse effects are typically mild to moderate in severity and often dose-related.[13]

• Common ADRs: In controlled clinical trials, the most frequent adverse reactions occurring more often than with placebo were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%).[5]
• Reasons for Discontinuation: Approximately 6% of patients discontinued Ranolazine due to an adverse event, compared to 3% on placebo. The most common events leading to discontinuation were dizziness (1.3%), nausea (1%), asthenia, constipation, and headache (each approximately 0.5%).[11] Doses exceeding the maximum recommended 1000 mg twice daily are poorly tolerated.[13]
• Less Common and Other ADRs: Other reported side effects include palpitations, tinnitus, vertigo, blurred vision, abdominal pain, dry mouth, vomiting, and peripheral edema.[13] Post-marketing surveillance has identified rare but potentially serious events, including neurologic symptoms (e.g., tremor, paresthesia, confusion, hallucinations), angioedema, and acute renal failure in specific at-risk populations.[4]

Warnings and Precautions

Renal Function and Serum Creatinine

Ranolazine is associated with a predictable and generally benign effect on renal biomarkers. It consistently produces a small elevation in serum creatinine (SCr), typically around 0.1 mg/dL, regardless of baseline renal function.[11] This elevation is not indicative of true kidney injury. It occurs because Ranolazine or its metabolites inhibit the tubular secretion of creatinine in the kidneys, a process separate from glomerular filtration. This effect has a rapid onset, does not progress with long-term therapy, is reversible upon discontinuation of the drug, and is not accompanied by a corresponding rise in blood urea nitrogen (BUN).[11]

This distinction is clinically vital. An uninformed clinician, observing a rise in SCr, might incorrectly diagnose drug-induced nephrotoxicity and inappropriately discontinue a beneficial therapy. It is crucial to differentiate this predictable, benign pharmacodynamic effect from the rare but serious cases of true acute renal failure that have been reported in patients with pre-existing severe renal impairment (CrCl < 30 mL/min) who are initiated on Ranolazine.[13] Therefore, while the small SCr rise in most patients is expected and not alarming, renal function should be monitored periodically in patients with moderate to severe renal impairment (CrCl < 60 mL/min) to watch for any marked or progressive increases that might signal true renal injury.[3]

Contraindications

The use of Ranolazine is strictly contraindicated in certain situations due to the high risk of significantly increased drug exposure and adverse events:

• Concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir).[13]
• Concomitant use of inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort).[13]
• Patients with liver cirrhosis or moderate to severe hepatic impairment.[5]

The Clinical Significance of QT Interval Prolongation: A Safety Paradox

The most complex aspect of Ranolazine's safety profile is its effect on the QT interval.

