CardioSource WorldNews | Page 26

CLINICAL

NEWS JOURNAL WRAP
Survival of Patients With Down
Syndrome and Congenital Heart Disease
While patients with Down syndrome
and congenital heart disease (CHD)
have impaired rates of survival,
surgery to decrease the likelihood of

Eisenmenger syndrome may lead to
increased survival in these patients,
according to new research published
in Heart.

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 beta-blockers, 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 (BID)
and increase to 1000 mg BID, 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 BID. 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
BID 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:
• Taking strong inhibitors of CYP3A • Taking inducers of CYP3A • With liver cirrhosis
WARNINGS AND PRECAUTIONS:
QT Interval Prolongation: Ranolazine blocks IKr and prolongs the QTc interval in a
dose-related manner. Clinical experience in an acute coronary syndrome population did not
show an increased risk of proarrhythmia or sudden death. However, there is little experience
with high doses (>1000 mg BID) 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 (SCr)
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 SCr
accompanied by an increase in BUN.
ADVERSE REACTIONS: Adverse Reactions from Clinical Trial Experience:
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 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 for >1 year, 613 for >2 years, 531
for >3 years, and 326 for >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 BID 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. 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 SCr 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 BID had no effect upon the glomerular filtration rate.
More marked and progressive increases in SCr, associated with increases in BUN or
potassium, indicating acute renal failure, have been reported after initiation of RANEXA
in patients with severe renal impairment.
RAPJ16CDNY6146_BriefSummary_5-16_Update_r4.indd 1

Using the National German Registry for CHD, patients with Down
syndrome were identified and stratified according to the development
of Eisenmenger syndrome (defined
as pulmonary hypertension with
cyanosis and a nonrestrictive intraor extra-cardiac communication).

Postmarketing Experience
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 anti-diabetic medication.
Psychiatric Disorders – hallucination
Renal and Urinary Disorders – dysuria, urinary retention
Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash
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 BID 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.
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 of 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 BID
and metformin results in increased plasma levels of metformin. When RANEXA 1000 mg BID
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 BID.
USE IN SPECIFIC POPULATIONS: Pregnancy: There are no available data on RANEXA use
in pregnant women to inform any drug-associated risks. 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 maximum recommended human dose [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: 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. 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 BID for 5 days (lead-in phase) followed by
1000 mg BID (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.

Patients with atrial septal defects
alone were excluded.
A total of 894 patients were
included in the study, 84% of whom
were intervened upon, with 57% of
procedures performed within the
first year of life. Reflecting current
practice, the likelihood of therapy
before 1 year of age ranged from 0%
in the 1950s, 2% in the 1970s, and
86% for the years 2000 and beyond.
Over a median follow-up of approximately 18 years, 60 developed
Eisenmenger syndrome, 53% of
whom came from the 1950s cohort,
with only 0.5% from the post-year
2000 cohort. Those intervened
upon beyond the first year of life
had a significantly increased risk for
developing Eisenmenger syndrome.
The most common diagnosis was
atrioventricular (AV) canal defect,
but patent ductus arteriosus (PDA)
was the most common lesion for
those with Eisenmenger syndrome.
The median age at death was 22
years, with a 75% survival for
the entire cohort at age 40 years.
Eisenmenger syndrome is the only
significant predictor of outcome
after adjustment for age and era of
birth. Down syndrome patients had
an overall worse survival compared
to the general German population,
with or without Eisenmenger syndrome, although survival was worse
in the former.
Eisenmenger syndrome is detrimental to the survival of patients
with Down syndrome and CHD.
Repair of significant left-to-right
shunts within the first year of life
improves the long-term survival
of patients with Down syndrome,
although their longevity does not
approach that of the general German population. ■
Körten M-A, Helm PC, Abdul-Khaliq
H, et al. Heart. 2016;doi:10.1136/
heartjnl-2016-309437

©2016 Gilead Sciences, Inc All rights reserved. REF11943 05/16
©2016 Gilead Sciences, Inc All rights reserved. RANP0417 07/16
7/7/16 3:23 PM

August 2016