Valsartan with hydrochlorothiazide, tablets, 80 mg - 12.5 mg, 160 mg - 12.5 mg and 160 mg – 25 mg Co-Diovan®, July 2008
Public summary document for Valsartan with hydrochlorothiazide, tablets, 80 mg - 12.5 mg, 160 mg - 12.5 mg and 160 mg – 25 mg Co-Diovan®, July 2008
Page last updated: 31 October 2008
Public Summary Documents
Product: Valsartan with hydrochlorothiazide,
tablets, 80 mg - 12.5 mg, 160 mg - 12.5 mg and 160 mg – 25 mg
Co-Diovan®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought listing of valsartan with hydrochlorothiazide
(HCTZ) in fixed dose combination tablets as a restricted benefit
for patients with hypertension that is not adequately controlled
with either valsartan or HCTZ monotherapy.
2. Background
The combination item containing valsartan with HCTZ had not been
considered by the PBAC. HCTZ as a single ingredient product has
been listed on the PBS since 1 May 1964. Valsartan as a single
ingredient product is not currently listed on the PBS.
3. Registration Status
Valsartan with HCTZ has been TGA registered since 31 May 2005.
Valsartan with HCTZ is indicated for the treatment of hypertension.
Treatment should not be initiated with the combination
products.
4. Listing Requested and PBAC’s View
Restricted benefit
Hypertension in patients who are not adequately controlled with
either hydrochlorothiazide or valsartan monotherapy.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The new listing will provide another alternative angiotensin II
antagonist with diuretic treatment option for hypertension which is
not adequately controlled with monotherapy and lifestyle
modifications.
6. Comparator
The submission nominated the following comparators:
a) Each of the individual components (valsartan and
hydrochlorothiazide (HCTZ) given alone;
b) Each of the individual components (valsartan and HCTZ) given
concomitantly.
The PBAC considered this was appropriate.
7. Clinical Trials
The submission presented 12 randomised trials comparing the fixed
dose combination valsartan/HCTZ and the individual components in
patients with hypertension. The submission presented three
pharmacokinetic studies comparing fixed combination vs. free
components.
A list of the trials and associated reports published at the time
of submission is as follows:
| Trial/First author | Protocol title/Publication title | Publication citation |
| Study 301 Benz JR et al | Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy. | Journal of Human Hypertension. 1998. 12(12):861-6 |
| Study 2301 Pool JL et al | Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: A double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. | Clinical Therapeutics. 2007. 29(1): 61-73 |
| Study 0201 Carretta R et al | Pulse pressure responses in patients treated with valsartan and hydrochlorothiazide combination therapy. | European Heart Journal. 2002, 236-49. |
| Carretta R et al | Pulse pressure responses in patients treated with valsartan and hydrochlorothiazide combination therapy. | Journal of International Medical Research. 2003. 31 (5), 370-377. |
| Mallion J-M et al. | Valsartan/hydrochlorothiazide is effective in hypertensive patients inadequately controlled by valsartan monotherapy. | Blood Pressure, Supplement. 2003, 12 (1), 36-43. |
| Lacourciere Y et al, 2005 | Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, doub le-blind, parallel-group trial. | Clinical Therapeutics. 2005. Jul. 27(7):1013-21. |
| Lacourciere Y et al, 2004 | Effective blood-pressure control with valsartan/HCTZ combination therapy in patients with moderate to severe systolic hypertension: The VALOR trial. | American Journal of Hypertension. 2004. 17 (5 PART 2), 115A. |
| Trenkwalder et al, 2004 | Efficacy and safety of valsartan 160mg/hydrochlorothiazide 25mg combination in patients with hypertension not adequately controlled by valsartan 160mg/hydrochlorothiazide 12.5mg. | Clinical Drug Investigation. 2004, 24 (10): 593-602. |
| Trenkwalder P et al, 2004 | Valsartan 160/ HCTZ 25 effectively reduces blood pressure in hypertensive patients not controlled by valsartan 160/ HCTZ 12.5. | Journal of Hypertension. 2004. 22 (SUPPL. 1), S194 |
