CLINICAL INNOVATORS
sion that are beyond the usual dietary (low sodium)
and drug therapies. We found evidence to support
several techniques. The most notable examples that I
recommend to my patients are Transcendental Meditation, device-guided slow breathing, aerobic exercise
(e.g., running), and isometric exercise (sustained
S:7 in
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 potential 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.
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 teratogeni 6