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Publication Date: June 2006
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RANOLAZINE (RANEXA): A NOVEL
AGENT FOR ANGINA


Richard A. Lawrence, Pharm.D. Candidate


In the United States approximately 6.5 million
people are affected by chronic angina.' Current anti-
anginal medications work by reducing myocardial
oxygen demand (P-blockers, calcium channel block-
ers, and nitrates) or improving oxygen supply
(calcium channel blockers and nitrates). As many as
26% of patients continue to experience angina at-
tacks despite medication and/or revascularization.2
There is a clear need for additional, pharmacologic
agents to address the treatment gap that exists in the
management of angina.
Ranolazine (Ranexa) is a new medication de-
rived from piperazine for the treatment of severe
chronic angina.3 It is devoid of hemodynamic ef-
fects.2,3,4 Ranolazine, marketed by CV Therapeutics,
was approved by the FDA on January 31, 2006.5 It is
the first drug in a new class of medications, meta-
bolic modulators.6 This paper will discuss the phar-
macology, pharmacokinetics, clinical trials, admini-
stration, precautions, and cost of ranolazine.

Pharmacology and Pharmacokinetics
During an ischemic attack fatty acid levels rise,
which promotes increased myocardial uptake and
oxidation of fatty acids and reduced carbohydrate


uptake. This imbalance of energy uptake leads to
both oxygen wasting and lactate accumulation. Fatty
acid oxidation is an inefficient use of oxygen. Carbo-
hydrate (glucose, lactate, and pyruvate) oxidation is a
more efficient use of oxygen since it provides 11%
more adenosine triphosphate [ATP] per 02 mole-
cule.3 Ranolazine appears to inhibit oxidation of fatty
acids, forcing the myocardium to use the more effi-
cient substrate, carbohydrates, for ATP production,
especially in times of elevated fatty acid levels. This
shift reduces the amount of oxygen that the cardiac
muscle needs to function and aids in glycolysis and
pyruvate oxidation coupling, reducing lactate accre-
tion and resultant tissue necrosis. 4
Ranolazine is administered orally twice a day and
is available in 500 mg extended-release tablets. Peak
plasma levels are seen in 2-5 hours with no change in
area under the curve (AUC) and maximum plasma
concentration (Cmax) when administered with or
without food. Ranolazine is approximately 62% pro-
tein bound. Metabolism is primarily by CYP3A and
CYP2D6. Ranolazine is also a P-glycoprotein sub-
strate, making it susceptible to drug interactions.
Ranolazine is contraindicated with moderate or po-
tent CYP3A inhibitors. The half-life of the extended-
rIa U I


mm


SPharmaNote


VOLUME 21, ISSUE 9 JUNE 2006
_. r


INSIDE THIS ISSUE:
RANOLAZINE (RANEXAR): A NOVEL AGENT FOR
ANGINA


Volume 21, Issue 9, June 2006


PharmaNote







Table 1. Mean exercise treadmill test (ETT) in the MARISA trial.4

Ranolazine dose
Placebo (seconds) 500mg BID* 1000mg BID* 1500mg BID*
Trough Peak Trough Peak Trough Peak Trough Peak
23.8 29.3 33.7 50.1 45.9 55.5
Exercise duration (s)** 505.7 501.7 2
(4.7) (5.8) (6.7) (10.0) (9.1) (11.1)
27.0 35.5 45.9 56.4 59.6 68.5
Time to angina (s)** 407.3 416.3 2 3 4 .6.5
(6.6) (8.5) (11.3) (13.5) (14.6) (16.5)
Time to 1mm ST-segment 4 436 27.6 38.8 44.5 55.6 64.6 69.0
depression (s)** (6.2) (8.9) (10.0) (12.7) (14.6) (15.8)
* BID= twice a day. ** All results represent increases over placebo and showed statistical significance with p<0.005.


release tablets is about seven hours, whereas its me-
tabolites display longer half-lives, though it is un-
known if they have pharmacological activity. Elimi-
nation is 75% renal and 25% fecal with <5% ex-
creted unchanged by either route.7

Clinical Trials
To date there have been several clinical trials in-
volving ranolazine alone or in combination with
other anti-anginal medications. The Monotherapy
Assessment of Ranolazine In Stable Angina
(MARISA), Combination Assessment of Ranolazine
In Stable Angina (CARISA), and Efficacy of
Ranolazine In Chronic Angina (ERICA) serve as the
basis for FDA approval and are reviewed below.
The MARISA trial4 evaluated ranolazine in 191
patients with angina-limited exercise. The study was
a randomized, double-blind, four-period, crossover
study comparing ranolazine extended-release 500 mg,
1000 mg, 1500 mg, and placebo all administered
twice a day for one week. Patients were evaluated
using exercise treadmill tests (ETT). All doses of
ranolazine resulted in improved exercise tolerance,
time to angina, and time to 1mm ST-segment depres-
sion (Table 1). Hemodynamic changes at rest and at
maximal exercise where minimal and dose-related
QTc interval increases were 6 ms, 7 ms, and 11 ms at
trough and 5 ms, 6 ms, and 14 ms at peak for
ranolazine doses of 500 mg, 1000 mg, and 1500 mg
twice daily, respectively.
The CARISA trial2 followed 823 patients for 12
weeks. Placebo, 750 mg, or 1000 mg of ranolazine
all administered twice daily were added to existing
background anti-anginal therapy. The study was a
randomized, double-blind, three-group study that en-
rolled patients receiving anti-anginal medication to
evaluate if ranolazine could improve patients' exer-