| Trenkwalder P et al, 2003 | Blood pressure reduction with valsartan 160/HCTZ 25 in hypertensive patients uncontrolled by valsartan 160/HCTZ 12.5. | Deutsche Medizinische Wochenschrift. 2003. 128 (SUPPL. 3), S163. |
| Fogari et al, 2006 | Hydrochlorothiazide added to valsartan is more effective than when added to olmesartan in reducing blood pressure in moderately hypertensive patients inadequately controlled by monotherapy. | Advances in Therapy. 2006 Sep-Oct. 23(5):680-95. |
| Hua and Li, 2004 | Efficacy and safety of combination of Valsartan with hydrochlorothiazide in the management of patients with essential hypertension. | American Journal of Hypertension. 2004. 17 (5 PART 2), 111A-112A. |
| Della Chiesa et al, 2003 | Sexual activity in hypertensive men. | Journal of Human Hypertension. 2003. 17 (8), 515-521. |
| Schmidt et al, 2001 | Antihypertensive effects of valsartan/hydrochlorothiazide combination in essential hypertension. | Blood Pressure. 2001, 10(4):230-7. |
| Waeber et al, 2001 | Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone. | Journal of Hypertension. 2001. 19 (11), 2097-2104. |
| Hilleman et al, 2001 | Cost-effectiveness evaluation of fixed-dose combination of angiotensin-II receptor blockers with and without hydrochlorothiazide. | American Journal of Hypertension. 2001. 14 (4 Pt 2), 112A-113A (Abs P-250). |
| Black et al, 2000 | Valsartan in combination with hydrochlorothiazide reduces the incidence of diuretic-induced hypokalemia: an integrated analysis of clinical data. | Journal of the Renin-Angiotensin-Aldosterone System. 2000. 1 (1), 102 (Abs PG. 18). |
8. Results of Trials
The key results from the published trials and associated reports
comparing the effectiveness as measured by mean change in blood
pressure (mmHg) showed that there was a statistically significant
difference in diastolic/systolic blood pressure (D/SBP), favouring
valsartan/HCTZ combination therapy, compared to either drug alone.
The PBAC considered that this is likely to be a clinically
important difference because of the size of the effect and
pharmacological plausibility.
The results from the published pharmacokinetic studies (apart from
Study 07) showed that
the combination therapy compared with the concomitant
administration of the separate components could be considered
bioequivalent.
Overall, the occurrence of adverse events was low and consistent
with the side effect profiles of the two component monotherapies.
The most common adverse events were headaches and dizziness.
9. Clinical Claim
The submission claimed that the fixed combination is as effective
as the individual components given concomitantly. The submission
claimed superior efficacy for the combination product compared to
constituent monotherapies.
For PBAC’s view, see Recommendations and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as fixed valsartan/HCTZ
combination once daily and concomitant valsartan and HCTZ once
daily.
11. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost/year to the PBS to be
less than $10 million in Year 4. The PBAC considered that the
submission’s estimate to be an underestimate.
12. Recommendation and Reasons
The PBAC recommended listing of valsartan with hydrochlorothiazide
in accordance with the combination guidelines, on a
cost-minimisation basis compared with its constituent components
valsartan and hydrochlorothiazide at equivalent doses.
The PBAC noted that valsartan will be supplied on the PBS from 1
March 2009 and therefore this combination product can only be
listed from that date.
The PBAC also noted that there is currently no evidence to support
an advantage in efficacy, safety or compliance for this combination
product over alternative therapy in accordance with subsection 101
(4AC) of the National Health Act.
Recommendation
VALSARTAN with HYDROCHLOROTHIAZIDE, tablets, 80 mg - 12.5 mg, 160
mg - 12.5 mg and 160 mg – 25 mg.
Restriction: Restricted benefit
Hypertension in patients who are not adequately controlled with
either hydrochlorothiazide or valsartan monotherapy.
Maximum quantity: 28
Repeats: 5
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor chose not to comment.
