RANOLAZINEDr. Merajuddin shah, MD, DM (Cardiology)

Al-Kareem Cardiac Center, Srinagar, Kashmir

METABOLIC MANUPULATION OF ISCHEMIC HEART DISEASE. A NOVEL APPROACH TO TREATMENT --------Leong Lee , EHJ, 2004

RANOLAZINEA Piperazine Derivative

Chronic Angina

• A condition that impairs quality of life and is associated with decreased life expectancy

• Current major drug therapiesNitratesß-blockers, Calcium antagonistsAll these affect HR and BP

Ranolazine

• A drug that reduces angina symptoms, with a mechanism of action different from that of currently available pharmacological therapies.

• Do not affect HR & BP.Ranolazine was approved on January 27, 2006,

in the United States for use in patients with chronic angina who continue to be

symptomatic on ß-blockers, calcium antagonists, or nitrates.

Eur Heart J. 2004;6(suppl I):I3–I7.

Primary Mechanism of Action: Inhibition of Late Na channel

NCX: Sodium-calcium exchange

Mechanism of action

• In ischemia, number of late Na channel (I-Na) increases which leads to calcium overload through Na-Ca exchange.

• Ranolazine block these late Na channel, and hence prevent the calcium overload which in turn decreases mechanical dysfunction, abnormal contraction and relaxation, and diastolic tension.

• Ranolazine (therapeutically conc.up to 10 µmol/L) selectively inhibit late INa (IC50=5 to 21 µmol/L)

• No effect on either the fast sodium current responsible for the upstroke of the action potential (IC50 value of 244 µmol/L for peak INa) or the Na+-H+ and Na+-Ca2+ exchangers.

Thus, ranolazine is a relatively selective inhibitor for late INa

J Cardiovasc Pharmacol Ther. 2004; 9: S65–S83

• IC50 values for various currents:– Late INa+ 5.9 umol/L– IKr 11.5 umol/L– Late ICa+ 50 umol/L– INa-Ca 91 umol/L– Peak ICa+ 296 umol/L– IKs (17%) 30 umol/L

Ranolazine & inhibition of various currents

Circulation. 2004;110:904-910

Pharmacokinetics• Food - no effect on Bioavailability The absolute bioavailability - 35% to 50%.

Elimination• 80% - by cytochrome P450 (CYP) 3A enzymes• 10-15% by CYP2D6 • 5% Glucuronidation• 5% Excreted unchanged in Urine.

• Elimination half-life 7 hrs - ER formulation

Drug–Drug Interaction• Diltiazem (≥240 mg daily) - ↑ ranolazine plasma levels - 1.5-fold

• Ranolazine has no significant effect on diltiazem pharmacokinetics

• Verapamil (≥360 mg daily) - 2.3-fold ↑ in ranolazine plasma levels

• Ranolazine increases digoxin concentrations 1.4- to 1.6-fold at trough &2-fold at peak plasma levels

• Ranolazine is contraindicated in patients on potent and moderately potent CYP3A inhibitors such as ketoconazole,

diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice

Drug–Drug Interaction• Simvastatin Cmax is ↑ by 2-fold after ranolazine;• Simvastatin - no significant effect on ranolazine

pharmacokinetics.• In phase II studies of ranolazine with patients on statin drugs, significant increases in creatine kinase,

clinical myositis, or elevated liver function tests have not been reported.

• No interactions with warfarin • Antiarrhythmic drugs

Class Ia: quinidine Class III: dofetilide, sotalol Certain antipsychotics: Thioridazine, ziprasidone

Monotherapy Assessment of Ranolazine In Stable AnginaMARISA

• Patients withdrawn from other anti-anginals(N = 191 randomized)

• Randomized, double-blind, 4-period crossover– 1-wk treatment periods – Placebo vs 500, 1000, and 1500 mg bid

• Exercise tests after each week of treatment– At trough (12 hr after dosing)– At peak (4 hr after dosing)

J Am Coll Cardiol 2004;43:1375-82.

Monotherapy With Ranolazine Increases Exercise Performance at Trough and Peak

MARISA

N = 175, All/Near Completers population; LS means ± SE.**p < 0.01 vs placebo; ***p < 0.001 vs. placebo

400

440

480

520

560

Exercise duration Timeto angina

Time to 1-mmST depression

Exercise duration Timeto angina

Time to 1-mmST depression

Tim

e, s

ec

PeakTrough

***

*** ***

***

******

******

***

*****

***

*****

*** ******

***

Placebo 500 mg bid

1000 mg bid 1500 mg bid

Combination Assessment of Ranolazine In Stable Angina

CARISA • Randomization criteria identical to MARISA except for

background therapy– Atenolol 50 mg qd (n = 354), or – Amlodipine 5 mg qd (n = 256), or– Diltiazem CD 180 mg qd (n = 213)

• Three parallel groups for 12 wk of treatment– Placebo– Ranolazine 750 mg bid– Ranolazine 1000 mg bid

• Exercise testing– At trough after 2, 6, and 12 wk of treatment– At peak after 2 and 12 wk of treatment

JAMA 2004;291:309-316.

Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times at Trough and Peak

CARISA

Ch

ang

e fr

om

bas

elin

e, s

ec

N = 791, ITT/LOCF; LS mean ± SE.*p < 0.05; **p ≤ 0.01; ***p ≤ 0.001 vs placebo.

50

100

150

Exerciseduration

Time to 1-mmST depression

Timeto angina

PeakTrough

***

** **

*****

* *

**

Placebo 750 mg bid 1000 mg bid

*

Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin Consumption

CARISA

0

1

2

3

4

5

6

Baseline Double-blind Baseline Double-blind

Nu

mb

er

per

wk

PlaceboRanolazine 750 mg bidRanolazine 1000 mg bid

Angina attacks Nitroglycerin consumption

***

N = 791, ITT/LOCF; LS mean ± SE.*p < 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo

******

ERICA: Study design

Ranolazine extended-release 500 mg bid

(1 week) then 1000 mg bidn = 281

Placebon = 284

History of CAD* Stable angina (≥3 angina episodes/week) Amlodipine

10 mg/dayN = 565

7 weeks

Primary efficacy variable:Angina frequency (weekly average)

RandomizedDouble-blind

Evaluation of Ranolazine In Chronic Angina

*≥60% stenosis, previous MI, and/or stress-induced perfusion defect Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Ranolazine reduces angina frequency and nitrate consumption

PlacPlaceboeboRRannanolazine 1000 mg bid

Nitroglycerin useAngina episodes

P = 0.028

P = 0.014

N = 564 on amlodipine 10 mg/day

0

1

2

3

4

5

6

Baseline Week 7 Baseline Week 7

Mean number

per week

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: No significant effect on heart rate or BP

PlaceboPlacebo Ranolazine 1000 bidRanolazine 1000 bid PP

Heart rate Heart rate (bpm)(bpm)

↓↓1.61.6 ↓↓2.02.0 0.660.66

Systolic BP Systolic BP (mm Hg)(mm Hg)

↓↓1.71.7 ↓↓2.02.0 0.720.72

Diastolic BP Diastolic BP (mm Hg)(mm Hg)

↓↓0.60.6 ↓↓1.01.0 0.610.61

N = 564 on amlodipine 10 mg/day; Supine measurement

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

Ranolazine Is at Least as Effective as Atenolol 100 mg DailyRAN080

LS

mea

n

± SE

, se

c

300

320

340

360

380

400

420

440

460

Time to onset of angina Time to 1-mm ST-depression

p < 0.001

p < 0.001 p = 0.18

p < 0.001

p < 0.001 p = 0.86

Exercise duration

p < 0.04

p < 0.001 p = 0.006

Placebo Ranolazine IR 400 mg tid(1741 ± 1026 ng base/mL)

Atenolol 100 mg od

All patients analysis, N = 154.

MERLIN-TIMI 36

• Randomized, placebo controlled tiral.• Subjects: 6560 patients hospitalized with

NSTEMI were randomized to ranolazine or placebo, in addition to standard therapy.

• Initially ranolazine was given intravenous infusion followed by oral ranolazine.

• Median duration of cECG monitoring was 6.8 days.

Circulation 2007;116:1647-1652.

MERLIN-TIMI 36: SUMMARY

• In more than 6300 patients admitted with NSTEMI, treatment with ranolzine resulted in significantly lower incidence of

– ventricular tachycardia, – Supraventricular tachycardia, and – Significant ventricular pauses.

Circulation 2007;116:1647-1652.

Summary—Anti-Anginal and Anti-Ischemic Efficacy of Ranolazine

• Dose and plasma concentration dependent

• Consistent throughout a broad population of chronic angina patients

• Not dependent on decreases in blood pressure or heart rate

• At least as great as atenolol 100 mg qd (RAN080)

• In patients on atenolol or diltiazem at doses considered optimal by their physicians (RAN072)

SafetyCommon reported adverse events are:- Dizziness:- 6.2%Dizziness:- 6.2% Headache:- 5.5%Headache:- 5.5% Constipation:- 4.5%Constipation:- 4.5% Nausea:- 4.4%Nausea:- 4.4%

CARISA: the average increase in QTc was 6.1 and 9.2 ms at the ranolazine doses of 750mg and 1000mg twice daily.NO CASES OF TORSADES DE POINTES HAVE BEEN SEEN IN PATIENTS WHO RECEIVED RANOLAZINE IN CLINICAL TRIALS TO DATE

Contraindications

• Preexisting QT prolongation• On drugs that prolong QT interval• Hepatic impairment• Patients taking drugs which inhibit CYP3A.• In patients on potent and moderately potent

CYP3A inhibitors such as ketoconazole, diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, and grapefruit juice.

Indications & Dosage

• Treatment of Chronic angina.• Patients who have not achieved an adequate

response with other antianginal drug.• It should be used in combination with beta-

blockers, amlodipine, or nitrates.• 500mg bid initially, can be increased to 1000 mg

bid.• Max. recommended daily dose is 1000 mg bid.• Helps in lowering HbA1c in patients with DM

Summary— Ranolazine Efficacy and Safety

• Efficacy demonstrated in 5 double-blind, randomized, placebo-controlled trials

• Safe and well tolerated

• Adverse events are generally dose dependent and manageable by typical dose titration

• No evidence for an adverse effect of ranolazine on survival

Caroza: A Novel Key For Angina