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CLINICAL

NEWS

American College of Cardiology Extended Learning

Corlanor® (ivabradine)

Ivabradine
N=3260

Placebo
N=3278

Bradycardia

10%

2.2%

Hypertension, blood
pressure increased

8.9%

7.8%

Atrial fibrillation

8.3%

6.6%

Phosphenes, visual
brightness

2.8%

0.5%

S:10 in

BRIEF SUMMARY OF PRESCRIBING INFORMATION
Please see package insert for full Prescribing Information
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.
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 present
• Resting 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. WARNINGS AND PRECAUTIONS
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 patientyear 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). 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

between clopidogrel discontinuation and stent
thrombosis ranged from days to months to years.
The authors concluded: “There appears to be no definable ‘safe’ time when antiplatelet therapy may be
discontinued without potential stent thrombosis.”

director of the Center for Heart & Vascular Health
at Christiana Care Health System in Delaware. He
was one of the coauthors of the Dual Antiplatelet Therapy (DAPT) Study,2 the only randomized
controlled trial (RCT) sufficiently powered to
assess rates of stent thrombosis and major adverse
cardiac and cerebrovascular events (MACCE)
DRAWING LESSONS FROM DAPT
S:7 in
after stenting. The study found that continuing
Kirk N. Garratt, MD, is the associate medical
DAPT from 12 to 30 months after
DES placement provided important
reductions in in-stent thrombosis and
rd
Luminous Phenomena (Phosphenes)
Monitor pregnant women with chronic heart failure in 3
trimester of pregnancy for preterm birth.
Phosphenes are phenomena described as a transiently
MACCE.
enhanced brightness in a limited area of the visual field, halos,
Data
image decomposition (stroboscopic or kaleidoscopic effects),
During the primary-analysis periAnimal Data
colored bright lights, or multiple images (retinal persistency).
In pregnant rats, oral administration of ivabradine during
od
(month
12 to month 30), all-cause
Phosphenes are usually triggered by sudden variations in
the period of organogenesis (gestation day 6-15) at doses of
light intensity. Corlanor can cause phosphenes, thought to be
2.3, 4.6, 9.3, or 19 mg/kg/day resulted in fetal toxicity and
mortality
was
2.0% in the group that
mediated through Corlanor’s effects on retinal photoreceptors
teratogenic effects. Increased intrauterine and post-natal
[see Clinical Pharmacology (12.1)]. Onset is generally within
continued
to
receive
thienopyridine
mortality and cardiac malformations were observed at doses
the first 2 months of treatment, after which they may occur
≥ 2.3 mg/kg/day (equivalent to the human exposure at the MRHD
and 1.5% in the placebo group, with
repeatedly. Phosphenes were generally reported to be of mild to
based on AUC0-24hr). Teratogenic effects including interventricular
moderate intensity and led to treatment discontinuation in < 1%
septal defect and complex anomalies of major arteries were
a p value of
of patients; most resolved during or after treatment.
observed at doses ≥ 4.6 mg/kg/day (approximately 3 times the
human exposure at the MRHD based on AUC0-24hr).
6.2 Postmarketing Experience
0.05. During
Because these reactions are reported voluntarily from a
In pregnant rabbits, oral administration of ivabradine during the
the secondarypopulation of uncertain size, it is not always possible to
period of organogenesis (gestation day 6-18) at doses of 7, 14,
estimate their frequency reliably or establish a causal
or 28 mg/kg/day resulted in fetal toxicity and teratogenicity.
analysis period
relationship to drug exposure.
Treatment with all doses ≥ 7 mg/kg/day (equ ivalent to the
The following adverse reactions have been identified during
(month 12 to
human exposure at the MRHD based on AUC0-24hr) caused an
post-approval use of Corlanor: syncope, hypotension,
increase in post-implantation loss. At the high dose of 28 mg/kg/
month 33), allangioedema, erythema, rash, pruritus, urticaria, vertigo,
day (approximately 15 times the human exposure at the MRHD
