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What is Ranexa and how is information technology used?

Ranexa is a prescription medicine used to treat the symptoms of breast pain (Angina). Ranexa may be used alone or with other medications.

Ranexa belongs to a class of drugs called Antianginal, Not-nitrates.

Information technology is not known if Ranexa is rubber and effective in children younger than xviii years of age.

What are the possible side effects of Ranexa?

Ranexa may cause serious side effects including:

• lightheadedness,
• fast or pounding heartbeats,
• fluttering in your chest,
• little or no urination,
• painful or difficult urination,
• swelling in your feet or ankles,
• feeling tired, and
• shortness of breath

Go medical help right abroad, if y'all have any of the symptoms listed above.

The most common side effects of Ranexa include:

• nausea,
• constipation,
• headache, and
• dizziness

Tell the doctor if y'all have whatsoever side effect that bothers you or that does not become abroad.

These are not all the possible side effects of Ranexa. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side furnishings. You may report side effects to FDA at ane-800-FDA-1088.

DESCRIPTION

RANEXA (ranolazine) Extended-release Tablets

Ranolazine is a racemic mixture, chemically described as ane-piperazineacetamide, N-(2,six-dimethylphenyl)-iv-[2-hydroxy-iii-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C₂₄H₃₃N₃O₄, a molecular weight of 427.54 g/mole, and the following structural formula:

Ranolazine is a white to fair solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.

RANEXA tablets incorporate 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Atomic number 26 Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the grand mg tablet include lactose monohydrate, triacetin, and Fe Oxide Yellow.

ii pharmacies near 11430 have coupons for Ranexa (Brand Names:Ranexa for lx Tablets Extended Release 12 Hour)

INDICATIONS

RANEXA^® is indicated for the treatment of chronic angina.

RANEXA may exist used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

DOSAGE AND Administration

Dosing Information

Initiate RANEXA dosing at 500 mg twice daily and increase to 1000 mg twice daily, every bit needed, based on clinical symptoms. Have RANEXA with or without meals. Swallow RANEXA tablets whole; do non beat out, 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; practise not double the next dose.

Dose Modification

Dose adjustments may exist needed when RANEXA is taken in combination with certain other drugs [see DRUG INTERACTIONS]. Limit the maximum dose of RANEXA to 500 mg twice daily in patients on moderate CYP3A inhibitors such equally diltiazem, verapamil, and erythromycin. Use of RANEXA with stiff CYP3A inhibitors is contraindicated [see CONTRAINDICATIONS, DRUG INTERACTIONS]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to RANEXA. Titrate RANEXA based on clinical response [see DRUG INTERACTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

RANEXA is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:

• 500 mg tablets are light orange, with GSI500 on i side
• g mg tablets are stake yellow, with GSI1000 on one side

Storage And Handling

RANEXA is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:

• 500 mg tablets are light orange, with GSI500 on one side
• 1000 mg tablets are pale yellowish, with GSI1000 on one side RANEXA (ranolazine) extended-release tablets are available in:

	Forcefulness	NDC
Unit of measurement-of-Use Bottle (60 Tablets)	500 mg	61958-1003-one
Unit-of-Utilise Bottle (60 Tablets)	1000 mg	61958-1004-i

Shop RANEXA tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).

Manufactured for: Gilead Sciences, Inc. Foster City, CA 94404. Aug 2019

SLIDESHOW

Heart Illness: Symptoms, Signs, and Causes See Slideshow

SIDE EFFECTS

Clinical Trial Experience

Considering 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-bullheaded, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In improver, upon study completion, 1251 patients received treatment with RANEXA in open-label, long-term studies; 1227 patients were exposed to RANEXA for more 1 year, 613 patients for more than than 2 years, 531 patients for more than than three years, and 326 patients for more than than 4 years.

