DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle

Main information

  • Trade name:
  • DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 187395
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

187395

DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle

ARTG entry for

Medicine Registered

Sponsor

Alphapharm Pty Ltd

Postal Address

PO Box R1462,ROYAL EXCHANGE, NSW, 1225

Australia

ARTG Start Date

26/08/2014

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle

Product Type

Single Medicine Product

Effective date

7/01/2016

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Dilart™HCT is indicated for the treatment of hypertension. Treatment should not be initiated with these combinations.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

36 Months

Store below 25

degrees Celsius

Child resistant closure

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. DILART HCT 80/12.5 mg valsartan 80 mg/hydrochlorothiazide 12.5 mg film-coated tablet bottle

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

A light orange, film-coated, oval, biconvex tablet debossed with VH 1 on

one side of the tablet and M on other side.

Active Ingredients

Hydrochlorothiazide

12.5 mg

Valsartan

80 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

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Public Summary

Page 1 of

Produced at 29.11.2017 at 01:52:52 AEDT

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Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

DILART HCT

Valsartan and Hydrochlorothiazide Film-Coated Tablets

PRODUCT INFORMATION

NAME OF THE MEDICINE

Dilart

HCT is available in five strengths: Dilart HCT 80/12.5, Dilart HCT 160/12.5 Dilart HCT 160/25, Dilart

HCT 320/12.5 and Dilart HCT 320/25.

Active ingredient

Valsartan

Hydrochlorothiazide

Structural formula:

Molecular formula

Molecular weight

435.5

297.72

CAS Registry No.

137862-53-4

58-93-5

DESCRIPTION

Valsartan [N-Pentanoyl-N-[2’-(1H-tetrazol-5-yl)biphenyl-4ylmethyl]-L-valine] is a fine white powder soluble

in methanol, neutral and basic aqueous solutions, and very slightly soluble in solutions with pH < 7.

Hydrochlorothiazide

[6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide]

structurally related to the thiazide group of diuretics. It is a white or almost white powder. Hydrochlorothiazide

is very slightly soluble in water and freely soluble in dimethylsulfoxide.

Dilart HCT 80/12.5 contains valsartan 80 mg and hydrochlorothiazide 12.5 mg; Dilart HCT 160/12.5 contains

valsartan 160 mg and hydrochlorothiazide 12.5 mg; Dilart HCT 160/25 contains valsartan 160 mg and

hydrochlorothiazide 25 mg; Dilart HCT 320/12.5 contains valsartan 320 mg and hydrochlorothiazide 12.5 mg;

Dilart HCT 320/25 contains valsartan 320 mg and hydrochlorothiazide 25 mg.

Excipients

Valsartan

hydrochlorothiazide

tablets

80/12.5:

colloidal

anhydrous

silica;

sodium

lauryl

sulphate

crospovidone; povidone; magnesium stearate; microcrystalline cellulose; pregelatanized maize starch, lactose,

and proprietary ingredient Opadry II complete film coating system 03F84793 pink (ARTG no. 107334).

Valsartan

hydrochlorothiazide

tablets

160/12.5:

colloidal

anhydrous

silica;

sodium

lauryl

sulphate

crospovidone; povidone; magnesium stearate; microcrystalline cellulose; pregelatanized maize starch, lactose,

and proprietary ingredient Opadry II complete film coating system 03B57310 brown (ARTG no. 107338).

Dilart HCT – Product Information

Valsartan

hydrochlorothiazide

tablets

160/25:

colloidal

anhydrous

silica;

sodium

lauryl

sulphate

crospovidone; povidone; magnesium stearate; microcrystalline cellulose; pregelatanized maize starch, lactose,

and proprietary ingredient Opadry II complete film coating system 03F86873 brown (ARTG no. 107335).

Valsartan

hydrochlorothiazide

tablets

320/12.5:

colloidal

anhydrous

silica;

sodium

lauryl

sulphate

crospovidone; povidone; magnesium stearate; microcrystalline cellulose; pregelatanized maize starch, lactose,

and proprietary ingredient Opadry II complete film coating system 03F84782 pink (ARTG no. 107336).

