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INTERVIEW

we have outlined several standard situations: D and
L transposition of the great arteries (which come
with different position of the left ventricle inside
the chest and different role of the morphological
ventricles inside the heart). We have also shown
a nice 3D printing of a Fontan circulation where a

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%

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,
angioedema, erythema, rash, pruritus, urticaria, vertigo,
diplopia, and visual impairment.
7. DRUG INTERACTIONS
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 betablocker. 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. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based 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 pote ntial risk to the fetus.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Stroke 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.

Do you think that this is going to start being
more widely used within the next 5 years?
I think right now it is a little bit like what we went
through with mechanical circulatory support itself
where, say, 5 or 10 years ago, there were only maybe 500 to 700 implants in the United States. People

Monitor pregnant women with chronic heart failure in 3rd
trimester of pregnancy for preterm birth.
Data
Animal Data
In 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 Summary
There 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.
Data
Lactating 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
Contraception
Females
Corlanor 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 betastimulating agents such as isoproterenol, may be considered.
This Brief Summary is based on the Corlanor® Prescribing
Information v1, 04/15

“For me, this was
completely new.
This was a really
new adventure.
It’s a concept.”

saw patients with very advanced HF
and they simply said, “That’s it.” Admittedly, the technology 10 years ago
was not where it is now. I am certain
that at this very moment in time,
there is a very large number of patients with transposition of the great
arteries (with Fontan circulation)
where mechanical circulatory support
could be attempted and could possibly
lead them to a situation where they
get a heart transplant in the future, or
where they can live with mechanical
circulatory support like many destination therapy patients do right now.
For me, this was completely new.
This was a really new adventure. It’s
a concept. Right now, I think we are
largely agnostic as to which patients
can benefit from mechanical support. So we
are extremely
To watch the interexcited that
view with Ulrich
we’re reaching
P. Jorde, MD, visit
the CSWN YouTube
the readers of
channel by scanning
JACC: Heart
the QR code below.
Failure, and
they hopefully
will spread the
word. Don’ t
give up. Let’s
move to the
next level. ■
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

patient had a Mustard procedure in the past, and
now mechanical circulatory support is considered.
We printed out the entire baffle of this heart so we
could orient ourselves within it, but also were able
to [evaluate] outside on the table where the blood
S:7 in
would flow and what obstructions there might be.

REFERENCE
Kanwal M, Saeed O, Zaidi A, et al. JCHF.
2016;4:301-11.

Corlanor® (ivabradine)
Manufactured for: Amgen Inc.
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

June 2016