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CLINICAL

NEWS JACC in a FLASH
of life saved, and acute reperfusion
therapy with 0.90 (SE 0.11) years
of life saved among eligible patients.
In adjusted analyses, D2B times
≤ 90 minutes were associated with
0.98 (SE 0.47) years of life saved
and D2N times ≤ 30 minutes were
associated with 0.52 (SE 0.17)

years of life saved. Overall, select
AMI-based therapies (aspirin, betablockade, acute reperfusion, D2B
≤ 90 minutes, and D2N ≤ 30 minutes) were associated with increased
life expectancy among older patients.
“This is a valuable contribution that establishes the long-term

benefits and increased longevity
(over 17 years of follow-up) associated with the use of guideline-based
AMI therapies,” writes Prashant
Vaishnava, MD, in an ACC.org
Journal Scan. “This is particularly
important and novel, given the
focus on an older population. Future

efforts should focus on mechanisms
through which to improve adherence to guideline-based care for
acute coronary syndromes.” ■
Bucholz EM, Butala NM, Normand ST,
Wang Y, Krumholz HM.. J Am Coll Cardiol.
2016;67(20):2378-91.

T:6.875”

RANEXA® (ranolazine)
Brief summary of full Prescribing Information.
Please see full Prescribing Information. Rx Only.

INDICATIONS AND USAGE:
RANEXA® is indicated for the treatment of chronic angina. RANEXA may be used with betablockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE
inhibitors, and angiotensin receptor blockers.
DOSAGE AND ADMINISTRATION:
Initiate RANEXA dosing at 500 mg twice daily and increase to 1000 m g twice daily, as needed,
based on clinical symptoms. Take RANEXA with or without meals. Swallow RANEXA tablets
whole; do not crush, break, or chew. The maximum recommended daily dose of RANEXA is
1000 mg twice daily. If a dose of RANEXA is missed, take the prescribed dose at the next
scheduled time; do not double the next dose.
Dose Modification: Dose adjustments may be needed when RANEXA is taken in combination
with certain other drugs. Limit the maximum dose of RANEXA to 500 mg twice daily in patients
on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of P-gp
inhibitors, such as cyclosporine, may increase exposure to RANEXA. Titrate RANEXA based on
clinical response.
CONTRAINDICATIONS:
RANEXA is contraindicated in patients:
• Taking strong inhibitors of CYP3A
• Taking inducers of CYP3A
• With liver cirrhosis

ADVERSE REACTIONS:
Adverse Reactions from Clinical Trial Experience: Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and may not reflect
the rates observed in practice. A total of 2018 patients with chronic angina were treated with
ranolazine in controlled clinical trials. Of the patients treated with RANEXA, 1026 were enrolled
in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up
to 12 weeks’ duration. In addition, upon study completion, 1251 patients received treatment with
RANEXA in open-label, long-term studies; 1227 patients were exposed to RANEXA for more than
1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients
for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with
RANEXA because of an adverse event in controlled studies in angina patients compared to about
3% on placebo. The most common adverse events that led to discontinuation more frequently on
RANEXA than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia,
constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily
are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported
treatment-emergent adverse reactions (> 4% and more common on RANEXA than on placebo)
were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness
may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction
profile was observed.
The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated
with RANEXA and were more frequent than the incidence observed in placebo-treated patients:
Cardiac Disorders – bradycardia, palpitations
Ear and Labyrinth Disorders – tinnitus, vertigo
Eye Disorders – blurred vision
Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia
General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema
Metabolism and Nutrition Disorders – anorexia
Nervous System Disorders – syncope (vasovagal)
Psychiatric Disorders – confusional state
Renal and Urinary Disorders – hematuria
Respiratory, Thoracic, and Mediastinal Disorders – dyspnea
Skin and Subcutaneous Tissue Disorders – hyperhidrosis
Vascular Disorders – hypotension, orthostatic hypotension
Other (< 0.5%) but potentially medically important adverse reactions observed more frequently
with RANEXA than placebo treatment in all controlled studies included: angioedema, renal
failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor,
pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia.
A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a
benefit for RANEXA, but there was no apparent proarrhythmic effect in these high-risk patients.
Laboratory Abnormalities
RANEXA produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal
function, likely because of inhibition of creatinine’s tubular secretion. In general, the elevation
has a rapid onset, shows no signs of progression during long-term therapy, is reversible after
discontinuation of RANEXA, and is not accompanied by changes in BUN. In healthy volunteers,
RANEXA 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked
and progressive increases in serum creatinine, associated with increases in BUN or potassium,
indicating acute renal failure, have been reported after initiation of RANEXA in patients with
severe renal impairment.