At recommended doses, almost 6% of patients discontinued treatment with RANEXA because of an adverse event in controlled studies in angina patients compared to about three% on placebo. The near common agin events that led to discontinuation more oftentimes 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 (>iv% and more common on RANEXA than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (four.4%). Dizziness may exist 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.five to iv.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 – intestinal pain, dry oral cavity, vomiting, dyspepsia

General Disorders and Administrative Site Agin 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%) simply potentially medically of import 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 big clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for RANEXA, but in that location was no credible proarrhythmic effect in these high-chance patients [see Clinical Studies].

Laboratory Abnormalities

RANEXA produces elevations of serum creatinine by 0.one mg/dL, regardless of previous renal function, likely because of inhibition of creatinine'due south tubular secretion. In full general, the tiptop 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 charge per unit. More than marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported later on initiation of RANEXA in patients with severe renal impairment [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Postmarketing Experience

The post-obit adverse reactions take been identified during postapproval use of RANEXA. Considering these reactions are reported voluntarily from a population of uncertain size, information technology is not always possible to reliably approximate their frequency or plant a causal relationship to drug exposure:

Nervous System Disorders – Aberrant coordination, myoclonus, paresthesia, tremor, 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 increment 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

DRUG INTERACTIONS

Effects Of Other Drugs On Ranolazine

Stiff CYP3A Inhibitors

Exercise not use RANEXA with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [meet CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

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 [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

P-Gp Inhibitors

Concomitant use of RANEXA and P-gp inhibitors, such every bit 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 [encounter DOSAGE AND Administration].

CYP3A Inducers

Do not utilise RANEXA with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

Furnishings Of Ranolazine On Other Drugs

Drugs Metabolized By CYP3A

Limit the dose of simvastatin in patients on any dose of RANEXA to xx mg once daily, when ranolazine is co-administered. Dose aligning of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (east.m., cyclosporine, tacrolimus, sirolimus) may exist required as RANEXA may increase plasma concentrations of these drugs [see CLINICAL PHARMACOLOGY].

Drugs Transported Past P-Gp

Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may take to be adapted [see CLINICAL PHARMACOLOGY].

Drugs Metabolized By CYP2D6

The exposure to CYP2D6 substrates, such equally tricyclic antidepressants and antipsychotics, may be increased during co-administration with RANEXA, and lower doses of these drugs may be required.

Drugs Transported Past OCT2

In subjects with type two diabetes mellitus, concomitant employ 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/24-hour interval. Monitor claret glucose levels and risks associated with high exposures of metformin.

Metformin exposure was not significantly increased when given with RANEXA 500 mg twice daily [see CLINICAL PHARMACOLOGY].

WARNINGS

Included as part of the "PRECAUTIONS" Section

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 bear witness an increased risk of proarrhythmia or sudden death [see Clinical Studies]. However, there is footling 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 caused 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 (eastward.g., marked increase in serum creatinine associated with an increase in claret urea nitrogen [BUN]), discontinue RANEXA and care for accordingly [run across Apply In Specific Populations].

Monitor renal function later initiation and periodically in patients with moderate to severe renal impairment (CrCL <sixty mL/min) for increases in serum creatinine accompanied past an increment in BUN.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Inform patients that RANEXA volition not abate an acute angina episode.

Strong CY3PA Inhibitors, CYP3A Inducers, Liver Cirrhosis

• Inform patients that RANEXA should not be used with drugs that are strong CYP3A inhibitors (e.grand., ketoconazole, clarithromycin, nefazodone, ritonavir) [(see CONTRAINDICATIONS, DRUG INTERACTIONS].
• Inform patients that RANEXA should not be used with drugs that are inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort) [(come across CONTRAINDICATIONS, DRUG INTERACTIONS].
• Inform patients that RANEXA should non exist used in patients with liver cirrhosis [(see CONTRAINDICATIONS, Use In Specific Populations].

Moderate CYP3A Inhibitors, P-Gp Inhibitors, Grapefruit Products

• Advise patients to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (due east.yard., diltiazem, verapamil, erythromycin) [come across DRUG INTERACTIONS].
• Propose patients to inform their physician if they are receiving drugs that are P-gp inhibitors (e.grand., cyclosporine) [see DRUG INTERACTIONS].
• Advise patients to limit grapefruit juice or grapefruit products when taking RANEXA [see DRUG INTERACTIONS].