Valsartan

hydrochlorothiazide

tablets

320/25:

colloidal

anhydrous

silica;

sodium

lauryl

sulphate

crospovidone; povidone; magnesium stearate; microcrystalline cellulose; pregelatanized maize starch, lactose,

and proprietary ingredient Opadry II complete film coating system 03F82965 yellow (ARTG no. 107337).

PHARMACOLOGY

Pharmacodynamics

The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from

angiotensin I through angiotensin converting enzyme (ACE). Angiotensin II binds to specific receptors located

in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular

both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin

II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone

secretion.

Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on

the AT

receptor subtype, which is responsible for the known actions of angiotensin II. The AT

receptor subtype

has not been definitely shown to be associated with cardiovascular homeostasis. The increased plasma levels of

Ang II following AT

receptor blockade with valsartan may stimulate the unblocked AT

receptor. This may

counteract the effect of blocking the AT

receptor. Valsartan does not exhibit any partial agonist activity at the

receptor and about a 20,000-fold greater affinity for the AT

receptor than for the AT

receptor.

Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades

bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II

antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE

inhibitor, the incidence of dry cough was significantly (P < 0.05) less in patients treated with valsartan than in

those treated with an ACE inhibitor (2.4% versus 7.9% respectively). In a clinical trial of patients with a history

of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those

receiving a thiazide diuretic experienced cough, compared to 68.9% of those treated with an ACE inhibitor (P <

0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in

cardiovascular regulation.

Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting

pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2

hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists

over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure

with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. When valsartan

is combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.

In multiple dose studies in hypertensive patients valsartan had no notable effects on total cholesterol, fasting

triglycerides, or fasting serum glucose. Valsartan has no uricosuric effect.

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that

there is a high affinity receptor in the renal cortex with the primary binding site for the thiazide diuretic action

and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through

inhibition of the Na

symporter which affects mechanisms of electrolyte reabsorption. Inhibition of the Na

Dilart HCT – Product Information

symporter directly increases excretion of sodium and chloride in approximately equivalent amounts. It also

indirectly reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and

urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin

II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated

with these diuretics.

Pharmacokinetics

Valsartan

Peak plasma concentrations are reached 2 to 4 hours after dosing. The amount absorbed varies widely. Mean

absolute bioavailability is 23% and the bioavailability relative to an oral solution is 59%.

The pharmacokinetics of valsartan are linear over the dose range 80-320 mg. There is no change in the kinetics

of valsartan on repeated administration and little accumulation when dosed once daily. Plasma concentrations are

similar in males and females.

When valsartan is given with food, the area under the plasma concentration-time curve (AUC) of valsartan is

reduced by 48% although, from about 8 h post dosing, plasma valsartan concentrations are similar for the fed and

fasted group.

Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady-state volume of distribution

is low (about 17 L) indicating that valsartan does not distribute into tissues extensively.

Valsartan

does

not undergo extensive

biotransformation. Only approximately

of absorbed drug

metabolised. The primary metabolite is valeryl 4-hydroxy valsartan, which is pharmacologically inactive. The

enzyme(s) responsible for valsartan metabolism have not been identified.

Valsartan shows bi-exponential decay kinetics with a t

1/2α

of about 1h and a t

1/2β

of about 9.5 hours. After oral

dosing, 83% of the dose is excreted in the faeces and 13% in the urine, mainly as unchanged compound. Following

intravenous administration, renal clearance of valsartan accounts for about 30% of total plasma clearance. Plasma

clearance is relatively slow (about 2 L/h) when compared with hepatic blood flow (about 30 L/h).

Hydrochlorothiazide

The absorption of hydrochlorothiazide after an oral dose is rapid (t

about 2 hours), with similar absorption

characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-

80% after oral administration.

The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the

kinetics of hydrochlorothiazide on repeated administration, and accumulation is minimal when administered once

daily.

The distribution and elimination kinetics have generally been described by a bi-exponential decay function, with

a terminal half-life of 6-15 hours. Greater than 95% of the absorbed dose is excreted as unchanged compound in

the urine.

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan.

Co-administration of hydrochlorothiazide decreased peak concentrations of valsartan by 13% and systemic

exposure to valsartan by 17%. This observed interaction has no impact on the combined use of valsartan and

hydrochlorothiazide, since controlled clinical trials have shown a clear antihypertensive effect, greater than that

obtained with either drug administered alone, or placebo.