DRUG INTERACTIONS: Effects of Other Drugs on Ranolazine
Strong CYP3A Inhibitors : Do not use RANEXA with strong CYP3A inhibitors, including
ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and
saquinavir. Moderate CYP3A Inhibitors : Limit the dose of RANEXA to 500 mg twice daily
in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin,
fluconazole, and grapefruit juice or grapefruit-containing products. P-gp Inhibitors :
Concomitant use of RANEXA and P-gp inhibitors, such as cyclosporine, may result in
increases in ranolazine concentrations. Titrate RANEXA based on clinical response in patients
concomitantly treated with predominant P-gp inhibitors such as cyclosporine. CYP3A
Inducers : Do not use RANEXA with CYP3A inducers such as rifampin, rifabutin, rifapentine,
phenobarbital, phenytoin, carbamazepine, and St. John’s wort.
Effects of Ranolazine on Other Drugs
Drugs Metabolized by CYP3A : Limit the dose of simvastatin in patients on any dose of
RANEXA to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other
sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic
range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as RANEXA may increase
plasma concentrations of these drugs. Drugs Transported by P-gp : Concomitant use of
ranolazine and digoxin results in increased exposure to digoxin. The dose o f digoxin may have
to be adjusted. Drugs Metabolized by CYP2D6 : The exposure to CYP2D6 substrates, such
as tricyclic antidepressants and antipsychotics, may be increased during co-administration with
RANEXA, and lower doses of these drugs may be required. Drugs Transported by OCT2 :
In subjects with type 2 diabetes mellitus, concomitant use of RANEXA 1000 mg twice daily and
metformin results in increased plasma levels of metformin. When RANEXA 1000 mg twice daily
is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor
blood glucose levels and risks associated with high exposures of metformin. Metformin
exposure was not significantly increased when given with RANEXA 500 mg twice daily.
USE IN SPECIFIC POPULATIONS:
Pregnancy: Risk Summary - There are no available data on RANEXA use in pregnant women
to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal
harm at exposures 4 times the maximum recommended human dose (MRHD) (see Data). In the
U.S. general population, the estimated background risk of major birth defects and of miscarriage
of clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data - Animal Data:
Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine
during organogenesis. In rats, decreased fetal weight and reduced ossification were observed
at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss.
No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at
exposures (AUC) equal to the MRHD. Lactation: Risk Summary - There are no data on the
presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk
production. However, ranolazine is present in rat milk. The developmental and health benefits
of breastfeeding should be considered along with the mother’s clinical need for RANEXA and
any potential adverse effects on the breastfed infant from RANEXA or from the underlying
maternal condition. Adult female rats were administered ranolazine orally from gestation day 6
through postnatal day 20. No adverse effects on pup development, behavior, or reproduction
parameters were observed at a maternal dosage level of 60 mg/kg/day (equal to the MRHD
based on AUC). At maternally toxic doses, male and female pups exhibited increased mortality
and decreased body weight, and female pups showed increased motor activity. The pups were
potentially exposed to low amounts of ranolazine via the maternal milk. Pediatric Use: Safety
and effectiveness have not been established in pediatric patients. Geriatric Use: Of the chronic
angina patients treated with RANEXA in controlled studies, 496 (48%) were ≥ 65 years of age,
and 114 (11%) were ≥ 75 years of age. No overall differences in efficacy were observed between
older and younger patients. There were no differences in safety for patients ≥ 65 years compared
to younger patients, but patients ≥ 75 years of age on RANEXA, compared to placebo, had a
higher incidence of adverse events, serious adverse events, and drug discontinuations due to
adverse events. In general, dose selection for an elderly patient should usually start at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease, or other drug therapy. Use in Patients with Hepatic
Impairment: RANEXA is contraindicated in patients with liver cirrhosis. In a study of cirrhotic
patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild
(Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with
moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic
impairment. This increase was not enough to account for the 3-fold increase in QT prolongation
seen in cirrhotic patients with mild to moderate hepatic impairment. Use in Patients with Renal
Impairment: A pharmacokinetic study of RANEXA in subjects with severe renal impairment
(CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after
receiving RANEXA 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice
a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and
potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required
hemodialysis, while the other 2 subjects improved upon drug discontinuation. Monitor renal
function periodically in patients with moderate to severe renal impairment. Discontinue RANEXA
if acute renal failure develops. In a separate study, Cmax was increased between 40% and 50%
in patients with mild, moderate, or severe renal impairment compared to patients with no renal
impairment, suggesting a similar increase in exposure in patients with renal failure independent
of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in
patients on dialysis. Use in Patients with Heart Failure: Heart failure (NYHA Class I to IV)
had no significant effect on ranolazine pharmacokinetics. RANEXA had minimal effects on heart
rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose
adjustment of RANEXA is required in patients with heart failure. Use in Patients with Diabetes
Mellitus: A population pharmacokinetic evaluation of data from angina patients and healthy
subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is
required in patients with diabetes.
RANEXA produces small reductions in HbA1c in patients with diabetes, the clinical significance
of which is unknown. RANEXA should not be considered a treatment for diabetes.

