Valsartan (Diovan) and combinations with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge)

• Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor antagonists.
• If blood pressure is not controlled by valsartan 160 mg, add a second drug rather than increasing the dose to 320 mg. Increasing the dose from 160 mg to 320 mg provides marginal additional blood pressure reduction.
• Establish the effective dose using individual drugs before prescribing the appropriate combination.
• Check electrolytes and renal function before and 1–2 weeks after starting valsartan, after each dose increment or if changed clinical circumstances are likely to worsen renal function (e.g. dehydration).
• Avoid angiotensin II-receptor antagonists (including valsartan) in combination with a nonsteroidal anti-inflammatory drug and a diuretic (including hydrochlorothiazide) — particularly in elderly people or people with pre-existing renal impairment — because combining these three drug classes increases the risk of acute renal failure.

Valsartan (Diovan) — unrestricted benefit

Valsartan is listed on the Pharmaceutical Benefits Scheme (PBS) as an unrestricted benefit¹, as are other angiotensin II-receptor antagonists.²

Valsartan with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) — restricted benefit

Valsartan with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) is restricted for people with hypertension not controlled with valsartan, hydrochlorothiazide or amlodipine monotherapy.^3,4

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended valsartan for listing on a cost-minimisation basis — that is, similar efficacy and cost — with irbesartan. The equi-effective doses were taken to be valsartan 320 mg and irbesartan 300 mg.¹

The PBAC recommended valsartan with hydrochlorothiazide or amlodipine for listing on a cost-minimisation basis compared with the corresponding strengths of the individual drugs given concomitantly.^3,4

Valsartan is an angiotensin II-receptor antagonist that has been available overseas for several years.

Angiotensin II-receptor antagonists have similar blood pressure reducing effects to those of other major antihypertensive drug classes.^5,6 This class of drugs is an option for initial therapy for people with hypertension and may be useful for those with particular comorbidities (e.g. diabetic nephropathy) or intolerances (e.g. angiotensin-converting enzyme [ACE] inhibitor-induced cough). Other options for initial therapy include low-dose thiazide diuretics, dihydropyridine calcium-channel blockers or angiotensin-converting enzyme inhibitors.⁷

If blood pressure is not controlled by valsartan 160 mg, add a second drug from a different pharmacological class rather than increasing the valsartan dose to 320 mg,⁷ and consider comorbidities when choosing the second drug (see Add a second drug for people with hypertension not controlled by monotherapy).

For more information about managing hypertension as a cardiovascular risk factor, refer to NPS News 52 and Prescribing Practice Review 38.^8,9

Valsartan is also indicated for people with heart failure (New York Heart Association Class II–IV) unable to tolerate an angiotensin-converting enzyme inhibitor, and to improve survival after myocardial infarction in people who are clinically stable and have left ventricular failure or dysfunction.¹⁰ For more information about treating people with heart failure, refer to NPS News 57 and Prescribing Practice Review 41.^11,12

Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor antagonists

A meta-analysis of 46 short-term trials showed that all 9 angiotensin II-receptor antagonists assessed — including valsartan — reduced trough blood pressure to a similar extent: on average, systolic blood pressure was reduced by about 8 mmHg and diastolic blood pressure by about 5 mmHg. However, the true blood pressure reduction may be less because the meta-analysis showed some publication bias. Up to 70% of trough blood pressure reduction achieved by angiotensin II-receptor antagonists occurs at the recommended starting doses.¹³

Increasing the dose of valsartan from 160 mg to 320 mg provides marginal additional blood pressure reduction

Valsartan reduces blood pressure across its dose range, though an 80 mg dose achieves near maximal blood pressure reduction.¹³ Increasing the valsartan dose from 160 mg to 320 mg provides marginal additional blood pressure reduction (see Figure 1). This is unlikely to be clinically meaningful and increasing the dose increases the risk of adverse reactions.^13,14

Figure 1.
Mean reduction in trough systolic/diastolic blood pressure (mmHg) with valsartan.¹³

Add a second drug for people with hypertension not controlled by monotherapy

If target blood pressure reduction is not achieved with monotherapy, guidelines suggest adding a second drug (from a different pharmacological class (e.g. thiazide diuretic, calcium-channel blocker) at a low dose rather than increasing the dose of the first drug. This maximises blood pressure reduction while minimising adverse reactions.⁷ Combining valsartan with hydrochlorothiazide or amlodipine achieves significant additional blood pressure reduction (Figures 2, 3). Consider the combination of an angiotensin II-receptor antagonist (e.g. valsartan) with a:

• thiazide diuretic (e.g. hydrochlorothiazide) for people with hypertension and heart failure
• calcium-channel blocker (e.g. amlodipine) for people with hypertension and diabetes.

