CardioSource WorldNews | Page 36

LIVE COURSES2017

April 28 – 29
Puerto Rico Chapter of the American College of Cardiology
Cond . Medical Center Plaza Calle 3 SE # 1051 , Ofic . LC-10 Urb . La Riviera San Juan , Puerto Rico
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 I Kr 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 .
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 C max 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 , C max 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 .
© 2016 Gilead Sciences , Inc All rights reserved . REF11943 05 / 16 © 2016 Gilead Sciences , Inc All rights reserved . RANP0417 07 / 16
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