QT Interval Prolongation

• Inform patients that RANEXA may produce changes in the electrocardiogram (QTc interval prolongation) [see WARNINGS AND PRECAUTIONS].
• Suggest patients to inform their md of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (eastward.1000., quinidine) or Class III (due east.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (due east.yard., thioridazine, ziprasidone) [see WARNINGS AND PRECAUTIONS].

Use In Patients With Renal Impairment

Patients with astringent renal damage may be at run a risk of renal failure while on RANEXA. Advise patients to inform their dr. if they have impaired renal function earlier or while taking RANEXA [see WARNINGS AND PRECAUTIONS].

Dizziness, Fainting

• Inform patients that RANEXA may crusade dizziness and lightheadedness. Patients should know how they react to RANEXA before they operate an automobile or machinery, or appoint in activities requiring mental alertness or coordination [encounter Adverse REACTIONS].
• Advise patients to contact their physician if they experience fainting spells while taking RANEXA.

Assistants

• Instruct patients to swallow RANEXA tablets whole, with or without meals, and non to vanquish, break, or chew tablets. Inform patients that if a dose is missed, to accept the usual dose at the next scheduled time. The side by side dose should non be doubled. Inform patients that doses of RANEXA higher than 1000 mg twice daily should non be used [run into DOSAGE AND ADMINISTRATION].
• Advise patients to inform their physician of any other medications taken concurrently with RANEXA, including over-the-counter medications.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic cistron conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation analysis, and mouse and rat bone marrow micronucleus assays.

There was no prove of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/24-hour interval for 21 months in rats (900 mg/mⁱⁱ/solar day) and 50 mg/kg/twenty-four hours for 24 months in mice (150 mg/m^two/day). These maximally tolerated doses are 0.viii and 0.one times, respectively, the daily maximum recommended human dose (MRHD) of 2000 mg on a surface area ground. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily [see REFERENCES]. The clinical significance of this finding is unclear.

In male and female rats, oral assistants of ranolazine that produced exposures (AUC) approximatelty 3-fold or five-fold higher, respectively, than the MRHD had no effect on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

At that place are no bachelor data on RANEXA utilise in pregnant women to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures four times the maximum recommended homo dose (MRHD) (run into Data).

In the U.Southward. general population, the estimated background risk of major nascency defects and of miscarriage of clinically recognized pregnancies is 2-iv% and fifteen-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 (respective to 4-fold the AUC for the MRHD) that acquired maternal weight loss. No agin 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 baby, or the effects on milk production. Nonetheless, ranolazine is present in rat milk [encounter Apply In Specific Populations]. The developmental and health benefits of breastfeeding should exist considered forth 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 twenty-four hour period 20. No agin furnishings on pup development, behavior, or reproduction parameters were observed at a maternal dosage level of lx mg/kg/24-hour interval (equal to the MHRD based on AUC). At maternally toxic doses, male and female pups exhibited increased bloodshed and decreased trunk weight, and female person pups showed increased motor activeness. The pups were potentially exposed to low amounts of ranolazine via the maternal milk.

Pediatric Use

Prophylactic and effectiveness have not been established in pediatric patients.

Geriatric Utilise

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 historic period. 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, merely patients ≥75 years of historic period 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 finish of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.

Employ In Patients With Hepatic Harm

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, just increased eighty% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not plenty to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [run across CLINICAL PHARMACOLOGY].

Use In Patients With Renal Impairment

A pharmacokinetic study of RANEXA in subjects with severe renal impairment (CrCL <thirty mL/min) was stopped when 2 of 4 subjects developed astute renal failure after receiving RANEXA 500 mg twice daily for 5 days (lead-in stage) followed past chiliad mg twice a day (1 dose in 1 subject field and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg pb-in phase. One subject required hemodialysis, while the other ii subjects improved upon drug discontinuation [see WARNINGS AND PRECAUTIONS]. Monitor renal function periodically in patients with moderate to severe renal harm. Discontinue RANEXA if acute renal failure develops.

