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

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RANOLAZINEDr. Merajuddin shah, MD, DM
(Cardiology)Al-Kareem Cardiac Center, Srinagar,
Kashmir
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METABOLIC MANUPULATION OF ISCHEMIC HEART DISEASE.
A NOVEL APPROACH TO TREATMENT --------Leong Lee ,
EHJ, 2004
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RANOLAZINEA Piperazine Derivative
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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

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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.

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Mechanisms of Action
Initially it was thought that primary mechanism
of action is inhibition of fatty acid oxidation,
and promotion of glucose oxidation
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Primary Mechanism of Action Inhibition of Late
Na channel
NCX Sodium-calcium exchange
Eur Heart J. 20046(suppl I)I3I7.
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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.

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• Ranolazine (therapeutically conc.up to 10 µmol/L)
  selectively inhibit late INa (IC505 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 S65S83
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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. 2004110904-910
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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

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DrugDrug 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

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DrugDrug 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

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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 2004431375-82.
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Monotherapy With Ranolazine Increases Exercise
Performance at Trough and Peak MARISA
Peak
Trough


















Placebo
500 mg bid
N 175, All/Near Completers population LS
means SE. p lt 0.01 vs placebo p lt 0.001
vs. placebo
1500 mg bid
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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 2004291309-316.
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Ranolazine With a Beta- or Calcium Blocker
Increases Exercise Times at Trough and Peak
CARISA
Peak
Trough










Change from baseline, sec
N 791, ITT/LOCF LS mean SE. p lt 0.05 p
0.01 p 0.001 vs placebo.
Placebo
750 mg bid
1000 mg bid
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Ranolazine Decreases Weekly Angina Attacks and
Nitroglycerin ConsumptionCARISA




Angina attacks
Nitroglycerin consumption
N 791, ITT/LOCF LS mean SE. p lt 0.05, p
0.01, p 0.001 vs placebo
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ERICA Study design
Evaluation of Ranolazine In Chronic Angina
History of CAD
Stable angina (3 angina
episodes/week) Amlodipine 10 mg/dayN
565
Ranolazine extended-release 500 mg bid (1 week)
then 1000 mg bidn 281
Placebon 284
RandomizedDouble-blind
7 weeks
Primary efficacy variableAngina frequency
(weekly average)
60 stenosis, previous MI, and/or
stress-induced perfusion defect
Stone PH et al. J Am Coll Cardiol. 200648566-75.
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ERICA Ranolazine reduces angina frequency and
nitrate consumption
N 564 on amlodipine 10
mg/day
6
5
P 0.028
4
Mean number per week
P 0.014
3
2
1
0
Baseline
Week 7
Baseline
Week 7
Nitroglycerin use
Angina episodes
PlacPlaceboebo
RRannanolazine 1000 mg bid
Stone PH et al. J Am Coll Cardiol. 200648566-75.
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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. 200648566-75.
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Ranolazine Is at Least as Effective as Atenolol
100 mg DailyRAN080
Time to onset of angina
Time to 1-mm ST-depression
Exercise duration
p lt 0.001
p 0.18
p lt 0.001
p lt 0.001
p 0.86
LS mean SE, sec
p lt 0.001
All patients analysis, N 154.
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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 20071161647-1652.
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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 20071161647-1652.
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SummaryAnti-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)

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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
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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.

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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

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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

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Caroza A Novel Key For Angina