Pharmacokinetics in the elderly

Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly

compared to younger patients.

Dilart HCT – Product Information

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and

hypertensive elderly subjects compared to young healthy volunteers. No dosage adjustment of valsartan and

hydrochlorothiazide tablets is necessary in elderly patients.

Pharmacokinetics in children

The pharmacokinetics of valsartan and hydrochlorothiazide tablets have not been investigated in children.

Pharmacokinetics in patients with renal impairment

As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, there is no

apparent correlation between renal function (measured by creatinine clearance) and systemic exposure to

valsartan (measured by AUC) in patients with different degrees of renal failure. A trial in 5 normotensive patients

undergoing haemodialysis demonstrated that complete loss of renal function does not lead to a gross increase in

the exposure to valsartan and does not have a major impact on the kinetics of valsartan. This study also confirmed

that valsartan is not removed from the plasma by haemodialysis.

Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule.

As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked

effect on the kinetics of hydrochlorothiazide (see CONTRAINDICATIONS and PRECAUTIONS).

In patients with severe renal impairment (creatinine clearance <30 mL/min) and patients undergoing dialysis, no

data are available for valsartan and hydrochlorothiazide tablets (see CONTRAINDICATIONS).

Pharmacokinetics in patients with hepatic impairment

About 70% of the absorbed valsartan dose is excreted in the bile, mainly as unchanged compound. The AUC

with valsartan has been observed to approximately double in patients with mild or moderate hepatic impairment

including patients with biliary obstructive disorders (see PRECAUTIONS - Impaired hepatic function). There

data

available

valsartan

patients

with

severe

hepatic

dysfunction

(see

CONTRAINDICATIONS).

Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.

CLINICAL TRIALS

The combination of valsartan and hydrochlorothiazide in once daily doses ranging from 80/12.5 mg to 160/25

mg was studied in three controlled studies (19, 301 and 201) and two uncontrolled studies (11E and 31E) in

patients with hypertension.

Study 19 evaluated the effect of valsartan monotherapy (80 mg and 160 mg) and valsartan 80 mg in combination

with 12.5 mg or 25 mg hydrochlorothiazide. A total of 708 patients whose hypertension remained inadequately

controlled after 4 weeks of treatment with valsartan 80 mg were randomised to one of four treatments for an 8-

week period. Valsartan 80 mg combined with either 12.5 mg or 25 mg hydrochlorothiazide produced a greater

blood pressure lowering effect than increasing the dose of valsartan to 160 mg. The additional diastolic blood

pressure reduction with valsartan 80 mg/hydrochlorothiazide 12.5 mg was a statistically (p=0.002) and clinically

(3.2mmHg) significant improvement over 80 mg valsartan.

Study 301 was a placebo controlled, randomised, double-blind study to evaluate the efficacy, safety and

tolerability of once daily dosing of 25 mg or 12.5 mg hydrochlorothiazide in combination with valsartan 80 mg

or 160 mg in hypertensive patients. In this study, 871 patients were randomised into one of nine treatment groups

for an 8-week period. The primary efficacy variable was the mean change from baseline in trough sitting diastolic

blood pressure (MSDBP). Secondary efficacy variables were mean change from baseline in trough sitting systolic

blood pressure (MSSBP) and response rates, defined as the proportion of patients with SDBP <90 mmHg at

endpoint or a drop ≥10 mmHg from base line.

The decrease in blood pressure with the combination of valsartan 160 mg with either 12.5 or 25 mg

hydrochlorothiazide was clinically and statistically significantly greater than placebo or monotherapy with

Dilart HCT – Product Information

valsartan 160 mg or the corresponding does of hydrochlorothiazide alone. A positive dose response in MSDBP,

and in MSSBP was observed when either hydrochlorothiazide dose was combined with valsartan 80 mg or 160

following

table

summarises

additional

blood

pressure

reduction

seen

with

valsartan

hydrochlorothiazide tablets compared to monotherapy and placebo.

Table 1

Study

301

Additional

blood

pressure

reduction

(MSSBP

/

MSDBP,

mmHg)

with

valsartan/hydrochlorothiazide combination therapy compared to valsartan and hydrochlorothiazide

monotherapy and placebo.

