NDC 55513-813 Corlanor

Ivabradine

NDC Product Code 55513-813

NDC 55513-813-28

Package Description: 28 AMPULE in 1 CARTON > 5 mL in 1 AMPULE (55513-813-01)

NDC Product Information

Corlanor with NDC 55513-813 is a a human prescription drug product labeled by Amgen Inc. The generic name of Corlanor is ivabradine. The product's dosage form is solution and is administered via oral form.

Labeler Name: Amgen Inc

Dosage Form: Solution - A clear, homogeneous liquid1 dosage form that contains one or more chemical substances dissolved in a solvent or mixture of mutually miscible solvents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Corlanor Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • IVABRADINE HYDROCHLORIDE 5 mg/5mL

Administration Route(s)

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The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hyperpolarization-activated Cyclic Nucleotide-gated Channel Blocker - [EPC] (Established Pharmacologic Class)
  • Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

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Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Amgen Inc
Labeler Code: 55513
FDA Application Number: NDA209964 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-19-2019 What is the Start Marketing Date?
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Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
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Corlanor Product Label Images

Corlanor Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.       Indications And Usage

Corlanor is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

2.       Dosage And Administration

The recommended starting dose of Corlanor is 5 mg twice daily with meals. Assess patient after two weeks and adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm) as shown in Table 1. Thereafter, adjust dose as needed based on resting heart rate and tolerability. The maximum dose is 7.5 mg twice daily.In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate [see Warnings and Precautions (5.3)].Table 1. Dose AdjustmentHeart RateDose Adjustment> 60 bpmIncrease dose by 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg twice daily50-60 bpmMaintain dose< 50 bpm or signs and symptoms of bradycardiaDecrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy**[see Warnings and Precautions (5.3)]

3.       Dosage Forms And Strengths

Corlanor 5 mg: salmon-colored, oval-shaped, film-coated tablet, scored on both edges, debossed with “5” on one face and bisected on the other face. The tablet is scored and can be divided into equal halves to provide a 2.5 mg dose.Corlanor 7.5 mg: salmon-colored, triangular-shaped, film-coated tablet debossed with “7.5” on one face and plain on the other face.

4.       Contraindications

  • Corlanor is contraindicated in patients with:Acute decompensated heart failure Blood pressure less than 90/50 mmHg Sick sinus syndrome, sinoatrial block, or 3rd degree AV block, unless a functioning demand pacemaker is presentResting heart rate less than 60 bpm prior to treatment [see Warnings and Precautions (5.3)]Severe hepatic impairment [see Use in Specific Populations (8.6)]Pacemaker dependence (heart rate maintained exclusively by the pacemaker) [see Drug Interactions (7.3)]Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors [see Drug Interactions (7.1)]

5.1       Fetal Toxicity

Corlanor may cause fetal toxicity when administered to a pregnant woman based on findings in animal studies. Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1 to 3 times the human exposures (AUC0-24hr) at the maximum recommended human dose (MRHD) [see Use in Specific Populations (8.1)]. Advise females to use effective contraception when taking Corlanor [see Use in Specific Populations (8.3)].

5.2       Atrial Fibrillation

Corlanor increases the risk of atrial fibrillation. In SHIFT, the rate of atrial fibrillation was 5.0% per patient-year in patients treated with Corlanor and 3.9% per patient-year in patients treated with placebo [see Clinical Studies (14)]. Regularly monitor cardiac rhythm. Discontinue Corlanor if atrial fibrillation develops.

5.3       Bradycardia And Conduction Disturbances

Bradycardia, sinus arrest, and heart block have occurred with Corlanor. The rate of bradycardia was 6.0% per patient-year in patients treated with Corlanor (2.7% symptomatic; 3.4% asymptomatic) and 1.3% per patient-year in patients treated with placebo. Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., 1st or 2nd degree atrioventricular block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone).  Bradycardia may increase the risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs [see Adverse Reactions (6.2)].Concurrent use of verapamil or diltiazem will increase Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided [see Clinical Pharmacology (12.3)]. Avoid use of Corlanor in patients with 2nd degree atrioventricular block, unless a functioning demand pacemaker is present [see Contraindications (4) and Dosage and Administration (2)].