• Mechanism of Prolongation: Ranolazine blocks the IKr​ potassium channel, a key current responsible for ventricular repolarization. This action directly leads to a prolongation of the action potential duration, which manifests as a dose- and plasma concentration-dependent increase in the QTc interval on the ECG.[1] The mean increase at therapeutic doses is modest, typically 2 to 7 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation can be 15 msec or more.[10]
• Low Proarrhythmic Risk: Despite this clear QT-prolonging effect, Ranolazine has demonstrated a surprisingly low risk of inducing proarrhythmia. In multiple large-scale clinical trials, including the MERLIN-TIMI 36 study which enrolled over 6,500 high-risk patients with acute coronary syndrome, Ranolazine was not associated with an increased incidence of the life-threatening arrhythmia Torsades de Pointes (TdP) or sudden cardiac death.[12] In fact, these trials often reported a statistically significant reduction in the incidence of various ventricular and supraventricular arrhythmias in patients treated with Ranolazine compared to placebo.[37]
• Resolving the Paradox: The resolution of this paradox lies in Ranolazine's dual mechanism of action on cardiac ion channels. While the blockade of IKr​ is a potentially proarrhythmic action that prolongs the action potential, the primary therapeutic mechanism—the inhibition of the late sodium current (INaL​)—is strongly anti-arrhythmic. TdP is typically initiated by triggers known as early afterdepolarizations (EADs), which occur during the prolonged plateau phase of the action potential. The substrate for TdP is an increased dispersion of repolarization times across the ventricular wall. Ranolazine's inhibition of INaL​ actively suppresses the formation of EADs and has been shown to reduce, rather than increase, the transmural dispersion of repolarization.[14] In essence, the anti-arrhythmic effect of INaL​ blockade appears to counteract the pro-arrhythmic potential of IKr​ blockade.
• Clinical Implications: This unique electrophysiological profile means that the modest QT prolongation observed with Ranolazine does not carry the same ominous clinical implications as it does for "pure" IKr​ blockers like sotalol or dofetilide.[14] Nevertheless, caution remains prudent. The risk of arrhythmia, while low, is not zero and may be increased by certain underlying risk factors. Therefore, Ranolazine should be used with caution in patients with a personal or family history of congenital long QT syndrome, known acquired QT prolongation, or in combination with other drugs that also prolong the QT interval, as the effects could be additive.[11] A single case report has described TdP in a complex patient with multiple confounding factors, including severe renal impairment and concomitant use of amiodarone, highlighting the importance of adhering to prescribing guidelines.[45]

Drug-Drug Interactions (DDIs)

The safe and effective use of Ranolazine is critically dependent on the management of its extensive and complex drug-drug interaction profile. As a substrate for multiple metabolic pathways and an inhibitor of others, Ranolazine can be both the "victim" of interactions that alter its own concentration and the "perpetrator" of interactions that alter the concentrations of other drugs. A thorough medication review is mandatory before initiating therapy.

The interactions are primarily driven by its metabolism via CYP3A4 and CYP2D6, its transport by P-glycoprotein (P-gp), and its own inhibitory effects on CYP2D6, P-gp, and the renal transporter OCT2.[27] These interactions are summarized in Table 3.

Table 3: Clinically Significant Drug-Drug Interactions with Ranolazine

Interacting Drug/Class	Mechanism of Interaction	Effect on Ranolazine or Interacting Drug	Clinical Management Recommendation	Source(s)
Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, nefazodone)	Inhibition of Ranolazine's primary metabolic pathway.	Increases Ranolazine AUC 3- to 3.9-fold, significantly increasing risk of toxicity and QT prolongation.	Contraindicated.	27
Moderate CYP3A4 Inhibitors (e.g., diltiazem, verapamil, erythromycin, fluconazole, grapefruit juice)	Inhibition of Ranolazine's primary metabolic pathway.	Increases Ranolazine AUC 1.5- to 2.4-fold.	Limit Ranolazine dose to a maximum of 500 mg twice daily.	11
Strong CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort)	Induction of Ranolazine's primary metabolic pathway.	Decreases Ranolazine AUC by approximately 95%, leading to loss of efficacy.	Contraindicated.	11
P-glycoprotein (P-gp) Inhibitors (e.g., cyclosporine, verapamil)	Inhibition of P-gp-mediated efflux, increasing Ranolazine absorption.	Increases Ranolazine plasma concentrations. Verapamil increases AUC 2.2-fold.	Titrate Ranolazine dose based on clinical response. Caution advised.	21
Digoxin (P-gp Substrate)	Ranolazine inhibits P-gp-mediated efflux of digoxin.	Increases plasma digoxin concentrations by approximately 1.5-fold.	Monitor digoxin levels after initiating or terminating Ranolazine therapy. Digoxin dose reduction may be required.	20
Simvastatin (CYP3A4 Substrate)	Ranolazine weakly inhibits CYP3A4-mediated metabolism of simvastatin.	Increases plasma concentrations of simvastatin and its active metabolite by approximately 2-fold.	Limit simvastatin dose (e.g., to 20 mg/day) when co-administered with Ranolazine.	20
Metformin (OCT2 Substrate)	Ranolazine inhibits renal tubular secretion of metformin via the OCT2 transporter.	Increases metformin plasma concentrations.	Limit metformin dose (e.g., to 1700 mg/day) when used with Ranolazine 1000 mg twice daily. Monitor for metformin-related adverse effects.	3
CYP2D6 Substrates (e.g., metoprolol, tricyclic antidepressants, some antipsychotics)	Ranolazine is a mild-to-moderate inhibitor of CYP2D6.	Increases plasma concentrations of CYP2D6 substrates. Metoprolol exposure increased 1.8-fold.	Lower doses of sensitive CYP2D6 substrates may be required. Caution and monitoring advised.	27