“Is cholesterol
efflux indeed
a rate-limiting
step for reverse
cholesterol
transport,
ultimately
turning its
modification
into a target for
pharmacological
intervention?”

T:9.875”

WARNINGS AND PRECAUTIONS:
QT Interval Prolongation: Ranolazine blocks IKr and prolongs the QTc interval in a doserelated manner. Clinical experience in an acute coronary syndrome population d id not show an
increased risk of proarrhythmia or sudden death. However, there is little experience with high
doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel
variants resulting in a long QT interval, in patients with a family history of (or congenital) long
QT syndrome, or in patients with known acquired QT interval prolongation.
Renal Failure: Acute renal failure has been observed in some patients with severe renal
impairment (creatinine clearance [CrCL] < 30 mL/min) while taking RANEXA. If acute renal
failure develops (e.g., marked increase in serum creatinine associated with an increase in
blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately. Monitor renal
function after initiation and periodically in patients with moderate to severe renal impairment
(CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

Postmarketing Experience
The following adverse reactions have been identified during postapproval use of RANEXA. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug exposure:
Nervous System Disorders – Tremor, paresthesia, abnormal coordination, and other serious
neurologic adverse events have been reported to occur, sometimes concurrently, in patients
taking ranolazine. The onset of events was often associated with an increase in ranolazine dose
or exposure. Many patients reported symptom resolution following drug discontinuation or
dose decrease.
Metabolism and Nutrition Disorders – Cases of hypoglycemia have been reported in diabetic
patients on antidiabetic medication.
Psychiatric Disorders – hallucination
Renal and Urinary Disorders – dysuria, urinary retention
Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash

— Philippe Pibarot, DVM, PhD,
and John Webb, MD

02/16
©2016 Gilead
Gilead Sciences,
Sciences,Inc
IncAllAllrights
rightsreserved.
reserved.RANP0361
REF11138 01/16

June 2016
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