1. RANOLAZINE Dr. Merajuddin shah, MD, DM (Cardiology) Al-Kareem Cardiac Center, Srinagar, Kashmir

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

3. RANOLAZINE A Piperazine Derivative

5. Chronic Angina
A condition that impairs quality of life and is associated with decreased life expectancy
Current major drug therapies
Nitrates
ß-blockers,
Calcium antagonists
All these affect HR and BP

6. 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.

7. Mechanisms of Action
Initially it was thought that primary mechanism of action is inhibition of fatty acid oxidation, and promotion of glucose oxidation

8. Primary Mechanism of Action: Inhibition of Late Na channel
NCX: Sodium-calcium exchange
Eur Heart J. 2004;6(suppl I):I3–I7.

9. 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.

10. Thus, ranolazine is a relatively selective inhibitor for late INa
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

11. Ranolazine & inhibition of various currents
IC50 values for various currents:
Late INa umol/L
IKr umol/L
Late ICa umol/L
INa-Ca umol/L
Peak ICa umol/L
IKs (17%) umol/L
Circulation. 2004;110:

12. Pharmacokinetics Elimination 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

13. Drug–Drug Interaction
Diltiazem (≥240 mg daily) - ↑ ranolazine plasma levels fold
Ranolazine has no significant effect on diltiazem pharmacokinetics
Verapamil (≥360 mg daily) 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

14. 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

15. Monotherapy Assessment of Ranolazine In Stable Angina MARISA
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:

16. Monotherapy With Ranolazine Increases Exercise Performance at Trough and Peak MARISA
***
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***
*** **
***
***
***
***
***
***
***
***
***
***
***
*** **
N = 175, All/Near Completers population; LS means ± SE.
**p < 0.01 vs placebo; ***p < vs. placebo
Placebo
500 mg bid
1000 mg bid
1500 mg bid

17. 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:

18. Change from baseline, sec
Ranolazine With a Beta- or Calcium Blocker Increases Exercise Times at Trough and Peak CARISA
Trough
Peak * * ** ** * *
***
*** ** *
Change from baseline, sec
N = 791, ITT/LOCF; LS mean ± SE.
*p < 0.05; **p ≤ 0.01; ***p ≤ vs placebo.
Placebo
750 mg bid
1000 mg bid

19. Nitroglycerin consumption
Ranolazine Decreases Weekly Angina Attacks and Nitroglycerin Consumption CARISA **
*** *
***
Angina attacks
Nitroglycerin consumption
N = 791, ITT/LOCF; LS mean ± SE.
*p < 0.05, **p ≤ 0.01, ***p ≤ vs placebo

20. ERICA: Study design Evaluation of Ranolazine In Chronic Angina
History of CAD* Stable angina (≥3 angina episodes/week) Amlodipine 10 mg/day N = 565
Ranolazine extended-release 500 mg bid (1 week) then 1000 mg bid n = 281
Placebo n = 284
Randomized Double-blind
7 weeks
Primary efficacy variable: Angina frequency (weekly average)
*≥60% stenosis, previous MI, and/or stress-induced perfusion defect
Stone PH et al. J Am Coll Cardiol. 2006;48:

21. Amlodipine was to be started at least 2 weeks PRIOR to the qualification period
Those taking Dig, perhexiline, trimetazidine, beta blockers, OTHER calcium channel blockers had to be withdrawn 4 weeks prior to initiation of study drug

22. ERICA: Ranolazine reduces angina frequency and nitrate consumption
N = 564 on amlodipine 10 mg/day 6 5 4
P =
Mean number per week
P = 0.014 3 2 1
NOTE THE EFFECT OF PLACEBO ON THE NUMBER OF ANGINA EPISODES AND ALSO NITROGLYCERIN USE, THUS THE NEED FOR HAVING A PLACEBO IN ANY RANDOMIZED TRIAL IS VERY IMPORTANT
AGAIN SHOWING THAT RANOLAZINE DECREASED FREQ OF ANGINA (P=.028 AND NTG USE P=.014)
Baseline
Week 7
Baseline
Week 7
Angina episodes
Nitroglycerin use
PlacPlaceboebo
RRannanolazine 1000 mg bid
Stone PH et al. J Am Coll Cardiol. 2006;48:

23. ERICA: No significant effect on heart rate or BP
N = 564 on amlodipine 10 mg/day; Supine measurement
Placebo
Ranolazine 1000 bid P
Heart rate (bpm)
↓1.6
↓2.0
0.66
Systolic BP (mm Hg)
↓1.7
0.72
Diastolic BP (mm Hg)
↓0.6
↓1.0
0.61
Stone PH et al. J Am Coll Cardiol. 2006;48:

24. Ranolazine Is at Least as Effective as Atenolol 100 mg Daily RAN080
Time to onset of angina
Time to 1-mm ST-depression
Exercise duration
p < 0.001
p = 0.006
p < 0.04
p < 0.001
p = 0.18
p < 0.001
p < 0.001
p = 0.86
LS mean ± SE, sec
p < 0.001
Placebo
Ranolazine IR 400 mg tid
(1741 ± 1026 ng base/mL)
Atenolol 100 mg od
All patients analysis, N = 154.

25. 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:

26. 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:

27. 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)

28. Safety Common reported adverse events are:-
Dizziness:- 6.2%
Headache:- 5.5%
Constipation:- 4.5%
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

29. 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.

30. 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

31. 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

32. Caroza: A Novel Key For Angina