cise tolerance. At baseline, 44.6% of the patients
were on atenolol, 29.8% on amlodipine, and 25.6%
on diltiazem. The results are shown in Table 2. No
clinically significant hemodynamic changes were
reported and dose related QTc interval changes were
6.1 ms for ranolazine 750 mg twice daily and 9.2 ms
for 1000 mg twice daily.
The ERICA trial8 has yet to be published, though
the abstract is available. The trial enrolled 565 pa-
tients being treated with amlodipine 10 mg. Patients
were treated with ranolazine 500 mg twice a day and
titrated to 1000 mg twice daily or placebo and fol-
lowed for six weeks in a double-blind fashion.
Ranolazine provided incremental benefit (see Table
3.) in patients with angina. These results appear to be
consistent across age, gender, and background nitrate
subgroups.

Dosing and Administration
Ranolazine is available as 500 mg extended-
release oral tablets and is indicated for the treatment
of chronic angina. Due to risks of QTc prolongation
it should be reserved for patients that have had an
inadequate response to other treatment modalities.
Treatment with ranolazine should be initiated at 500
mg twice daily and titrated to 1000 mg twice a day if
the initial response is suboptimal. The maximum
daily dose is 1000 mg twice daily. If a dose is missed,
it should be skipped and the next dose taken as
scheduled.7
The dose of ranolazine should be reduced in pa-
tients with mild to severe renal or hepatic impair-
ment.9'10 Blood pressure and ECG monitoring is indi-
cated due to the potential for QTc prolongation. No
dosing adjustments are required according to age or
gender or in patients with diabetes mellitus or con-
gestive heart failure (CHF) NYHA Class I to IV.


PharmaNote Volume 21, Issue 9, June 2006


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PharmaNote







Table 2. Mean ETT results for ranolazine and placebo in the CARISA trial.2

Increase versus placebo

Ranolazine Dose 750 mg BID* 1000 mg BID*
Trough Peak Trough Peak

Exercise duration (s) 23.7** 34.0** 24.0** 26.1**

Time to angina (s) 29.7** 38.0** 26.0** 37.9**

Time to ECG ischemia (s) 19.9 40.8** 21.1 34.5**

* BID =twice a day. ** Results showed statistical significance with p<0.03.


Studies have not assessed whether dosing adjust-
ments are needed according to hemodialysis, race or
in pediatric patients.7

Contraindications
Ranolazine is contraindicated in patients with
pre-existing or history of QT prolongation or con-
comitant use of drugs that prolong the QT interval,
hepatic impairment, ventricular arrhythmias, or use
of potent CYP3A inhibitors. It should be used with
caution in patients with cardiac arrhythmias or renal
impairment.7
Ranolazine is pregnancy category C and it is un-
known whether ranolazine, or its metabolites, are
excreted into breast milk.7

Toxicity and Safety
Ranolazine's adverse event profile is dose-related.
The most frequently reported adverse drug events at
500 mg and 1000 mg twice a day are dizziness (1.1%,
5%), asthenia (0%, 1.7%), constipation (0%, 1.7%),
angina pectoris (5%, 1.7%), nausea (<1%, 1.1%),
and headache (<1%, 1.1%).4 No cases of overdose
have been reported but ECG monitoring and suppor-
tive care should be initiated in such cases due to con-
centration dependent QTc prolongation.7


Drug Interactions
Drug interactions with ranolazine result from in-
hibition of CYP3A by other medications including
the potent inhibitor ketoconazole and moderately po-
tent inhibitor diltiazem. Less potent inhibitors and
substrates such as simvastatin and cimetidine do not
appear to affect the plasma concentration. Verapamil,
a CYP3A and P-glycoprotein inhibitor, increases
plasma concentrations significantly. Consequently
when administering ranolazine care should be used
with concurrent use of CYP3A and/or P-glycoprotein
inhibitors as plasma concentrations may increase 1.8-
to 3.2-fold. The potent CYP2D6 inhibitor paroxetine,
at 20 mg daily increased ranolazine plasma concen-
trations 1.2-fold. The manufacturer does not recom-
mend dosage adjustments in cases of concomitant
CYP2D6 inhibitor use. Digoxin does not affect
ranolazine concentrations.7'11
In vitro studies indicate that ranolazine and its 0-
demethylated metabolite are inhibitors of CYP3A
and CYP2D6. Ranolazine does not inhibit CYP1A2,
2C9, 2C19, and 2E1. Ranolazine increases serum
levels of simvastatin, a CYP3A substrate, by 2-fold.
Diltiazem is unaffected by ranolazine. CYP2D6 is
inhibited to a lesser degree however medications that
are 2D6 substrates may require reduced doses. Di-
goxin levels are increased 1.5-fold when used in con-
junction with ranolazine.7'11


Table 3. Mean number of angina attacks and nitroglycerin* use per week in ERICA trial.