6.       Adverse Reactions

  • Clinically significant adverse reactions that appear in other sections of the labeling include:Fetal Toxicity [see Warnings and Precautions (5.1)]Atrial Fibrillation [see Warnings and Precautions (5.2)]Bradycardia and Conduction Disturbances [see Warnings and Precautions (5.3)]

6.1       Clinical Trials 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.In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), safety was evaluated in 3260 patients treated with Corlanor and 3278 patients given placebo.  The median duration of Corlanor exposure was 21.5 months.The most common adverse drug reactions in the SHIFT trial are shown in Table 2 [see also Warnings and Precautions (5.2), (5.3)]. Table 2. Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT IvabradineN=3260PlaceboN=3278Bradycardia10%2.2%Hypertension, blood pressure increased8.9%7.8%Atrial fibrillation8.3%6.6%Phosphenes, visual brightness2.8%0.5%Luminous Phenomena (Phosphenes)Phosphenes are phenomena described as a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency).  Phosphenes are usually triggered by sudden variations in light intensity.  Corlanor can cause phosphenes, thought to be mediated through Corlanor’s effects on retinal photoreceptors [see Clinical Pharmacology (12.1)]. Onset is generally within the first 2 months of treatment, after which they may occur repeatedly.  Phosphenes were generally reported to be of mild to moderate intensity and led to treatment discontinuation in < 1% of patients; most resolved during or after treatment.

6.2       Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.The following adverse reactions have been identified during post-approval use of Corlanor: syncope, hypotension, torsade de pointes, ventricular fibrillation, ventricular tachycardia, angioedema, erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment.

7.1       Cytochrome P450-Based Interactions

Corlanor is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations, and use of CYP3A4 inducers decreases them.  Increased plasma concentrations may exacerbate bradycardia and conduction disturbances.The concomitant use of strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) and Clinical Pharmacology (12.3)].  Examples of strong CYP3A4 inhibitors include azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., clarithromycin, telithromycin), HIV protease inhibitors (e.g., nelfinavir), and nefazodone.Avoid concomitant use of moderate CYP3A4 inhibitors when using Corlanor.  Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Avoid concomitant use of CYP3A4 inducers when using Corlanor.  Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin [see Clinical Pharmacology (12.3)].

7.2       Negative Chronotropes

Most patients receiving Corlanor will also be treated with a beta-blocker. The risk of bradycardia increases with concomitant administration of drugs that slow heart rate (e.g., digoxin, amiodarone, beta-blockers).  Monitor heart rate in patients taking Corlanor with other negative chronotropes.

7.3       Pacemakers

Corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute [see Dosage and Administration (2)]. Patients with demand pacemakers set to a rate ≥ 60 beats per minute cannot achieve a target heart rate < 60 beats per minute, and these patients were excluded from clinical trials [see Clinical Studies (14)]. The use of Corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