Additional blood pressure reduction

with:

Valsartan and

hydrochlorothiazide

Tablets 80/12.5

Valsartan and

hydrochlorothiazide

Tablets 160/12.5

Valsartan and

hydrochlorothiazide

Tablets 160/25

Compared to:

valsartan 80 mg

7.7 / 3.2

valsartan 160 mg

5.6 / 4.1

10.3 / 5.9

hydrochlorothiazide 12.5 mg

9.2 / 4.7

10.5 / 6.4

hydrochlorothiazide 25 mg

9.7 / 6.0

placebo

14.6 / 7.7

15.8 / 9.4

20.5 / 11.2

Study 201 was an active controlled, randomised, double-blind study to compare the combination of valsartan 160

mg plus hydrochlorothiazide at doses of 12.5 mg and 25 mg with valsartan 160 mg monotherapy in patients

whose hypertension was inadequately controlled (i.e. 95 mmHg < MSDBP < 110 mmHg) after 4 weeks on

valsartan 160 mg monotherapy. In this study, 2002 patients were randomized into three treatment arms for a

duration of 8-weeks.

The addition of 12.5 mg HCT to valsartan 160 mg resulted in additional lowering of systolic BP of 3.74 mmHg

and diastolic BP of 1.65 mmHg compared to valsartan alone. The addition of 25 mg HCT to valsartan 160 mg

resulted in an additional lowering of 5.92 mmHg systolic BP and 3.16 mmHg diastolic BP compared to valsartan

alone.

The main objective for the extension studies 11E and 31E was to obtain long term tolerability, safety and efficacy

data in adult patients with hypertension treated with valsartan and hydrochlorothiazide. Patients whose blood

pressure was inadequately controlled in the extension phase of these studies could have hydrochlorothiazide 12.5

or 25 mg in addition to valsartan therapy. More than 350 patients were treated with hydrochlorothiazide in

combination with valsartan for a period of one to three years.

These studies demonstrated that long-term treatment with valsartan in combination with hydrochlorothiazide was

efficacious in lowering blood pressure and maintained significant antihypertensive effect in patients with

hypertension, with no evidence of development of tolerance. These studies also demonstrated that long-term

combination treatment was safe and well-tolerated.

The combination of valsartan and hydrochlorothiazide in once daily doses of 320/12.5 mg and 320/25 mg has

been shown to be efficacious in the treatment of patients with essential hypertension in a large placebo-controlled

study C2301; and in the treatment of patients with essential hypertension not adequately controlled with valsartan

320 mg monotherapy in an active-controlled study C2302.

Study C2301 was a multicenter, double-blind, randomized, placebo-controlled, multifactorial, 8-arm parallel

design study comparing the efficacy and safety of the combination therapy of valsartan/HCT (320/12.5 mg,

320/25 mg, 160/12.5 mg) to their respective monotherapies, valsartan (160 mg, 320 mg), HCT (12.5 mg, 25 mg)

or to placebo once daily for 8 weeks in patients with essential hypertension (MSDBP ≥ 95 mmHg and < 110

mmHg). The first week post-randomization was a forced titration period for patients randomized to the

valsartan/HCT 320/12.5 and 320/25 mg treatment groups. During this period, patients randomized to the

valsartan/HCT 320/12.5 and 320/25 mg treatment groups received valsartan/HCT 160/12.5 mg, while patients

randomized to the remaining six treatment groups received their respective final doses. From the second post-

randomization week through the end of the study (week 8), all treatment groups received their final dose giving

a minimum of 7 weeks on each of the final doses. A total of 1652 patients were enrolled into the single-blind

Dilart HCT – Product Information

period of the study and 1346 patients were randomized into the double-blind treatment phase. A total of 1329

patients were included in the primary efficacy population (ITT) and 1161 patients completed the study.

In patients with essential hypertension, global assessment of MSDBP and MSSBP reductions at endpoint shows

that both monotherapy treatments contribute to the overall effect of the combination treatment on blood pressure

reduction (p < 0.0001 for both valsartan and HCT).

Statistically significant greater reductions in both MSDBP and MSSBP were observed for both valsartan/HCT

320/12.5 mg and valsartan/HCT 320/25 mg compared with placebo and each of the respective monotherapy doses

(p < 0.0001 for all comparisons).