In a separate study, Cmax was increased between 40% and 50% in patients with balmy, moderate, or severe renal damage compared to patients with no renal impairment, suggesting a like increment in exposure in patients with renal failure contained of the degree of damage. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.

Employ In Patients With Center Failure

Heart failure (NYHA Grade I to IV) had no significant event on ranolazine pharmacokinetics. RANEXA had minimal effects on heart rate and claret pressure in patients with angina and heart failure NYHA Class I to Iv. No dose adjustment of RANEXA is required in patients with eye 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 non be considered a treatment for diabetes.

REFERENCES

Chiliad.A. Suckow et al. The anti-ischemia agent ranolazine promotes the evolution of abdominal tumors in APC (min/+) mice. Cancer Messages 209(2004):165−9.

Overdosage & Contraindications

OVERDOSE

High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Severe tremor, unsteady gait/incoordination, dysphasia, and hallucinations accept been reported in cases of overdose with RANEXA.

Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in immigration ranolazine.

CONTRAINDICATIONS

RANEXA is contraindicated in patients:

• Taking strong inhibitors of CYP3A [see DRUG INTERACTIONS]
• Taking inducers of CYP3A [see DRUG INTERACTIONS]
• With liver cirrhosis [meet Use In Specific Populations]

CLINICAL PHARMACOLOGY

Machinery Of Action

The machinery of action of ranolazine's antianginal effects has non been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or claret force per unit area. It does non touch on the rate-pressure level product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium electric current (I_Na). However, the relationship of this inhibition to angina symptoms is uncertain.

The QT prolongation effect of ranolazine on the surface electrocardiogram is the upshot of inhibition of I_Kr, which prolongs the ventricular activeness potential.

Pharmacodynamics

Hemodynamic Effects

Patients with chronic angina treated with RANEXA in controlled clinical studies had minimal changes in mean heart rate (<2 bpm) and systolic claret force per unit area (<3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients.

Electrocardiographic Effects

Dose and plasma concentration-related increases in the QTc interval [run across WARNINGS AND PRECAUTIONS], reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with RANEXA. These effects are believed to exist caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of almost 2.6 msec/1000 ng/mL, through exposures respective to doses several-fold higher than the maximum recommended dose of thou mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax post-obit repeat dosing at 1000 mg twice daily, the hateful alter in QTc is about 6 msec, just in the five% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see CONTRAINDICATIONS].

Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine.

No proarrhythmic effects were observed on seven-day Holter recordings in 3162 acute coronary syndrome patients treated with RANEXA. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with RANEXA (eighty%) versus placebo (87%), including ventricular tachycardia ≥3 beats (52% versus 61%). Notwithstanding, this difference in arrhythmias did not atomic number 82 to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms.

Pharmacokinetics

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the hateful steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R-and (-) Southward-enantiomers of ranolazine are similar in healthy volunteers. The credible final half-life of ranolazine is 7 hours. Steady land is more often than not achieved within iii days of twice-daily dosing with RANEXA. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-τ increase slightly more than proportionally to dose, 2.2-and 2.iv-fold, respectively. With twice-daily dosing, the trough:pinnacle ratio of the ranolazine plasma concentration is 0.3 to 0.half-dozen. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.

Absorption And Distribution

Afterward oral administration of RANEXA, peak plasma concentrations of ranolazine are reached betwixt 2 and 5 hours. Later oral assistants of ¹⁴C-ranolazine as a solution, 73% of the dose is systemically bachelor as ranolazine or metabolites. The bioavailability of ranolazine from RANEXA tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the assimilation of ranolazine.