Figure 2.
Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and hydrochlorothiazide*.^15,16

Figure 3.
Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and amlodipine.¹⁷

Consider a fixed-dose combination for people on stable doses of the individual drugs

Fixed-dose combination therapy may be a more convenient option for people who have inadequate blood pressure control with monotherapy and whose doses of the individual drugs in combination are stable. Compared with taking valsartan, hydrochlorothiazide or amlodipine as separate tablets, the combination tablets allow people to take fewer tablets each day and are cheaper because only one co-payment is required for both medicines. However, the usual considerations that apply to combination tablets remain important.¹⁸Do not start valsartan, amlodipine or hydrochlorothiazide therapy with a fixed-dose combination. Establish the effective dose using the individual drugs before prescribing the appropriate combination.⁷ Consider whether the available strengths of the combination allow the same doses of valsartan, hydrochlorothiazide or amlodipine to be given: not all strengths of each drug are available in a combination tablet (see Table 1).

Some common adverse effects for valsartan include dizziness, hypotension and hyperkalaemia.¹⁰

As for all angiotensin II-receptor antagonists:

• stop potassium supplements and potassium-sparing diuretics before starting valsartan⁵
• valsartan can worsen renal impairment¹⁰ and increase the risk of renal failure⁵
• check electrolytes and renal function before and 1–2 weeks after starting valsartan, after each dose increment or if changed clinical circumstances are likely to worsen renal function (e.g. dehydration)⁶
• valsartan is contraindicated in pregnant women and women planning to become pregnant because it may cause foetal and neonatal morbidity and death¹⁰
• avoid valsartan in breastfeeding women (there are no data for this group)⁵
• avoid angiotensin II-receptor antagonists (including valsartan) in combination with a nonsteroidal anti-inflammatory drug and a diuretic (including hydrochlorothiazide) — particularly in elderly people or those with pre-existing renal impairment — because combining these three drug classes increases the risk of acute renal failure.^19,20

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

In hypertension, the usual dose of valsartan is 80 mg once daily. Maximum blood pressure reduction is seen after 4 weeks: if necessary, increase to 160 mg once daily.

Add a second drug for people whose blood pressure is not controlled by valsartan 160 mg once daily. Increasing the once daily dose from 160 mg to 320 mg provides marginal additional blood pressure reduction.

Lower starting doses and maximum doses are recommended for people aged over 75 years, people with mild to moderate hepatic impairment or a creatinine clearance < 30 mL/minute.^5,10

Consider prescribing the appropriate combination when valsartan has been added to hydrochlorothiazide or amlodipine and the effective doses have been established and are stable (Table 1).

In heart failure or after myocardial infarction, valsartan is given twice daily, usually starting with a lower dose than for hypertension.^5,10

Table 1.
Dose strengths, appearance and availability on the PBS of valsartan, valsartan with hydrochlorothiazide and valsartan with amlodipine^10,21,22

Advise patients:

• to take valsartan or valsartan-containing combination tablets at about the same time each day
• which of their existing medicines are being replaced by valsartan or valsartan-containing combination tablets and to discard the unneeded medicines
• that some common adverse effects for valsartan include dizziness, hypotension and hyperkalaemia
• to have their renal function and electrolytes (including potassium) checked 1–2 weeks after starting therapy and at each dose change
• to tell their doctor or pharmacist that they are taking valsartan with hydrochlorothiazide if they need medicines to treat pain (e.g. nonsteroidal anti-inflammatory drugs).

Discuss the Diovan, Co-Diovan or Exforge Consumer Medicine Information (CMI) leaflet with the patient.