diplopia, and visual impairment.
based on AUC0-24hr), reduced fetal and placental weights were
cause mortality
observed, and evidence of teratogenicity (ectrodactylia observed
7. DRUG INTERACTIONS
To listen to an interin 2 of 148 fetuses from 2 of 18 litters) was demonstrated.
was 2.3% versus
7.1 Cytochrome P450-Based Interactions
In the pre- and postnatal study, pregnant rats received
Corlanor is primarily metabolized by CYP3A4. Concomitant
view with Kirk N.
1.8%
(HR:
1.36;
oral administration of ivabradine at doses of 2.5, 7, or
use of CYP3A4 inhibitors increases ivabradine plasma
Garratt, MD, on the
20 mg/kg/day from gestation day 6 to lactation day 20. Increased
concentrations, and use of CYP3A4 inducers decreases them.
p = 0.04) and
DAPT study, scan the
postnatal mortality associated with cardiac teratogenic findings
Increased plasma concentrations may exacerbate bradycardia
code. The interview
was observed in the F1 pups delivered by dams treated at the
and conduction disturbances.
the rate of death
high dose (approximately 15 times the human exposure at the
was conducted
The concomitant use of strong CYP3A4 inhibitors is
from noncardioMRHD based on AUC0-24hr).
contraindicated [see Contraindications (4) and Clinical
by Freek W. A.
8.2
Lactation
Pharmacology (12.3)]. Examples of strong CYP3A4 inhibitors
vascular causes
Verheugt, MD.
Risk Summary
include azole antifungals (e.g., itraconazole), macrolide
was 1.1% versus
There is no information regarding the presence of ivabradine in
antibiotics (e.g., clarithromycin, telithromycin), HIV protease
human milk, the effects of ivabradine on the breastfed infant, or
inhibitors (e.g., nelfinavir), and nefazodone.
0.6% (HR: 1.80;
the effects of the drug on milk production. Animal studies have
Avoid concomitant use of moderate CYP3A4 inhibitors when
shown, however, that ivabradine is present in rat milk [see Data].
using Corlanor. Examples of moderate CYP3A4 inhibitors
p = 0.01).
Because of the potential risk to breastfed infants from exposure
include diltiazem, verapamil, and grapefruit juice [see Warnings
to Corlanor, breastfeeding is not recommended.
Yet a suband Precautions (5.3) and Clinical Pharmacology (12.3)].
Data
Avoid concomitant use of CYP3A4 inducers when using
sequent
metaLactating rats received daily oral doses of [14C]-ivabradine
Corlanor. Examples of CYP3A4 inducers include St. John’s
(7 mg/kg) on post-parturition days 10 to 14; milk and maternal
wort, rifampicin, barbiturates, and phenytoin [see Clinical
analysis of 10
plasma were collected at 0.5 and 2.5 hours post-dose on
Pharmacology (12.3)].
trials,3 published
day 14. The ratios of total radioactivity associated with [14C]7.2 Negative Chronotropes
ivabradine or its metabolites in milk vs. plasma were 1.5 and
Most patients receiving Corlanor will also be treated with a betashortly after the DAPT results were
1.8, respectively, indicating that ivabradine is transferred to milk
blocker. The risk of bradycardia increases with concomitant
after oral administration.
announced, found that all-cause
administration of drugs that slow heart rate (e.g., digoxin,
8.3 Females and Males of Reproductive Potential
amiodarone, beta-blockers). Monitor heart rate in patients
mortality was increased with longer
Contraception
taking Corlanor with other negative chronotropes.
Females
7.3 Pacemakers
DAPT despite the fact that stent
Corlanor may cause fetal harm, based on animal data. Advise
Corlanor dosing is based on heart rate reduction, targeting
females of reproductive potential to use effective contraception
thrombosis and MI were significantly
a heart rate of 50 to 60 beats per minute [see Dosage and
during Corlanor treatment [see Use in Specific Populations (8.1)].
Administration (2)]. Patients with demand pacemakers set to
reduced with this strategy. Neverthe8.4 Pediatric Use
a rate ≥ 60 beats per minute cannot achieve a target heart rate
Safety and effectiveness in pediatric patients have not been
< 60 beats per minute, and these patients were excluded from
less, this reduction did not result in
established.
clinical trials [see Clinical Studies (14)]. The use of Corlanor is
a decrease in cardiac mortality with