Nutrient (high-fat breakfast) has no of import consequence on the Cmax and AUC of ranolazine. Therefore, RANEXA may exist taken without regard to meals. Over the concentration range of 0.25 to 10 μg/mL, ranolazine is approximately 62% spring to human plasma proteins.

Metabolism And Excretion

Ranolazine is metabolized mainly past CYP3A and, to a lesser extent, past CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized chop-chop and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and carrion. The pharmacologic activity of the metabolites has not been well characterized. Subsequently dosing to steady country with 500 mg to 1500 mg twice daily, the four virtually abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent one-half-lives ranging from 6 to 22 hours.

Drug Interactions

Outcome Of Other Drugs On Ranolazine

In vitro data point that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is as well a substrate of P-glycoprotein.

Strong CYP3A Inhibitors

Plasma levels of ranolazine with RANEXA k mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see CONTRAINDICATIONS].

Moderate CYP3A Inhibitors

Plasma levels of ranolazine with RANEXA m mg twice daily are increased by fifty to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with RANEXA 750 mg twice daily are increased by 100% by verapamil 120 mg iii times daily [see DRUG INTERACTIONS].

Weak CYP3A Inhibitors

The weak CYP3A inhibitors simvastatin (20 mg one time daily) and cimetidine (400 mg three times daily) practice not increase the exposure to ranolazine in good for you volunteers.

CYP3A Inducers

Rifampin 600 mg in one case daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) past approximately 95% [run into CONTRAINDICATIONS].

CYP2D6 Inhibitors

Paroxetine 20 mg in one case daily increased ranolazine concentrations by 20% in good for you volunteers receiving RANEXA 1000 mg twice daily. No dose adjustment of RANEXA is required in patients treated with CYP2D6 inhibitors.

Digoxin

Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily.

Effect Of Ranolazine On Other Drugs

In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2.

CYP3A Substrates

The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are increased past 100% in healthy volunteers receiving 80 mg in one case daily and RANEXA grand mg twice daily [run into DRUG INTERACTIONS]. Mean exposure to atorvastatin (fourscore mg daily) is increased by forty% following co-administration with RANEXA (g mg twice daily) in healthy volunteers. However, in 1 subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of RANEXA.

Diltiazem

The pharmacokinetics of diltiazem is non affected past ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and RANEXA thou mg twice daily.

P-gp Substrates

Ranolazine increases digoxin concentrations by fifty% in healthy volunteers receiving RANEXA k mg twice daily and digoxin 0.125 mg once daily [see DRUG INTERACTIONS].

CYP2D6 Substrates

RANEXA 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by eighty% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.

OCT2 Substrates

In subjects with type ii diabetes mellitus, the exposure to metformin is increased by 40% and lxxx% post-obit administration of ranolazine 500 mg twice daily and 1000 mg twice daily, respectively. If co-administered with RANEXA 1000 mg twice daily, practise not exceed metformin doses of 1700 mg/day [encounter DRUG INTERACTIONS].

Clinical Studies

Chronic Stable Angina

CARISA (Combination Cess of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily RANEXA 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study equally needed.

In this trial, statistically significant (p <0.05) increases in modified Bruce treadmill exercise elapsing and time to angina were observed for each RANEXA dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal furnishings on claret pressure and centre rate. The changes versus placebo in do parameters are presented in Table one. Do treadmill results showed no increase in outcome on exercise at the 1000 mg dose compared to the 750 mg dose.

Table one Exercise Treadmill Results (CARISA)

	Mean Departure from Placebo (sec)
Study	CARISA (North=791)
RANEXA Twice-daily Dose	750 mg	m mg
Exercise Duration
Trough	24a	24a
Peak	34b	26a
Time to Angina
Trough	30a	26a
Peak	38b	38b
Time to 1 mm ST-Segment
Low	twenty	21
Trough Peak	41b	35b
Tiptop
a p-value ≤0.05 b p-value ≤0.005

The furnishings of RANEXA on angina frequency and nitroglycerin utilise are shown in Table two.

