Ivabradine: Difference between revisions

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Ivabradine may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Ivabradine treatment.
Ivabradine may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Ivabradine treatment.
|overdose=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.
|overdose=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.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477495852
| IUPAC_name = 3-[3-({[(7''S'')-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1''H''-3-benzazepin-2-one
| image = iva1.png
| width = 200
| image2 = iva2.png
| width2 = 200
<!--Clinical data-->
| tradename =  Corlanor, Procoralan
| pronounce = {{IPAc-en|ɪ|ˈ|v|æ|b|r|ə|d|iː|n}}
| Drugs.com = {{drugs.com|international|ivabradine}}
| licence_EU = Procoralan
| pregnancy_AU = D
| legal_UK = POM
| routes_of_administration = Oral
<!--Pharmacokinetic data-->
| bioavailability = 40%
| protein_bound = 70%
| metabolism = Hepatic (first-pass) >50%, [[CYP3A4]]-mediated
| elimination_half-life = 2 hours
| excretion = [[Kidney|Renal]] and fecal
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 155974-00-8
| ATC_prefix = C01
| ATC_suffix = EB17
| PubChem = 132999
| IUPHAR_ligand = 2357
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = 
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 117373
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 85966
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 3H48L0LPZQ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07165
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 471737
<!--Chemical data-->
| C=27 | H=36 | N=2 | O=5
| molecular_weight = 468.585 g/mol
| smiles = O=C2N(CCc1cc(OC)c(OC)cc1C2)CCCN(C[C@@H]4c3cc(OC)c(OC)cc3C4)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ACRHBAYQBXXRTO-OAQYLSRUSA-N
}}
|mechAction=Ivabradine blocks the hyperpolarization-activated [[Cyclic-nucleotide-gated channel|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 node|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]].
|mechAction=Ivabradine blocks the hyperpolarization-activated [[Cyclic-nucleotide-gated channel|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 node|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]].



Revision as of 16:46, 27 January 2017

{{DrugProjectFormSinglePage |authorTag=Martin Nino [1] |genericName=Ivabradine |aOrAn=a |drugClass=hyperpolarization-activated cyclic nucleotide-gated channel blocker |indicationType=prevention |indication=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 |adverseReactions=bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes) ( ≥ 1%) |fdaLIADAdult=======Indications====== Ivabradine 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.

Dosage

The recommended starting dose of Ivabradine 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.

  • Table 1. Dose Adjustment
This image is provided by the National Library of Medicine.

|offLabelAdultGuideSupport=Stable angina, chronic, in combination with beta-blocker therapy [1] |fdaLIADPed=Safety and effectiveness in pediatric patients have not been established. |contraindications=Ivabradine is contraindicated in patients with:

|warnings=:*Fetal Toxicity Ivabradine 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 (AUC(0-24hr)) at the maximum recommended human dose (MRHD). Advise females to use effective contraception when taking Ivabradine.

Ivabradine increases the risk of atrial fibrillation. In SHIFT, the rate of atrial fibrillation was 5.0% per patient-year in patients treated with Ivabradine and 3.9% per patient-year in patients treated with placebo. Regularly monitor cardiac rhythm. Discontinue Ivabradine if atrial fibrillation develops.

Bradycardia, sinus arrest, and heart block have occurred with Ivabradine. The rate of bradycardia was 6.0% per patient-year in patients treated with Ivabradine (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 Ivabradine exposure, may themselves contribute to heart rate lowering, and should be avoided. Avoid use of Ivabradine in patients with 2nd degree atrioventricular block, unless a functioning demand pacemaker is present. |clinicalTrials=Clinically significant adverse reactions that appear in other sections of the labeling include:

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 Ivabradine and 3278 patients given placebo. The median duration of Ivabradine exposure was 21.5 months.

The most common adverse drug reactions in the SHIFT trial are shown in Table 2.

  • Table 2. Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT
This image is provided by the National Library of Medicine.

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. Ivabradine can cause phosphenes, thought to be mediated through Ivabradine’s effects on retinal photoreceptors. 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. |postmarketing=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 Ivabradine: syncope, hypotension, angioedema,erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment. |drugInteractions=:*Cytochrome P450-Based Interactions Ivabradine 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. 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 Ivabradine. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice.

Avoid concomitant use of CYP3A4 inducers when using Ivabradine. Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin.

Most patients receiving Ivabradine 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 Ivabradine with other negative chronotropes.

Ivabradine dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute. 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. The use of Ivabradine is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute. |FDAPregCat=N |useInPregnancyFDA=:*Risk Summary

Based on findings in animals, Ivabradine may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Ivabradine 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 (AUC(0-24hr)) 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 (AUC(0-24hr)) 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 Ivabradine, 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.

  • 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 AUC(0-24hr)). 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 AUC(0-24hr)).

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 AUC(0-24hr)) 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 AUC(0-24hr)), 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 AUC(0-24hr)). |useInNursing=:*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. Because of the potential risk to breastfed infants from exposure to Ivabradine, 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. |useInPed=Safety and effectiveness in pediatric patients have not been established. |useInGeri=No [[pharmacokinetic] differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population. However, Ivabradine has only been studied in a limited number of patients ≥ 75 years of age. |useInRenalImpair=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. |useInHepaticImpair=No dose adjustment is required in patients with mild or moderate hepatic impairment. Ivabradine 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. |useInReproPotential=:*Contraception

  • Females

Ivabradine may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Ivabradine treatment. |overdose=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.

|drugBox=

Template:Px
Template:Px
Ivabradine
Systematic (IUPAC) name
3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
Identifiers
CAS number 155974-00-8
ATC code C01EB17
PubChem 132999
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass 468.585 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 40%
Protein binding 70%
Metabolism Hepatic (first-pass) >50%, CYP3A4-mediated
Half life 2 hours
Excretion Renal and fecal
Therapeutic considerations
Licence data

EU

Pregnancy cat.

D(AU)

Legal status

POM(UK)

Routes Oral


|mechAction=Ivabradine 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.

Ivabradine 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 Ivabradine 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. |structure=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 Ivabradine
This image is provided by the National Library of Medicine.


  • Inactive Ingredients

|PD=Ivabradine 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).

Ivabradine 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. |PK=:*Absorption and Bioavailability

Following 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%. Ivabradine should be taken with meals.

Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approximately 100 L.

The 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 Interactions

The effects of coadministered drugs (CYP3A4 inhibitors, substrates, inducers, and other concomitantly administered drugs) on the pharmacokinetics of Ivabradine 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 Corlanor
This image is provided by the National Library of Medicine.

Digoxin exposure did not change when concomitantly administered with Ivabradine. No dose adjustment is required when Ivabradine is concomitantly administered with digoxin.

Ivabradine, 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 AUC(inf) 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 Ivabradine.

  • Specific Populations
  • Age

No pharmacokinetic differences (AUC or Cmax) have been observed between elderly (≥ 65 years) or very elderly (≥ 75 years) patients and the overall patient population.

In patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of Ivabradine were similar to that in patients with normal hepatic function. No data are available in patients with severe hepatic impairment (Child-Pugh C).

Renal impairment (creatinine clearance from 15 to 60 mL/min) has minimal effect on the pharmacokinetics of Ivabradine. No data are available for patients with creatinine clearance below 15 mL/min.

  • Pediatrics

The pharmacokinetics of Ivabradine have not been investigated in patients < 18 years of age. |nonClinToxic=======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 (AUC(0-24hr)) 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 (AUC(0-24hr)) at the MRHD.

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 AUC(0-24hr)) 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. }}