- Aust Prescr 2010;33:52-9
- 1 April 2010
- DOI: 10.18773/austprescr.2010.023
1.25 mg, 5 mg and 10 mg tablets
Approved indication: hypertension, chronic heart failure
Australian Medicines Handbook section 6.4.3
Nebivolol is indicated for the treatment of essential hypertension (no age limit), and for stable chronic heart failure in combination with conventional therapies for patients aged 70 or older. It works by blocking the beta1 adrenergic receptor, and has mild vasodilatory properties mediated through nitric oxide release. At doses up to 10 mg, it is selective for the beta1 adrenergic receptor, but at higher doses (and in poor metabolisers) it inhibits both beta1 and beta2 adrenergic receptors.
Peak plasma concentrations of this drug are reached 1.5-4 hours after oral administration. It is metabolised by cytochrome P450 2D6 and its elimination half-life is around 10 hours in most people (fast metabolisers), but 3-5 times longer in people who are slow metabolisers. Metabolites are excreted in urine and faeces in varying proportions depending on the individual's metabolism. As there are variations in the metabolism of nebivolol, the dose should be adjusted according to individual needs. Poor metabolisers may require a lower dose.
Once-daily nebivolol (1.25-40 mg) has been shown to reduce blood pressure in patients with mild-moderate hypertension in a number of placebo-controlled trials.12A nine-month extension of these trials compared nebivolol monotherapy to nebivolol given with other antihypertensive treatments in 845 people. (Of these patients, 81 had previously received placebo and 764 had received nebivolol.) Patients were given nebivolol monotherapy (5-20 mg). If they did not have an adequate response to this, a diuretic, calcium channel blocker (amlodipine) or another antihypertensive drug was added to their treatment. By the end of the study, mean diastolic and systolic blood pressures had decreased by 15 mmHg and 14.8 mmHg in the nebivolol group (606 patients) and by 12 mmHg and 16.2 mmHg in the nebivolol plus diuretic group (206 patients) from baseline of the original studies. There were too few patients in the other groups to conclude whether treatment had worked.3
In a meta-analysis of hypertension drugs, response rates to nebivolol (5 mg daily) were similar to other beta blockers, calcium channel antagonists and the angiotensin receptor antagonist losartan. Response rates to nebivolol were higher than for angiotensin converting enzyme inhibitors.4
In one of the original hypertension trials that tested nebivolol (1.25-40 mg) for 12 weeks, headache (6-9%), fatigue (1.2-4.8%) and dizziness (1-9%) were commonly reported adverse events. Patients treated with the higher doses of nebivolol (20 mg and 40 mg) had significantly more adverse events, possibly because nebivolol becomes less selective at higher doses. There were two serious adverse events that were thought to be possibly related to nebivolol (20 mg and 40 mg dose). Both were abnormal ECG readings which resolved spontaneously without treatment being interrupted. High-density lipoprotein cholesterol decreased significantly with increasing nebivolol dose, and increases in serum uric acid and phosphorus were observed at doses of 5 mg and above.1In the extension study, there were three patients with serious adverse events that were thought to be related to the study drug. These included right upper quadrant pain, bradycardia and peripheral oedema, and sexual dysfunction. Obese patients (≥ 30 kg/m2) tended to have more adverse events than patients who were not obese.3In the meta-analysis, adverse event rates for nebivolol were lower than for other beta blockers, calcium channel antagonists and losartan. The tolerability of nebivolol and ACE inhibitors was similar.4
In Australia, nebivolol has also been approved as an add-on treatment for heart failure in older patients. This is based on the SENIORS trial in 2128 patients aged 70 years and over with heart failure. This was a post hoc analysis and patients were not randomised to receive different doses of nebivolol. They were started on placebo, or a low dose of nebivolol which was gradually increased to 10 mg, if tolerated, over a maximum of 16 weeks. The target dose was reached by two-thirds of the patients in the nebivolol group and was associated with a significant reduction (relative risk reduction of 4.2%) in the composite end point of all-cause mortality or hospitalisation (due to a cardiovascular event), compared to placebo. However, nebivolol did not significantly reduce all-cause mortality alone. There was no significant benefit with low-dose nebivolol and patients who could not tolerate it had a higher risk of death or hospitalisation than those on placebo. It is not clear how nebivolol compares to other beta blockers in this population.5
In the heart failure trial, around 20% of patients had aggravated cardiac failure regardless of whether they were taking placebo or nebivolol. However, bradycardia was considerably more common with nebivolol than with placebo (11% vs 2.5% of patients). Dizziness was reported by 14% of patients in the nebivolol group and 13% in the placebo group.5
Spontaneous adverse events reported overseas with this drug have included abnormal liver function, acute pulmonary oedema, acute renal failure, myocardial infarction, Raynaud's phenomenon, thrombocytopenia and skin disorders including rashes. However, their frequency and causal relationship with nebivolol is not known.
Nebivolol has the potential to interact with many drugs, therefore it is important to read the product information before prescribing it. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, quinidine, thioridazine and cimetidine, are likely to increase nebivolol concentrations so patients' blood pressure should be monitored closely in case dose adjustment is required. Nebivolol is not recommended with the calcium channel antagonists verapamil and diltiazem, class I antiarrhythmic drugs (flecainide, disopyramide, lignocaine, mexiletine) and with centrally-acting antihypertensives (clonidine, moxonidine, methyldopa). Nebivolol should not be used with other beta blockers, including eye drops.
As beta blockade can depress myocardial contractility, it can worsen heart failure so nebivolol should not be given to patients with acute heart failure or untreated congestive heart failure. Other contraindications include sick sinus syndrome (without pacemaker), severe bradycardia, heart block (more than first degree), hypotension, severe circulatory disturbances, metabolic acidosis and history of bronchospasm.
As with other beta blockers, patients should be warned against stopping nebivolol abruptly as this can exacerbate angina and precipitate myocardial infarction and ventricular arrhythmias.
When used for hypertension, dose adjustment is required in patients with renal impairment. There are no data on the use of nebivolol in patients receiving dialysis. For chronic heart failure, dose adjustment is not needed in mild to moderate renal insufficiency. Nebivolol is not recommended for patients with severe renal impairment. This drug is contraindicated in patients with hepatic impairment.
Nebivolol seems to be as effective as other antihypertensive drugs at lowering blood pressure and it benefits some patients with heart failure. However, until long-term data on its clinical use are available, it is probably better to continue to use the more established beta blockers.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).