The bidirectional nature of Ranolazine's interaction profile creates a complex clinical management challenge, particularly in cardiovascular patients who are often on polypharmacy. It is not sufficient to only check for drugs that affect Ranolazine's metabolism (the "victim" interactions). Clinicians must also proactively consider how Ranolazine itself will affect the disposition of the patient's other medications (the "perpetrator" interactions).

For example, a patient with angina, heart failure, and diabetes might be on a regimen including diltiazem, digoxin, and metformin. Initiating Ranolazine in this patient requires a multi-step thought process:

1. The presence of diltiazem, a moderate CYP3A4 inhibitor, mandates that the Ranolazine dose be capped at 500 mg twice daily.[11]
2. Once Ranolazine is started, it will inhibit the P-gp-mediated clearance of digoxin, likely requiring a reduction in the digoxin dose and monitoring of serum levels to avoid toxicity.[27]
3. Simultaneously, Ranolazine will inhibit the OCT2-mediated renal secretion of metformin, necessitating a potential reduction in the metformin dose and closer monitoring of blood glucose and for signs of lactic acidosis.[28]

This scenario highlights that prescribing Ranolazine is not a simple act but a comprehensive process of medication therapy management. It elevates the importance of collaboration between physicians and clinical pharmacists to ensure a holistic review of the patient's entire medication list and to anticipate and manage this intricate web of potential interactions.

Dosage and Administration

Proper dosing and administration are essential for maximizing the efficacy and minimizing the risks associated with Ranolazine therapy. The guidelines are tailored to account for its extended-release formulation, non-linear pharmacokinetics, and interaction profile.

Available Formulations

Ranolazine is available in two oral formulations:

• Extended-Release Tablets: Supplied in strengths of 500 mg (typically light orange, oval-shaped) and 1000 mg (typically pale yellow, oval-shaped).[11]
• Extended-Release Granules for Suspension (Aspruzyo Sprinkle): Supplied in unit-dose sachets containing 500 mg or 1000 mg of coated granules. This formulation is intended for patients who have difficulty swallowing tablets.[1]

Standard Dosing and Administration

• Initial Dose: The recommended starting dose is 500 mg taken orally twice daily.[11] Some European guidelines suggest an initial dose of 375 mg twice daily.[27]
• Titration: Based on clinical symptoms and tolerability, the dose may be increased to the target maintenance dose of 1000 mg twice daily, typically after 2 to 4 weeks of treatment.[11]
• Maximum Dose: The maximum recommended daily dose is 1000 mg twice daily (total 2000 mg/day). Doses higher than this are poorly tolerated and should not be used.[11]
• Administration Instructions:
• Tablets should be swallowed whole and must not be crushed, broken, or chewed, as this would disrupt the extended-release mechanism.[11]
• Ranolazine can be taken with or without food.[11]
• If a dose is missed, the patient should take the next prescribed dose at the regularly scheduled time. The dose should not be doubled to make up for a missed one.[11]

Dose Adjustments in Specific Populations and Scenarios

Specific dose adjustments are required to ensure safety in the presence of certain interacting drugs or in patients with organ dysfunction. These are summarized in Table 4.

