AusPAR: Ivabradine - Therapeutic Goods Administration

AusPAR Coralan Ivabradine Servier Laboratories (Australia) Pty Ltd PM-2010-03269-3-3
Final 31 October 2012
Therapeutic Goods Administration
revascularisation (percutaneous coronary intervention or coronary artery bypass graft),
or had other significant cardiac or vascular conditions 6. Patients with moderate or severe
liver disease (Child-Pugh score > 7), severe renal disease (serum creatinine > 220 μmol/L)
or anaemia (blood haemoglobin < 110 g/L) were also excluded. Women who were
pregnant or breast feeding and women of childbearing potential who were not on estroprogestative,
progestative or intra-uterine contraception were also excluded.
Comment: The inclusion and exclusion criteria aimed to recruit a study population of
adult patients with chronic heart failure with NYHA Class II to IV, on stable and optimal
CHF medications and reduced LVEF. The selection of patients with stable background
treatment medications is consistent with the TGA adopted EU guidelines on the clinical
investigation of drugs for treatment of cardiac failure 7. In addition, patients needed to
be in documented sinus rhythm with a resting heart rate of ≥ 70 bpm. It is unclear what
rationale the criterion of a resting heart rate of ≥ 70 bpm was based on. A literature
search conducted by the evaluator shows that while clinical studies generally
supported the relationship between a higher heart rate and higher mortality or
morbidity in CHF patients, there is no definitive conclusion on what level of heart rate
constitutes increased risk. One of the currently approved indications for ivabradine is
the use in patients with chronic stable angina in “combination with atenolol 50mg once
daily when heart rate is >60 bpm and angina is inadequately controlled” 8 .
Study treatments
The study drug was oral ivabradine or placebo to be taken twice daily (b.d). During the
run-in period, no study treatment was dispensed. During the randomised double blind
treatment period, the starting dose of study treatment (ivabradine or placebo) for all
patients was 5 mg b.d at 12 hour intervals during meals. At 2 weeks (D014 visit), the dose
was either maintained, up-titrated to the target dose of 7.5 mg b.d or down-titrated to 2.5
mg b.d depending on resting HR on ECG and on tolerability. An upward adjustment to 7.5
mg b.d was recommended if the resting HR was > 60 bpm or downward to 2.5 mg b.d if it
was < 50 bpm or the patient was experiencing signs or symptoms relating to bradycardia.
Patients with HR between 50 and 60 bpm inclusive were maintained on the 5 mg dose.
At the D028 visit and at subsequent follow-up visits or at any time between 2 scheduled
visits, the study investigators could maintain the study drug dose (for patients taking 2.5
mg or 5 mg or 7.5 mg ivabradine or matching placebo) if the ECG resting HR was ≥ 50
bpm; adjust the dose to the next upper dose (for patients taking 2.5 mg or 5 mg ivabradine
or matching placebo) if the ECG resting HR was > 60 bpm; adjust the dose to the next
lower dose (for patients taking 5 mg or 7.5 mg ivabradine or matching placebo) if ECG
resting HR was < 50 bpm or the patient was experiencing signs or symptoms relating to
6 These were, history of stroke or cerebral transient ischaemic attack within the previous 4 weeks; severe
aortic or mitral stenosis, or severe aortic regurgitation, or severe primary mitral regurgitation;
scheduled surgery for valvular heart disease; active myocarditis; congenital heart diseases; previous
cardiac transplantation or on list for cardiac transplantation; cardiac resynchronisation therapy started
within the previous 6 months; pacemaker with atrial or ventricular pacing (except bi-ventricular pacing)
> 40% of the time, or with a stimulation threshold at the atrial or ventricular level ≥ 60 bpm; permanent
atrial fibrillation or flutter; sick sinus syndrome, sinoatrial block, 2nd and 3rd degree atrio-ventricular
block, history of symptomatic or sustained (≥ 30 sec) ventricular arrhythmia unless a cardioverter
defibrillator was implanted; any cardioverter defibrillator shock experienced within the previous 6
months; patients with familial history of or congenital long QT syndrome or treated with selected QT
prolonging products; severe or uncontrolled hypertension (sitting systolic blood pressure > 180 mmHg
or sitting diastolic blood pressure > 110 mmHg); sitting systolic blood pressure < 85 mmHg or current
symptomatic hypotension.
7 TGA adopted EU guideline: Notes for guidance on clinical investigation of medicinal products for
treatment of cardiac failure. (CPMP/EWP/235/95 Rev 1).
8 Australian Product Information, ivabradine.
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