not recommended in patients with demand pacemakers set to
8.5 Geriatric Use
rates ≥ 60 beats per minute.
No pharmacokinetic differences have been observed in elderly
longer DAPT.
(≥ 65 years) or very elderly (≥ 75 years) patients compared to
8. USE IN SPECIFIC POPULATIONS
the overall population. However, Corlanor has only been studied
8.1 Pregnancy
When all data are considered, Dr.
in a limited number of patients ≥ 75 years of age.
Risk Summary
Garratt
said a cogent argument can
Based on findings in animals, Corlanor may cause fetal harm
8.6 Hepatic Impairment
when administered to a pregnant woman. There are no
No dose adjustment is required in patients with mild or moderate
be made for using just 3 to 6 months
adequate and well-controlled studies of Corlanor in pregnant
hepatic impairment. Corlanor is contraindicated in patients with
women to inform any drug-associated risks. In animal
severe hepatic impairment (Child-Pugh C) as it has not been studied
DAPT in patients treated with conreproduction studies, oral administration of ivabradine to
in this population and an increase in systemic exposure is anticipated
temporary second-generation DES
pregnant rats during organogenesis at a dosage providing 1 to
[see Contraindications (4) and Clinical Pharmacology (12.3)].
3 times the human exposure (AUC0-24hr) at the MRHD resulted in
8.7 Renal Impairment
when the goal of treatment is to avoid
embryo-fetal toxicity and teratogenicity manifested as abnormal
No dosage adjustment is required for patients with creatinine
shape of t he heart, interventricular septal defect, and complex
stent thrombosis. Longer therapy
clearance 15 to 60 mL/min. No data are available for patients
anomalies of primary arteries. Increased postnatal mortality was
with creatinine clearance below 15 mL/min [see Clinical
should be recommended for patients
associated with these teratogenic effects in rats. In pregnant
Pharmacology (12.3)].
rabbits, increased post-implantation loss was noted at an
treated with first-generation drug10.
OVERDOSAGE
exposure (AUC0-24hr) 5 times the human exposure at the MRHD.
Overdose may lead to severe and prolonged bradycardia. In
Lower doses were not tested in rabbits. The background risk
eluting stents, for whom a persisting
the event of bradycardia with poor hemodynamic tolerance,
of major birth defects for the indicated population is unknown.
temporary
cardiac
pacing
may
be
required.
Supportive
treatment,
The estimated background risk of major birth defects in the U.S.
signal of risk is apparent, and for
including intravenous (IV) fluids, atropine, and intravenous betageneral population is 2 to 4%, however, and the estimated risk
stimulating agents such as isoproterenol, may be considered.
patients with low risk for bleeding
of miscarriage is 15 to 20% in clinically recognized pregnancies.
Advise a pregnant woman of the potential risk to the fetus.
This Brief Summary is based on the Corlanor® Prescribing
who wish to minimize their risk of
Clinical Considerations
Information v1, 04/15
Disease-associated maternal and/or embryo/fetal risk
atherothrombotic events, both related
Stroke volume and heart rate increase during pregnancy,
and unrelated to DES.
increasing cardiac output, especially during the first trimester.
Pregnant patients with left ventricular ejection fraction less
Now, to assist clinical decision®
than 35% on maximally tolerated doses of beta-blockers may
Corlanor (ivabradine)
be particularly heart-rate dependent for augmenting cardiac
Manufactured for: Amgen Inc.
making, the ACC/AHA have released

Thomas Jefferson University Hospital reported
“very, very late stent thrombosis” occurring more
than 5 years after DES placement. They found
seven patients in their center with definite late stent
thrombosis from 5.6 to 7.1 years after DES placement. None of the patients were taking clopidogrel
and only two were taking aspirin at the time of
their very, very late stent thrombosis. The interval

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.

One Amgen Center Drive
Thousand Oaks, California 91320-1799
Patent: http://pat.amgen.com/Corlanor/

© 2015 Amgen Inc. All rights reserved. Not for reproduction. USA-998-115485, v2 11/15

May 2016