• Elderly Patients: Due to a higher incidence of adverse effects and the potential for age-related decline in renal function leading to increased drug exposure, dosage in elderly patients should be selected cautiously. It is recommended to initiate therapy at the lower end of the dosage range (e.g., 500 mg twice daily) and titrate slowly based on response and tolerability.[27]

Table 4: Ranolazine Dose Adjustment Guidelines

Patient Population / Scenario	Recommended Action	Rationale
Concomitant Strong CYP3A4 Inhibitor	Contraindicated	Risk of markedly increased Ranolazine concentration and toxicity.
Concomitant Moderate CYP3A4 Inhibitor	Limit maximum dose to 500 mg twice daily.	Prevents excessive Ranolazine exposure.
Concomitant Strong CYP3A4 Inducer	Contraindicated	Risk of therapeutic failure due to sub-therapeutic Ranolazine levels.
Concomitant P-gp Inhibitor	Titrate Ranolazine dose cautiously based on clinical response.	P-gp inhibitors can increase Ranolazine exposure.
Severe Renal Impairment (CrCl < 30 mL/min)	Contraindicated (EMA) / Use with caution, monitor renal function, and discontinue if acute renal failure develops (FDA).	Increased drug exposure and risk of acute renal failure.
Moderate Renal Impairment (CrCl 30-60 mL/min)	Titrate dose with caution and monitor renal function periodically.	Increased drug exposure.
Moderate to Severe Hepatic Impairment / Cirrhosis	Contraindicated	Markedly increased drug exposure and risk of QT prolongation.
Mild Hepatic Impairment	Titrate dose with caution.	Potential for increased drug exposure.
Elderly Patients	Initiate at a low dose and titrate cautiously.	Higher incidence of adverse effects and potential for decreased renal clearance.

Regulatory Status and Commercial Landscape

Ranolazine's journey from discovery to its current position as a globally available medication reflects key trends in pharmaceutical development and market dynamics.

Regulatory History

• Development and Licensing: Ranolazine was originally discovered by Syntex, a subsidiary of Roche. In 1996, a small biopharmaceutical company, CV Therapeutics, licensed the North American and European rights to the compound and led its late-stage clinical development.[5] CV Therapeutics later acquired the remaining worldwide rights from Roche in 2006.[5]
• FDA Approval: The U.S. Food and Drug Administration (FDA) granted its first approval for Ranexa (Ranolazine) on January 27, 2006, for the treatment of chronic angina.[1] Key subsequent regulatory milestones in the U.S. include the approval of new mechanism of action labeling in 2007 and an expanded indication for first-line use in 2008.[35]
• European Approval: The European Medicines Agency (EMA) approved Ranolazine, marketed as Ranexa (and previously as Latixa), for the symptomatic treatment of stable angina pectoris in patients inadequately controlled by or intolerant to first-line antianginal therapies.[2]
• Corporate Acquisitions and Partnerships: In 2009, Gilead Sciences acquired CV Therapeutics, taking control of the Ranexa franchise.[5] For marketing in Europe and other international territories, Gilead has partnered with the Menarini Group.[5]

Brand and Generic Availability

• Brand Names: The original and most recognized brand name for Ranolazine is Ranexa.[1] A newer branded formulation of extended-release granules, designed for patients who cannot swallow tablets, is marketed as Aspruzyo Sprinkle.[1] In Canada, the brand name is Corzyna.[16]
• Generic Market Entry: Following the expiration of key patents, the market for Ranolazine has seen the entry of numerous generic manufacturers. This "patent cliff" has led to significant price erosion and wider accessibility of the drug.[50] Major pharmaceutical companies that manufacture and market generic Ranolazine include Teva Pharmaceutical Industries, Glenmark Pharmaceuticals, Camber Pharmaceuticals, Aurobindo Pharma, Mylan (now part of Viatris), and Dr. Reddy's Laboratories, among many others.[50] The availability of lower-cost generic alternatives has substantially impacted the commercial landscape, transforming Ranolazine from a proprietary, high-revenue product for its original developer to a widely available generic medication.[50]

Synthesis and Recommendations

Ranolazine has firmly established itself as a unique and valuable agent in the management of chronic cardiovascular disease. Its clinical utility, however, is intrinsically linked to a deep understanding of its complex pharmacology, which demands a higher level of clinical vigilance than many conventional therapies. This final synthesis provides an expert perspective on its place in therapy, key management principles, and future directions.

