Valsartan and combinations

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Valsartan

80 mg and 160 mg film-coated tablets
Approved indications: hypertension, heart failure
Australian Medicines Handbook section 6.3.5

Valsartan/hydrochlorothiazide

Co-Diovan (Novartis)
80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg film-coated tablets
Approved indication: hypertension
Australian Medicines Handbook section 6.3.5

Amlodipine/valsartan

Exforge (Novartis)
5 mg/80 mg, 5 mg/160 mg and 10 mg/160 mg film-coated tablets
Approved indication: hypertension
Australian Medicines Handbook section 6.3.5

Valsartan

Valsartan is an angiotensin II antagonist which was launched overseas more than 10 years ago, but was not marketed in Australia. Like other members of the class, such as candesartan and losartan, valsartan lowers blood pressure by acting at the angiotensin type I receptor.

The antihypertensive effect of valsartan reaches a maximum after four weeks. Although raising the dose can increase the antihypertensive effect, doubling the dose from 160 mg to 320 mg may only reduce blood pressure by an extra 1-2 mmHg, while increasing adverse effects such as dizziness.¹

Patients take the tablets once a day for hypertension and twice a day for heart failure. Most of the dose is excreted unchanged in bile, but it is recommended that the maximum dose should be limited in patients with severe renal impairment as well as in those with mild to moderate hepatic impairment. It is contraindicated in pregnancy.

A large trial has compared valsartan with amlodipine in more than 15 000 hypertensive patients. After a mean follow-up of 4.2 years the reduction in mean blood pressure was greater in patients taking amlodipine than in those taking valsartan. Systolic pressure fell by 17 mmHg with amlodipine and by 15 mmHg with valsartan, while the diastolic pressures fell by 10 mmHg and 8 mmHg. Although the composite end point of cardiovascular morbidity and mortality was not significantly different, there were more myocardial infarctions in the patients taking valsartan. The incidence of infarction per 1000 patient years was 11.4 with valsartan and 9.6 with amlodipine.²

Valsartan has been studied in patients with acute myocardial infarction. They were enrolled if they had signs of heart failure or left ventricular systolic dysfunction. More than 14 000 patients were randomised to receive valsartan, captopril or both drugs. After a median follow-up of 24.7 months, 19-20% of the patients in each group had died. Valsartan was not inferior to captopril, but their combination had no advantage and resulted in more patients stopping treatment because of adverse effects.³

Valsartan has also been used to treat chronic heart failure. In a controlled trial valsartan, or a placebo, was added to the treatment of 5010 patients with heart failure (New York Heart Association class II, III or IV). After a mean follow-up of 23 months, 19-20% of the patients in each group had died, however a combined end point of mortality and morbidity showed an advantage for valsartan. This was mainly because fewer patients, than in the placebo group, were admitted to hospital because of worsening heart failure (13.8% vs 18.2%). Valsartan should not be used in patients who are already taking an ACE inhibitor and a beta blocker. In the trial, adding valsartan to this combination significantly increased mortality.⁴

Valsartan with hydrochlorothiazide

In the comparison with amlodipine, more of the patients taking valsartan needed to take additional drugs, such as hydrochlorothiazide, to control their blood pressure.² These patients can now be considered for management with a combination tablet containing valsartan and hydrochlorothiazide.

There is an interaction between the drugs. Hydrochlorothiazide reduces the concentrations of valsartan and valsartan reduces the availability of hydrochlorothiazide. These changes do not negate the antihypertensive effect.

The combination of valsartan and hydrochlorothiazide was compared with valsartan in a placebo-controlled trial involving 871 patients with essential hypertension. These patients were randomised to one of nine groups using different doses of the combination, or monotherapy. After eight weeks all the active treatments had reduced the mean sitting blood pressure significantly more than placebo. Any combination of valsartan and hydrochlorothiazide reduced blood pressure more than either drug alone. For example, valsartan 80 mg with 12.5 mg of hydrochlorothiazide will reduce the diastolic pressure by 3.2 mmHg more than 80 mg valsartan and by 4.7 mmHg more than 12.5 mg hydrochlorothiazide.⁵

Another trial compared two combinations of valsartan and hydrochlorothiazide with valsartan alone in 774 patients with systolic hypertension. After eight weeks the mean sitting systolic blood pressure had been reduced by 20.7 mmHg with valsartan 160 mg. In combination with hydrochlorothiazide 12.5 mg the reduction was 27.9 mmHg and with hydrochlorothiazide 25 mg it was 28.3 mmHg.⁶

The combination of valsartan and hydrochlorothiazide has also been compared with amlodipine. In addition to hypertension, the 1088 patients in this study all had at least one other cardiovascular risk factor. After 24 weeks amlodipine 10 mg had reduced the mean systolic sitting blood pressure by 27.6 mmHg. Valsartan reduced the pressure by 27.1 mmHg when combined with hydrochlorothiazide 12.5 mg and by 29.7 mmHg with hydrochlorothiazide 25 mg.⁷

The main adverse effects of the combinations are dizziness, headache and fatigue.⁵ Approximately 4% of patients will have a greater than 20% decrease in serum potassium.

Amlodipine with valsartan

Valsartan has also been combined with a calcium channel blocker to treat hypertension. The combination of amlodipine and valsartan is taken once daily. The bioavailability of the tablet is equivalent to that of its components when they are given separately. There is no significant interaction between the drugs, so their pharmacokinetic parameters are expected to be the same when they are given in a combined formulation.

Two placebo-controlled studies involving more than 3000 patients have compared the antihypertensive effects of amlodipine and valsartan alone with different strengths of the combination. Over eight weeks, most of the combined formulations produced significantly larger reductions in blood pressure than either drug alone or placebo.⁸

Another study compared the combined tablets (amlodipine 5 mg or 10 mg with valsartan 160 mg) with a combination of lisinopril and hydrochlorothiazide in 130 patients who had diastolic blood pressures of 110-119 mmHg. After six weeks both combinations had controlled the diastolic blood pressure in 77-80% of patients. The mean reduction in diastolic pressure with amlodipine and valsartan was 29 mmHg and with lisinopril and hydrochlorothiazide it was 28 mmHg.⁹

Combination products expose patients to the adverse effects of both components, but in some cases one drug may ameliorate the effects of the other. Peripheral oedema occurs in approximately 5% of those taking amlodipine and valsartan. This is significantly less than with amlodipine alone (9%), but more than with valsartan alone (2%).8 Less frequent reactions are headache and dizziness.

Most patients will need more than one drug to control their blood pressure, but the treatment of hypertension should not begin with a combination product. Ideally, the doses of the individual drugs should be titrated to an optimum dose. If these doses correspond to those of a combination product, the patient can be switched to the combination. The problem with fixed dose combinations is that the ability to titrate the dose is limited.¹⁰

manufacturer provided some product information

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

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).