Table 2 Angina Frequency and Nitroglycerin Use (CARISA)

		Placebo	RANEXA 750 mga	RANEXA 1000 mga
Angina Frequency(attacks/week)	N	258	272	261
	Mean	iii.3	two.5	2.1
	P-value vs placebo	-	0.006	<0.001
Nitroglycerin Use(doses/week)	N	252	262	244
	Mean	3.1	2.1	1.8
	P-value vs placebo	-	0.016	<0.001
a Twice daily

Tolerance to RANEXA did not develop after 12 weeks of therapy. Rebound increases in angina, every bit measured by exercise duration, have not been observed post-obit sharp discontinuation of RANEXA.

RANEXA has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of RANEXA 500 mg twice daily or placebo for 1 week, followed past 6 weeks of treatment with RANEXA k mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In add-on, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Tabular array 3. Statistically significant decreases in angina assail frequency (p=0.028) and nitroglycerin use (p=0.014) were observed with RANEXA compared to placebo. These treatment effects appeared consistent across historic period and use of long-interim nitrates.

Tabular array 3 Angina Frequency and Nitroglycerin Use (ERICA)

		Placebo	RANEXAa
Angina Frequency (attacks/week)	N	281	277
	Mean	4.3	3.iii
	Median	2.4	2.2
Nitroglycerin Use (doses/week)	Northward	281	277
	Mean	3.6	2.7
	Median	one.vii	1.3
a 1000 mg twice daily

Gender

Furnishings on angina frequency and practice tolerance were considerably smaller in women than in men. In CARISA, the comeback in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina assault frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.iii for males.

Race

There were bereft numbers of non-Caucasian patients to permit for analyses of efficacy or safety by racial subgroup.

Lack Of Benefit In Acute Coronary Syndrome

In a large (n=6560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no do good shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, every bit ventricular arrhythmias were less common on ranolazine [see CLINICAL PHARMACOLOGY], and there was no deviation between RANEXA and placebo in the risk of all-cause mortality (relative run a risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).

PATIENT Information

RANEXA^®
(rah NEX ah)
(ranolazine) extended-release tablets
Dosing Strengths:
500 mg tablets
one thousand mg tablets

Read this Patient Information before you start taking RANEXA and each fourth dimension y'all get a refill. There may be new data. This information does non take the place of talking with your doctor about your medical condition or treatment.

What is RANEXA?

RANEXA is a prescription medicine used to treat angina that keeps coming dorsum (chronic angina).

RANEXA may be used with other medicines that are used for eye problems and claret force per unit area command.

It is not known if RANEXA is condom and effective in children.

Who should not take RANEXA?

Practise not have RANEXA if:

• you take any of the post-obit medicines:
  • for fungus infection: ketoconazole (Nizoral^®), itraconazole (Sporanox^®, OnmelTM)
  • for infection: clarithromycin (Biaxin^®)
  • for depression: nefazodone
  • for HIV: nelfinavir (Viracept^®), ritonavir (Norvir^®), lopinavir and ritonavir (Kaletra^®), indinavir (Crixivan^®), saquinavir (Invirase^®)
  • for tuberculosis (TB): rifampin (Rifadin^®), rifabutin (Mycobutin^®), rifapentine (Priftin^®)
  • for seizures: phenobarbital, phenytoin (Phenytek^®, Dilantin^®, Dilantin125^®), carbamazepine (Tegretol^®)
  • St. John's wort (Hypericum perforatum)
• you take scarring (cirrhosis) of your liver

What should I tell my doctor before taking RANEXA?

Before you take RANEXA, tell your dr. if you lot:

• have or accept a family history of a heart problem, chosen 'QT prolongation' or 'long QT syndrome'.
• accept liver issues.
• accept kidney problems.
• are pregnant or plan to go pregnant. It is non known if RANEXA volition harm your unborn infant.
• are breast-feeding or plan to breast-feed. It is non known if RANEXA passes into your breast milk. You and your physician should decide if yous will breast-feed.