8.1       Pregnancy

Risk SummaryBased on findings in animals, Corlanor may cause fetal harm when administered to a pregnant woman.  There are no adequate and well-controlled studies of Corlanor in pregnant women to inform any drug-associated risks. In animal reproduction studies, oral administration of ivabradine to pregnant rats during organogenesis at a dosage providing 1 to 3 times the human exposure (AUC0-24hr) at the MRHD resulted in embryo-fetal toxicity and teratogenicity manifested as abnormal shape of the heart, interventricular septal defect, and complex anomalies of primary arteries. Increased postnatal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC0-24hr) 5 times the human exposure at the MRHD. Lower doses were not tested in rabbits. The background risk of major birth defects for the indicated population is unknown. The estimated background risk of major birth defects in the U.S. general population is 2 to 4%, however, and the estimated risk of miscarriage is 15 to 20% in clinically recognized pregnancies. Advise a pregnant woman of the potential risk to the fetus.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskStroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Pregnant patients with left ventricular ejection fraction less than 35% on maximally tolerated doses of beta-blockers may be particularly heart-rate dependent for augmenting cardiac output. Therefore, pregnant patients who are started on Corlanor, especially during the first trimester, should be followed closely for destabilization of their congestive heart failure that could result from heart rate slowing.Monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth.DataAnimal DataIn pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6-15) at doses of 2.3, 4.6, 9.3, or 19 mg/kg/day resulted in fetal toxicity and teratogenic effects. Increased intrauterine and post-natal mortality and cardiac malformations were observed at doses ≥ 2.3 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC0-24hr). Teratogenic effects including interventricular septal defect and complex anomalies of major arteries were observed at doses ≥ 4.6 mg/kg/day (approximately 3 times the human exposure at the MRHD based on AUC0-24hr). In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 6-18) at doses of 7, 14, or 28 mg/kg/day resulted in fetal toxicity and teratogenicity. Treatment with all doses ≥ 7 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC0-24hr) caused an increase in post-implantation loss. At the high dose of 28 mg/kg/day (approximately 15 times the human exposure at the MRHD based on AUC0-24hr), reduced fetal and placental weights were observed, and evidence of teratogenicity (ectrodactylia observed in 2 of 148 fetuses from 2 of 18 litters) was demonstrated. In the pre- and postnatal study, pregnant rats received oral administration of ivabradine at doses of 2.5, 7, or 20 mg/kg/day from gestation day 6 to lactation day 20. Increased postnatal mortality associated with cardiac teratogenic findings was observed in the F1 pups delivered by dams treated at the high dose (approximately 15 times the human exposure at the MRHD based on AUC0-24hr).

8.2       Lactation

Risk SummaryThere is no information regarding the presence of ivabradine in human milk, the effects of ivabradine on the breastfed infant, or the effects of the drug on milk production. Animal studies have shown, however, that ivabradine is present in rat milk [see Data]. Because of the potential risk to breastfed infants from exposure to Corlanor, breastfeeding is not recommended.DataLactating rats received daily oral doses of [14C]-ivabradine (7 mg/kg) on post-parturition days 10 to 14; milk and maternal plasma were collected at 0.5 and 2.5 hours post-dose on day 14. The ratios of total radioactivity associated with [14C]-ivabradine or its metabolites in milk vs. plasma were 1.5 and 1.8, respectively, indicating that ivabradine is transferred to milk after oral administration.

8.3       Females And Males Of Reproductive Potential

ContraceptionFemalesCorlanor may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Corlanor treatment [see Use in Specific Populations (8.1)].

8.4       Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5       Geriatric Use

No pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population.  However, Corlanor has only been studied in a limited number of patients ≥ 75 years of age.

8.6       Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. Corlanor is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as it has not been studied in this population and an increase in systemic exposure is anticipated [see Contraindications (4) and Clinical Pharmacology (12.3)].

8.7       Renal Impairment

No dosage adjustment is required for patients with creatinine clearance 15 to 60 mL/min. No data are available for patients with creatinine clearance below 15 mL/min [see Clinical Pharmacology (12.3)].

10.       Overdosage

Overdose may lead to severe and prolonged bradycardia. In the event of bradycardia with poor hemodynamic tolerance, temporary cardiac pacing may be required. Supportive treatment, including intravenous (IV) fluids, atropine, and intravenous beta-stimulating agents such as isoproterenol, may be considered.

11.       Description

Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If-current (If), resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility. The chemical name for ivabradine is 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride. The molecular formula is C27H36N2O5, HCl, and the molecular weight (free base + HCl) is 505.1 (468.6 + 36.5). The chemical structure of ivabradine is shown in Figure 1.Figure 1. Chemical Structure of IvabradineCorlanor tablets are formulated as salmon-colored, film-coated tablets for oral administration in strengths of 5 mg and 7.5 mg of ivabradine as the free base equivalent.Inactive IngredientsCoreLactose monohydrate, maize starch, maltodextrin, magnesium stearate, colloidal silicon dioxideFilm CoatingHypromellose, titanium dioxide, glycerol, magnesium stearate, polyethylene glycol 6000, yellow iron oxide, red iron oxide

12.1       Mechanism Of Action

Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker If current, which regulates heart rate. In clinical electrophysiology studies, the cardiac effects were most pronounced in the sinoatrial (SA) node, but prolongation of the AH interval has occurred on the surface ECG, as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility [see Clinical Pharmacology (12.2)].Corlanor can also inhibit the retinal current Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih by Corlanor may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field [see Adverse Reactions (6.1)].

