Ranolazine

C01E - Other cardiac preparations ATC C01EB18 Small molecule approved 2006 Oral Natural product

JFDA label: Ranexa 375mg

Mechanism of Action

Blocker of Sodium channel protein type 5 subunit alpha — Sodium channel protein type V alpha subunit blocker; Blocker of Sodium channel protein type 4 subunit alpha — Sodium channel protein type IV alpha subunit blocker

Target	Action	Gene / class
Sodium channel protein type 4 subunit alpha efficacy	BLOCKER	SCN4A
Sodium channel protein type 5 subunit alpha efficacy	BLOCKER	SCN5A

Indications

Approved

Chronic angina

Contraindications

Source: Lexicomp

Hepatic cirrhosis Absolute
concurrent CYP3A inducers Absolute
concurrent strong CYP3A inhibitors Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Common Bradycardia · hypotension · orthostatic hypotension · palpitation · peripheral edema · prolonged QT interval on ECG

Nervous system disorders (5)

Common confusion · Dizziness · headache · syncope · vertigo

Renal and urinary disorders (1)

Common Hematuria

Gastrointestinal disorders (7)

Common abdominal pain · anorexia · Constipation · dyspepsia · nausea · vomiting · xerostomia

Skin and subcutaneous tissue disorders (1)

Common Hyperhidrosis

Musculoskeletal and connective tissue disorders (1)

Common Weakness

Eye disorders (1)

Common Blurred vision

Ear and labyrinth disorders (1)

Common Tinnitus

Respiratory, thoracic and mediastinal disorders (1)

Common Dyspnea

Other (24)

Not Known Angioedema · ataxia · decreased glycosylated hemoglobin · decreased T-wave amplitude · dysuria · eosinophilia · hallucination · hypoesthesia · hypoglycemia (diabetic patients) · increased blood urea nitrogen · increased serum creatinine · leukopenia · pancytopenia · paresthesia · pruritus · pulmonary fibrosis · renal failure · skin rash · T-wave changes (notched) · thrombocytopenia · torsade de pointes (Morrow 2007) · tremor · urinary retention · urine discoloration

Dosing

Source: Lexicomp

Note: May be used with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-receptor blockers. Chronic angina: Oral: Initial: 500 mg twice daily; may increase to 1,000 mg twice daily as needed (based on symptoms); maximum recommended dose: 1,000 mg twice daily Missed doses: If a dose is missed, it should be taken at the next scheduled time; the next dose should not be doubled. Dosage adjustment for ranolazine with concomitant medications: Diltiazem, erythromycin, fluconazole, verapamil, and other moderate CYP3A inhibitors: Ranolazine dose should not exceed 500 mg twice daily CYP3A inducers or strong CYP3A inhibitors: Concomitant use is contraindicated P-glycoprotein inhibitors (eg, cyclosporine): Titrate ranolazine based on clinical response

Refer to adult dosing. Select dose cautiously, starting at the lower end of the dosing range.

There are no dosage adjustments provided in the manufacturer’s labeling. However, plasma ranolazine levels increased ~40% to 50% in patients with varying degrees of renal dysfunction. Discontinue if acute renal failure develops during treatment. Ranolazine has not been evaluated in patients requiring dialysis, although it is unlikely to be removed by hemodialysis due to plasma protein binding.

There are no dosage adjustments provided in the manufacturer’s labeling. Use is contraindicated with hepatic cirrhosis.

Warnings & Precautions

Source: Lexicomp

Altered cardiac conduction

Has been shown to prolong QTc interval in a dose/plasma concentration-related manner. At Tmaxfollowing repeat dosing at 1000 mg twice daily, the mean change in QTc is ~6 msec, but 5% of the population (with the highest plasma concentrations) has at least a 15 msec increase. Cirrhotic patients with mild to moderate hepatic impairment demonstrated a 3-fold increase QT prolongation; use is contraindicated in patients with liver cirrhosis. The incidence of symptomatic arrhythmias was similar to placebo in one trial (Morrow 2007). Risk versus benefit should be assessed in patients maintained on a higher dose (>2,000 mg/day) or exposure, concurrent use of other QT-prolonging drugs, potassium-channel variants known to cause QT prolongation, family history of or congenital long QT syndrome, or known acquired QT interval prolongation. Disease-related concerns:

Acute coronary syndrome

Ranolazine will not relieve acute angina episode and has not demonstrated benefit in acute coronary syndrome.