Tell your doctor most all the medicines y'all take, including all prescription and nonprescription medicines, vitamins, and herbal supplements. RANEXA may bear upon the way other medicines piece of work and other medicines may affect how RANEXA works.

Tell your doctor if you take medicines:

• for your center
• for cholesterol
• for diabetes
• for infection
• for fungus
• for transplant
• for nausea and airsickness because of cancer treatments
• for mental problems

Know the medicines you take. Go along a list of them to show your doctor or chemist when you get a new medicine.

How should I take RANEXA?

• Take RANEXA exactly as your doctor tells you.
• Your physician will tell you how much RANEXA to take and when to accept it.
• Do not change your dose unless your doctor tells you to.
• Tell your doctor if y'all still take symptoms of angina later starting RANEXA.
• Take RANEXA past mouth, with or without food.
• Consume the RANEXA tablets whole. Practice not crush, break, or chew RANEXA tablets earlier swallowing.
• If you miss a dose of RANEXA, look to take the next dose of RANEXA at your regular time. Do not brand up for the missed dose. Do not take more than than i dose at a time.
• If you take too much RANEXA, call your doc, or get to the nearest emergency room right away.

What should I avoid while taking RANEXA?

• Grapefruit and grapefruit juice. Limit products that have grapefruit in them. They tin cause your blood levels of RANEXA to increase.
• RANEXA tin can cause dizziness, lightheadedness, or fainting. If you have these symptoms, do not drive a automobile, utilise machinery, or do anything that needs you to be alert.

What are the possible side furnishings of RANEXA?

RANEXA may cause serious side effects, including:

• changes in the electrical activity of your heart called QT prolongation. Your doctor may cheque the electrical activity of your heart with an ECG. Tell your md correct away if you experience faint, airheaded, or feel your heart beating irregularly or fast while taking RANEXA. These may exist symptoms related to QT prolongation.
• kidney failure in people who already take severe kidney problems. Your doctor may need to do tests to check how your kidneys are working.

The most common side effects of RANEXA include:

• dizziness
• headache
• constipation
• nausea

Tell your doctor if you have any side effect that bothers y'all or does not go away.

These are not all the possible side effects of RANEXA. For more data, inquire your md or pharmacist.

Phone call your medico for medical communication most side effects. You may report side furnishings to FDA at 1-800-FDA-1088.

How should I store RANEXA?

Shop RANEXA tablets at room temperature betwixt 59° to 86°F (xv° to 30°C).

Keep RANEXA and all medicines out of the reach of children.

General information about RANEXA.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do non use RANEXA for a condition for which it was not prescribed. Do not give RANEXA to other people, fifty-fifty if they accept the same condition y'all take. It may harm them.

The Patient Information summarizes the most important information well-nigh RANEXA. If you would like more information, talk with your doc. You can ask your pharmacist or doctor for data almost RANEXA that is written for health professionals.

For more information, go to www.ranexa.com or phone call Gilead Sciences, Inc. at 1-800445-3235.

What is chronic angina?

Chronic angina means hurting or discomfort in the breast, jaw, shoulder, back, or arm that keeps coming back. There are other possible signs and symptoms of angina including shortness of jiff. Angina commonly comes on when y'all are active or under stress. Chronic angina is a symptom of a heart trouble called coronary heart disease (CHD), also known every bit coronary artery illness (CAD). When you have CHD, the blood vessels in your eye go stiff and narrow. Oxygen-rich blood cannot attain your centre musculus easily. Angina comes on when too little oxygen reaches your heart muscle.

What are the ingredients in RANEXA?

Active ingredient: ranolazine

Inactive ingredients:

500 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, polyvinyl booze, talc, Iron Oxide Yellow, and Iron Oxide Red.

1000 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Blazon C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, lactose monohydrate, triacetin, and Iron Oxide Yellow.

This Patient Information has been canonical by the U.S. Food and Drug Administration.

From

Written report Bug to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call one-800-FDA-1088.

Source: https://www.rxlist.com/ranexa-drug.htm

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