12.2       Pharmacodynamics

Corlanor causes a dose-dependent reduction in heart rate. The size of the effect is dependent on the baseline heart rate (i.e., greater heart rate reduction occurs in subjects with higher baseline heart rate). At recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. Analysis of heart rate reduction vs. dose indicates a plateau effect at doses > 20 mg twice daily. In a study of subjects with preexisting conduction system disease (first- or second-degree AV block or left or right bundle branch block) requiring electrophysiologic study, IV ivabradine (0.20 mg/kg) administration slowed the overall heart rate by approximately 15 bpm, increased the PR interval (29 msec), and increased the AH interval (27 msec).Corlanor does not have negative inotropic effects. Ivabradine increases the uncorrected QT interval with heart rate slowing but does not cause rate-corrected prolongation of QT.

12.3       Pharmacokinetics

Absorption and BioavailabilityFollowing oral administration, peak plasma ivabradine concentrations are reached in approximately 1 hour under fasting conditions. The absolute oral bioavailability of ivabradine is approximately 40% because of first-pass elimination in the gut and liver. Food delays absorption by approximately 1 hour and increases plasma exposure by 20% to 40%.  Corlanor should be taken with meals [see Dosage and Administration (2)].Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approximately 100 L.Metabolism and ExcretionThe pharmacokinetics of ivabradine are linear over an oral dose range of 0.5 mg to 24 mg. Ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation. The major metabolite is the N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine. The N-desmethylated derivative is also metabolized by CYP3A4. Ivabradine plasma levels decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours.The total clearance of ivabradine is 24 L/h, and renal clearance is approximately 4.2 L/h, with ~ 4% of an oral dose excreted unchanged in urine. The excretion of metabolites occurs to a similar extent via feces and urine. Drug InteractionsThe effects of coadministered drugs (CYP3A4 inhibitors, substrates, inducers, and other concomitantly administered drugs) on the pharmacokinetics of Corlanor were studied in several single- and multiple-dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 2.Figure 2. Impact of Coadministered Drugs on the Pharmacokinetics of CorlanorDigoxin exposure did not change when concomitantly administered with ivabradine. No dose adjustment is required when ivabradine is concomitantly administered with digoxin.Effect of Ivabradine on Metformin PharmacokineticsIvabradine, dosed at 10 mg twice daily to steady state, did not affect the pharmacokinetics of metformin (an organic cation transporter [OCT2] sensitive substrate). The geometric mean (90% confidence interval [CI]) ratios of Cmax and AUCinf of metformin, with and without ivabradine were 0.98 [0.83–1.15] and 1.02 [0.86–1.22], respectively. No dose adjustment is required for metformin when administered with Corlanor.Specific PopulationsAge No pharmacokinetic differences (AUC or Cmax) have been observed between elderly (≥ 65 years) or very elderly (≥ 75 years) patients and the overall patient population [see Use in Specific Populations (8.5)].Hepatic ImpairmentIn patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of Corlanor were similar to that in patients with normal hepatic function. No data are available in patients with severe hepatic impairment (Child-Pugh C) [see Contraindications (4)].Renal Impairment Renal impairment (creatinine clearance from 15 to 60 mL/min) has minimal effect on the pharmacokinetics of Corlanor. No data are available for patients with creatinine clearance below 15 mL/min.PediatricsThe pharmacokinetics of Corlanor have not been investigated in patients < 18 years of age.