Hepatic impairment

Ranolazine plasma levels increase by 30% in patients with mild (Child-Pugh class A) and by 80% in patients with moderate (Child-Pugh class B) hepatic impairment. Use is contraindicated in patients with cirrhosis.

Renal impairment

Acute renal failure has been observed in some patients with severe renal impairment (CrCl Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Use is contraindicated with inducers and strong inhibitors of CYP3A. Special populations:

Elderly

Use with caution in patients ≥75 years of age; they may experience more adverse events (including serious adverse events) and drug discontinuations due to adverse events.

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in animal reproduction studies.

Lactation

It is not known if ranolazine is excreted into breast milk. According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.

Monitoring

Clinical pearl	Baseline and follow up ECG to evaluate QT interval; monitor renal function periodically in patients with moderate to severe renal impairment, particularly for increases in serum creatinine accompanied by increased BUN; consider monitoring blood pressure in patients with renal dysfunction; correct and maintain serum potassium in normal limits

Chemistry & Properties

Formula	C24H33N3O4
Molecular weight	427.55 g/mol
IUPAC name	N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide
CAS	95635-55-5
PubChem CID	56959
InChIKey	`XKLMZUWKNUAPSZ-UHFFFAOYSA-N`
logP	2.31 (XLogP 2.7)
Polar surface area	74.27 Å²
H-bond acceptors / donors	6 / 2
Drug-likeness (QED)	0.64
Lipinski violations	0

SMILES

COc1ccccc1OCC(O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.335 h
Volume of distribution	1.409 L/kg
Protein binding	89.4%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2C19	Substrate	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aminoglutethimide	major
Anagrelide	major
Apalutamide	major
Aprepitant	major
Arsenic trioxide	major
Betrixaban	major
Bexarotene	major
Cabozantinib	major
Ceritinib	major
Chloroquine	major
Cisapride	major
Clarithromycin	major
Clotrimazole	major
Cobicistat	major
Crizotinib	major
Dabrafenib	major
Dexamethasone	major
Dolasetron	major
Edoxaban	major
Eliglustat	major
Enzalutamide	major
Erythromycin	major
Fedratinib	major
Fingolimod	major
Fluconazole	major
Griseofulvin	major
Halofantrine	major
Hydrocodone	major
Hydroxychloroquine	major
Idelalisib	major
Imatinib	major
Ivosidenib	major
Ketoconazole	major
Lapatinib	major
Lorlatinib	major
Lumacaftor	major
Lumefantrine	major
Macimorelin	major
Mitotane	major
Nilotinib	major

Showing 40 of 100+.

Registered Products (7)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
RANCV Extended Release Tablets	Tablet 1000 mg	10 tab pack varies	Manar Drug Store	1.280
RANCV Extended Release Tablets	Tablet 1000 mg	30 tab pack varies	Manar Drug Store	3.610
RAZINE 500mg Extended-Relase Tablet	Tablet Ranolazine 500 mg	30 tab	Reda Jardaneh Drug Store	10.400
RAZINE 1000mg Extended Release Tablets	Tablet Ranolazine 1000 mg	30 tab	Reda Jardaneh Drug Store	12.880
Ranexa	Tablet 375 mg	60 tab	ORIENT DRUG STORE CO	28.310
Ranexa	Tablet 750 mg	60 tab	ORIENT DRUG STORE CO	28.310
Ranexa	Tablet 500 mg	60 tab	ORIENT DRUG STORE CO	28.310