Carvedilol and Ivabradine

No dosage adjustment is required in patients with renal insufficiency and creatinine clearance above 15 mL/min and SBP >100 mmHg.

No data are available in patients with creatinine clearance below 15 mL/min. Carvedilol/ivabradine should be used with precaution in patients with creatinine clearance below 15 mL/min.

Monitoring of renal function is recommended in chronic heart failure patients with SBP <100 mmHg.

It may be necessary to adjust the dose in patients with mild to moderate hepatic impairment.

Caution should be exercised in patients with moderate hepatic impairment.

Based on existing data with the individual components, the use of carvedilol/ivabradine fixed-dose combination is contraindicated during pregnancy.

There are insufficient data on the use of carvedilol in pregnant women. Experimental animal studies have shown reproductive toxicity. The potential risk use in humans is unknown. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia, hypotension, respiratory depression and hypothermia) may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate during the postnatal period. There are no or limited amount of data from the use of ivabradine in pregnant women.

Animal studies with ivabradine have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects. The potential risk for humans is unknown.

Carvedilol/ivabradine combination is contraindicated during breast-feeding.

Animal studies have shown that carvedilol or its metabolites are excreted in the breast milk. It is not known whether carvedilol is excreted in the human breast milk.

Animal studies indicate that ivabradine is excreted in milk. Women that need treatment with ivabradine should stop breast-feeding and choose for another way of feeding their child.

Women of child-bearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment.

Fertility

There are no clinical data on fertility with the use of carvedilol/ivabradine.

Studies with carvedilol have shown impaired fertility in adult female rats. Studies in rats with ivabradine shown no effect on fertility in males and females.

Based on existing data with the individual components, the use of carvedilol/ivabradine fixed-dose combination may affect the ability to drive or use machinery.

Due to variability of individual reactions on carvedilol (such as dizziness, fatigue or decreased alertness), the ability to drive or operate machinery may be impaired. This is particularly true at the start of treatment, when the dose is increased, during the switch to a new preparation, or when taken together with alcohol.

Ivabradine may affect the patient’s ability to drive. Patients should be warned that ivabradine may cause transient luminous phenomena (consisting mainly of phosphenes). Luminous phenomena may occur in situations when there are sudden variations in light intensity, especially when driving at night. Ivabradine has no influence on the ability to use machines. However, in post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported.

Summary of the safety profile

For carvedilol, the frequency of undesirable effects is not dose-dependent, with the exception of dizziness, visual disturbances and bradycardia.

For ivabradine, the most common adverse reactions, luminous phenomena (phosphenes) and bradycardia are dose-dependent and related to the pharmacological effect of the medicinal product.

Tabulated list of adverse reactions

The following undesirable effects have been observed during treatment with carvedilol and ivabradine given separately and ranked under the MedDRA classification by body system and under heading of frequency using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

^* Frequency calculated from clinical trials for adverse events detected from spontaneous report.

Description of selected adverse reactions

Carvedilol

Dizziness, syncope, headache and debility are generally mild and are more likely to occur at the start of treatment.

Cardiac failure is an event commonly reported both in patients treated with placebo and in patients treated with carvedilol (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following acute myocardial infarction).

A reversible deterioration in renal function has been observed during treatment with carvedilol in patients with chronic cardiac insufficiency with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or basal renal insufficiency.

Non-selective beta-blockers in particular may cause latent diabetes to become manifest, manifest diabetes to be aggravated and blood glucose control to be impaired. The glucose balance may also be slightly upset during treatment with carvedilol, but this does not happen often.

Carvedilol may cause urinary incontinence in women. The problem is resolved once treatment is discontinued.

Ivabradine

Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple images (retinal persistency). The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.

Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.

In the SIGNIFY study, atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to a hazard ratio of 1.26, 95% CI [1.15-1.39].