13.1       Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of carcinogenicity when mice and rats received ivabradine up to 104 weeks by dietary administration. High doses in these studies were associated with mean ivabradine exposures of at least 37 times higher than the human exposure (AUC0-24hr) at the MRHD.Ivabradine tested negative in the following assays: bacterial reverse mutation (Ames) assay, in vivo bone marrow micronucleus assay in both mouse and rat, in vivo chromosomal aberration assay in rats, and in vivo unscheduled DNA synthesis assay in rats. Results of the in vitro chromosomal aberration assay were equivocal at concentrations approximately 1,500 times the human Cmax at the MRHD. Ivabradine tested positive in the mouse lymphoma assays and in vitro unscheduled DNA synthesis assay in rat hepatocytes at concentrations greater than 1,500 times the human Cmax at the MRHD.Reproduction toxicity studies in animals demonstrated that ivabradine did not affect fertility in male or female rats at exposures 46 to 133 times the human exposure (AUC0-24hr) at the MRHD.

13.2       Animal Toxicology And/Or Pharmacology

Reversible changes in retinal function were observed in dogs administered oral ivabradine at total doses of 2, 7, or 24 mg/kg/day (approximately 0.6 to 50 times the human exposure at the MRHD based on AUC0-24hr) for 52 weeks. Retinal function assessed by electroretinography demonstrated reductions in cone system responses, which reversed within a week post-dosing, and were not associated with damage to ocular structures as evaluated by light microscopy. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarization-activated Ih currents in the retina, which share homology with the cardiac pacemaker If current.

14.       Clinical Studies

SHIFTThe Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) was a randomized, double-blind trial comparing Corlanor and placebo in 6558 adult patients with stable NYHA class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm. Patients had to have been clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics, with fluid retention and symptoms of congestion minimized. Patients had to have been hospitalized for heart failure within 12 months prior to study entry.The underlying cause of CHF was coronary artery disease in 68% of patients. At baseline, approximately 49% of randomized subjects were NYHA class II, 50% were NYHA class III, and 2% were NYHA class IV. The mean left ventricular ejection fraction was 29%. All subjects were initiated on Corlanor 5 mg (or matching placebo) twice daily and the dose was increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated. The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.Most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses. The main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decompensation (9%), and bradycardia (6%). For the 11% of patients not receiving any beta-blocker at baseline, the main reasons were chronic obstructive pulmonary disease, hypotension, and asthma. Most patients were also taking ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). Few patients had an implantable cardioverter-defibrillator (ICD) (3.2%) or a cardiac resynchronization therapy (CRT) device (1.1%). Median follow-up was 22.9 months. At 1 month, 63%, 26%, and 8% of Corlanor-treated patients were taking 7.5, 5, and 2.5 mg BID, whereas 3% had withdrawn from the drug, primarily for bradycardia.SHIFT demonstrated that Corlanor reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82, 95% confidence interval [CI]: 0.75, 0.90, p < 0.0001) (Table 3). The treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure; there was no favorable effect on the mortality component of the primary endpoint. In the overall treatment population, Corlanor had no statistically significant benefit on cardiovascular death.Table 3. SHIFT – Incidence of the Primary Composite Endpoint and Components Corlanor(N = 3241)Placebo(N = 3264)Endpointn%% PYn%% PYHazard Ratio[95% CI]p-valuePrimary composite endpoint: Time to first hospitalization for worsening heart failure or cardiovascular deatha79324.514.593728.717.70.82[0.75 , 0.90]<0.0001     Hospitalization for worsening heart failure50515.69.266020.212.5     Cardiovascular death as first event2888.94.82778.54.7Subjects with events at any time     Hospitalization for worsening heart failureb51415.99.467220.612.70.74 [0.66 , 0.83]     Cardiovascular deathb44913.97.549115.08.30.91[0.80 , 1.03]a Subjects who died on the same calendar day as their first hospitalization for worsening heart failure are counted under cardiovascular death.    b Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.N: number of patients at risk; n: number of patients having experienced the endpoint; %: incidence rate = (n/N) x 100; % PY: annual incidence rate = (n/number of patient-years) x 100; CI: confidence intervalThe hazard ratio between treatment groups (ivabradine /placebo) was estimated based on an adjusted Cox proportional hazards model with beta-blocker intake at randomization (yes/no) as a covariate; p-value: Wald testThe Kaplan-Meier curve (Figure 3) shows time to first occurrence of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death in the overall study.Figure 3. SHIFT: Time to First Event of Primary Composite Endpoint A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. Many of these results are shown in Figure 4.  Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. Most of the results show effects consistent with the overall study result. Corlanor’s benefit on the primary endpoint in SHIFT appeared to decrease as the dose of beta-blockers increased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers. Figure 4. Effect of Treatment on Primary Composite Endpoint in SubgroupsNote: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.BEAUTIFUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart failureBEAUTIFUL was a randomized, double-blind, placebo-controlled trial in 10,917 adult patients with coronary artery disease, impaired left ventricular systolic function (ejection fraction < 40%) and resting heart rate ≥ 60 bpm. Patients had stable symptoms of heart failure and/or angina for at least 3 months, and were receiving conventional cardiovascular medications at stable doses for at least 1 month. Beta-blocker therapy was not required, nor was there a protocol mandate to achieve any specific dosing targets for patients who were taking beta-blockers. Patients were randomized 1:1 to Corlanor or placebo at an initial dose of 5 mg twice daily with the dose increased to 7.5 mg twice daily depending on resting heart rate and tolerability. The primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure. Most patients were NYHA class II (61.4%) or class III (23.2%) - none were class IV. Through a median follow-up of 19 months, Corlanor did not significantly affect the primary composite endpoint (HR 1.00, 95% CI = 0.91, 1.10).SIGNIFY was a randomized, double-blind trial administering Corlanor or placebo to 19,102 adult patients with stable coronary artery disease but without clinically evident heart failure (NYHA class I). Beta-blocker therapy was not required. Corlanor was initiated at a dose of 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5.0 mg twice daily to achieve a target heart rate of 55 to 60 bpm. The primary endpoint was a composite of the first occurrence of either cardiovascular death or myocardial infarction. Through a median follow-up of 24.1 months, Corlanor did not significantly affect the primary composite endpoint (HR 1.08, 95% CI = 0.96, 1.20).

