Transcript RANOLAZINE - Physicians Academy

RANOLAZINE
Dr. 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
RANOLAZINE
A Piperazine Derivative
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
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.
Primary Mechanism of Action: Inhibition of Late Na channel
NCX: Sodiumcalcium exchange
Eur Heart J. 2004;6(suppl I):I3–I7.
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
Ranolazine & inhibition of various currents
• 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
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 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;43:1375-82.
Monotherapy With Ranolazine Increases Exercise Performance
at Trough and Peak
MARISA
Peak
Trough
560
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***
*** ***
***
***
***
Time, sec
520
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480
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***
***
***
**
440
400
Exercise duration
Time
to angina
Time to 1-mm
ST depression
N = 175, All/Near Completers population;
LS means ± SE.
**p < 0.01 vs placebo; ***p < 0.001 vs. placebo
Exercise duration
Placebo
Time
to angina
500 mg bid
1000 mg bid
1500 mg bid
Time to 1-mm
ST depression
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
Peak
Change from baseline, sec
Trough
* *
150
** **
*
*
***
***
*
**
100
50
Exercise
duration
Time to 1-mm
ST depression
N = 791, ITT/LOCF; LS mean ± SE.
*p < 0.05; **p ≤ 0.01; ***p ≤ 0.001 vs placebo.
Time
to angina
Placebo
750 mg bid
1000 mg bid
Ranolazine Decreases Weekly Angina Attacks and
Nitroglycerin Consumption
CARISA
Placebo
Ranolazine 750 mg bid
Ranolazine 1000 mg bid
6
Number per wk
5
4
**
3
***
*
2
***
1
0
Baseline
Double-blind
Angina attacks
N = 791, ITT/LOCF; LS mean ± SE.
*p < 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo
Baseline
Double-blind
Nitroglycerin consumption
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
Randomized
Double-blind
Placebo
n = 284
7 weeks
Primary efficacy variable:
Angina frequency (weekly average)
*≥60% stenosis, previous MI, and/or stressinduced perfusion defect
Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.
ERICA: Ranolazine reduces angina frequency and nitrate consumption
N = 564 on amlodipine 10 mg/day
6
5
P = 0.028
4
Mean
number
3
per
week
2
P = 0.014
1
0
Baseline
Week 7
Angina episodes
Baseline
Week 7
Nitroglycerin use
PlacPlaceboebo
RRannanolazine 1000 mg bid
Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.
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
↓2.0
0.72
Diastolic BP
(mm Hg)
↓0.6
↓1.0
0.61
Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.
Ranolazine Is at Least as Effective as Atenolol 100 mg Daily
RAN080
Time to onset of angina
460
LS mean ± SE, sec
440
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
420
p < 0.001
p = 0.86
p < 0.001
400
380
360
340
320
300
Placebo
All patients analysis, N = 154.
Ranolazine IR 400 mg tid
(1741 ± 1026 ng base/mL)
Atenolol 100 mg od
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)
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
Contraindications
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•
•
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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 betablockers, 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