P value of
Baseline Placebo Ranolazine 1000mg BID Ranolazine vs. placebo
Number of angina attacks 5.6 3.2 2.8 0.028
Number of NTG use 4.6 2.6 2.0 0.014

* Tablets or sprays

PharmaNote Volume 21, Issue 9, June 2006







Cost
Ranexa 500 mg extended-release tablets are
available in 60 count unit-of-use bottles and 500
count pharmacy stock bottles.7 According to a phar-
maceutical distributor, the average wholesale price
(AWP) of one month supply is $206.25. The average
retail price for a one month supply in Gainesville,
Florida is $214.99.

Summary
Ranolazine (Ranexa) is a novel drug for the
treatment of chronic angina.1 It works through meta-
bolic modulation by decreasing fatty acid metabo-
lism in ischemic cardiac tissue with a concomitant
increase in carbohydrate utilization resulting in more
efficient energy synthesis.4 It is effective as mono-
therapy;4 however, it will likely have the greatest im-
pact when added to conventional therapy with agents
such as atenolol, diltiazem, or amlodipine.2

References
1. Thom T, et al. Heart Disease and Stroke Statis-
tics-2006 Update: A Report From the American
Heart Association Statistics Committee and
Stroke Statistics Subcommittee. Circulation 2006.
Available online at http://circ.ahajournals.org/
cgi/reprint/CIRCULATIONAHA. 105.171600
vl.pdf Accessed 4/19/06.
2. Chaitman BR, Pepine CJ, Parker JO, et al. Ef-
fects of ranolazine with atenolol, amlodipine, or
diltiazem on exercise tolerance and angina fre-
quency in patients with severe chronic angina.
JAMA 2004;291:309-16.
3. Tafreshi MJ and Fisher E. Ranolazine: A new
approach to management of patients with angina.
Ann ofPharmacotherapy 2006;40:689-93.
4. Chaitman BR, Skettino SL, Parker JO, et al.
Anti-ischemic effects and long-term survival dur-
ing ranolazine monotherapy in patients with
chronic severe angina. J Am Coll of Cardiol
2004;43:1375-82.
5. US Food and Drug Administration News http://
www. fd a. gov/bb s/topi c s/news/2006/
NEW01306.html Accessed on 4/10/06.
6. Anderson JR and Nawarskas JJ. Ranolazine: A
metabolic modulator for the treatment of chronic
stable angina. Cardiology in Review 2005;
13:202-10.
7. CV Therapeutics, Inc. Ranexa (ranolazine) Pre-
scribing Information. 2006.


8. Stone PH, et al. Anti-Anginal Efficacy of
Ranolazine When Added to Maximal Therapy
with Conventional Therapy: The Efficacy of
Ranolazine in Chronic Angina Trial [Abstract].
Presented at American Heart Association meet-
ing Nov 16, 2005.
9. Jerling M and Abdallah H. Effect of renal impair-
ment on multiple-dose pharmacokinetics of ex-
tended-release ranolazine. Clinical Pharmacol-
ogy and Therapeutics 2005;78(3):288-97.
10. Abdallah H and Jerling M. Effect of hepatic im-
pairment on the multiple-dose pharmacokinetics
of ranolazine sustained-release tablets. J Clin
Pharmacol 2005;45:802-9.
11. Jerling M, Huan BL, Leung K, et al. Studies to
investigate the pharmacokinetic interactions be-
tween ranolazine and ketoconazole, diltiazem, or
simvastatin during combined administration in
healthy subjects. J Clin Pharm 2005;45:422-33.



New Drug Approvals

Insulin detemir, a long-acting insulin, is now
available as Levemir (Novo Nordisk) in 10
ml vials and a 3 ml FlexPen (100 Units/ml) for
the treatment Type 1 diabetes mellitus (adults
and children) and Type 2 diabetes mellitus
(adults) when basal insulin is indicated.





The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice


John G. Gums
Pharm.D. Editor

R. Whit Curry, M.D. Associate Editor

Shawn D. Anderson, Assistant Editor
Pharm.D.

*0 XWK W^ S V ^ S W^V


PharmaNote Volume 21, Issue 9, June 2006


Volume 21, Issue 9, June 2006


PharmaNote




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