16.       How Supplied/Storage And Handling

  • Corlanor 5 mg tablets are formulated as salmon-colored, oval-shaped, film-coated tablets scored on both edges, marked with “5” on one face and bisected on the other face.  They are supplied as follows:Bottles of 60 tablets (NDC 55513-800-60)Bottles of 180 tablets (NDC 55513-800-80)Corlanor 7.5 mg tablets are formulated as salmon-colored, triangular-shaped, film-coated tablets debossed with “7.5” on one face and plain on the other face.  They are supplied as follows:Bottles of 60 tablets (NDC 55513-810-60)Bottles of 180 tablets (NDC 55513-810-80)StorageStore at 25ºC (77ºF); excursions permitted to 15º - 30ºC (59º - 86ºF) [see USP Controlled Room Temperature].

17.       Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide). Fetal ToxicityAdvise pregnant women of the potential risks to a fetus.Advise females of reproductive potential to use effective contraception and to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Low Heart RateAdvise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension [see Warnings and Precautions (5.3)].Atrial fibrillation Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath [see Warnings and Precautions (5.2)].PhosphenesAdvise patients about the possible occurrence of luminous phenomena (phosphenes). Advise patients to use caution if they are driving or using machines in situations where sudden changes in light intensity may occur, especially when driving at night.  Advise patients that phosphenes may subside spontaneously during continued treatment with Corlanor [see Adverse Reactions (6.1)].Drug InteractionsAdvise patients to avoid ingestion of grapefruit juice and St. John’s wort [see Drug Interactions (7.1)].Intake with FoodAdvise patients to take Corlanor twice daily with meals [see Dosage and Administration (2)].Corlanor® (ivabradine)Manufactured for:Amgen Inc.One Amgen Center DriveThousand Oaks, California 91320-1799Patent: http://pat.amgen.com/Corlanor/© 2017 Amgen Inc. All rights reserved.v2

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