Ranolazine's Unique Position in Therapy

Ranolazine's primary value lies in its novel mechanism of action. As a non-hemodynamic, metabolic-modulating, and ion-channel-targeting antianginal, it offers a therapeutic approach that is entirely complementary to traditional agents. By reducing ischemia-induced sodium and calcium overload, it alleviates angina without depressing heart rate or blood pressure. This makes it a particularly effective option for patients who remain symptomatic despite optimal doses of beta-blockers or calcium channel blockers, or for those in whom further intensification of these agents is limited by hypotension or bradycardia.

The ideal candidate for Ranolazine therapy is a patient with chronic stable angina who requires additional symptom control, especially if their baseline heart rate or blood pressure is at the lower end of the normal range. Conversely, Ranolazine should be approached with extreme caution or avoided altogether in patients with significant hepatic or severe renal impairment, and in those with complex polypharmacy involving multiple potent inhibitors or inducers of its metabolic pathways.

Key Principles for Clinical Management

To wield this powerful tool safely and effectively, clinicians must adhere to several core principles:

1. Meticulous Drug Interaction Screening: The single most critical step before prescribing Ranolazine is a comprehensive medication reconciliation. Given its heavy reliance on CYP3A4 for metabolism and its own inhibitory effects on P-gp, CYP2D6, and OCT2, a thorough assessment for potential drug-drug interactions is non-negotiable.
2. Adherence to the "Start Low, Titrate Slow" Strategy: The standard regimen of initiating at 500 mg twice daily and titrating to 1000 mg twice daily based on symptoms is not merely a suggestion but a necessity driven by the drug's non-linear pharmacokinetics. This approach allows for assessment of tolerability and mitigates the risk of toxicity associated with the disproportionate increase in exposure at higher doses.
3. Comprehensive Patient Education: Patients must be counseled on the most common side effects, particularly dizziness, which may affect their ability to drive or operate machinery. They must understand the critical importance of swallowing the tablets whole and not crushing them. Furthermore, they should be instructed to inform all of their healthcare providers, including pharmacists, that they are taking Ranolazine to prevent inadvertent prescribing of interacting medications.
4. Informed Interpretation of Laboratory Values: Clinicians must be educated on two key nuances of Ranolazine's profile. First, they must recognize that the small, stable increase in serum creatinine is a benign pharmacodynamic effect on tubular secretion and not a sign of nephrotoxicity. Second, they must understand the paradoxical nature of the QT prolongation—that while present, it does not confer the same proarrhythmic risk as it does with other agents, due to the counteracting anti-arrhythmic effect of INaL​ blockade.

Future Directions

The future of Ranolazine may lie in a more personalized approach to medicine. Its highly specific mechanism of targeting the late sodium current makes it an intriguing candidate for genetically defined channelopathies. The promising preclinical data for its use in Long QT Syndrome Type 3, a condition caused by a pathological increase in INaL​, suggests a potential evolution from a general antianginal to a targeted therapy for specific molecular defects.

Final Verdict

Ranolazine is a sophisticated and highly effective medication for its indicated purpose. It is not a simple "set and forget" drug. Its successful implementation requires a nuanced understanding of its unique pharmacology, a diligent approach to managing its complex interactions, and clear communication with the patient. When used with the respect its complexity demands, Ranolazine is an indispensable tool in the armamentarium for treating chronic angina, offering relief to many patients for whom other options have been exhausted or are unsuitable.

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