These results with both valsartan 320 mg/HCT combinations were clinically relevant with minimum differences

in MSDBP of at least 8.0 mmHg compared to placebo and at least 3.6 mmHg compared to their respective

monotherapies. Similarly, the results in MSSBP were clinically relevant with minimum differences of at least

15.8 mmHg compared to placebo and at least 8.0 mmHg compared to their respective monotherapies. These

results were valid across age, race and gender subgroups.

Dose-dependent hypokalaemia occurred in controlled clinical studies with valsartan + HCT. Hypokalaemia

occurred more frequently in patients given 25 mg HCT than in those given 12.5 mg HCT.

Dose-dependent orthostatic reactions were reported in < 1 % of patients given a combination of valsartan + HCT.

A dose-dependent increase in the frequency of “dizziness” was reported in patients treated with doses ranging

from valsartan 80 mg + HCT 12.5 mg to valsartan 160 mg + HCT 25 mg. In a non-controlled study in which

valsartan and hydrochlorothiazide tablets 160 mg/25 mg were given for 4 weeks to patients who had not been

adequately treated with valsartan 160 mg and HCT 12.5 mg, total cholesterol rose from 209 to 220 mg/dl.

Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and

morbidity are currently unknown.

Table 2 Study C2301 Additional blood pressure reduction (MSSBP / MSDBP, mmHg) with Dilart HCT

compared to valsartan and hydrochlorothiazide monotherapy and placebo at endpoint (ITT population)

Additional blood pressure reduction

with:

Valsartan and

hydrochlorothiazide

Tablets 160/12.5

Valsartan and

hydrochlorothiazide

Tablets 320/12.5

Valsartan and

hydrochlorothiazide

Tablets 320/25

Compared to:

valsartan 160 mg

5.9/3.5

valsartan 320 mg

8.0/3.7

11.0/5.3

hydrochlorothiazide 12.5 mg

9.2/6.2

10.5/6.0

hydrochlorothiazide 25 mg

10.2/5.8

valsartan/hydrochlorothiazide 160/12.5mg

4.3/1.4

placebo

14.4/8.2

15.8/8.0

18.8/9.6

* no significant difference observed between 320/12.5 vs. 160/12.5

Study C2302 was a multicenter, double-blind, randomized, active-controlled, parallel design study comparing

the efficacy and safety of the combination therapy of valsartan/HCT (320/12.5 mg, 320/25 mg) to the valsartan

320 mg monotherapy once daily for 8 weeks in patients with essential hypertension (MSDBP ≥ 90 mmHg and <

110 mmHg) not adequately controlled with valsartan 320 mg monotherapy. After a 1 to 4 week washout phase,

patients started the 4-week valsartan 320 mg run-in phase. Patients responding to treatment were discontinued

from the study, while patients not adequately controlled (MSDBP ≥ 90 mmHg and < 110 mmHg) entered the 8-

week double-blind phase and were randomized to one of three treatment groups: valsartan 320 mg, valsartan/HCT

320/12.5 mg or valsartan/HCT 320/25 mg. In total, 3805 patients were enrolled into the single-blind period of

the study and 2702 patients were randomized into the double-blind treatment phase. A total of 2675 patients were

included in the primary efficacy population (ITT) and 2579 patients completed the study.

In patients whose blood pressure was not adequately controlled with valsartan monotherapy, all treatments

produced reductions in MSDBP and MSSBP from baseline to endpoint. The reduction in MSDBP and MSSBP

Dilart HCT – Product Information

at endpoint was statistically significantly greater for the valsartan/HCT 320/12.5 mg and 320/25 mg combinations

than for valsartan 320 mg monotherapy (p < 0.0001).

The reductions in BP at endpoint with both valsartan/HCT combinations were clinically relevant compared to

valsartan monotherapy with minimum differences in MSDBP of at least 3.9 mmHg and minimum differences in

MSSBP of at least 7.5 mmHg. These results were valid across age and gender subgroups.

Diastolic response rates were 74.9% in the valsartan/HCT 320/25 mg and 68.8% in the valsartan/HCT 320/12.5

mg groups. Both combination doses show clinically and statistically greater diastolic response rates than the

valsartan monotherapy (52.7%). Similarly, diastolic control rates were significantly greater with valsartan/HCT

320/25 mg and 320/12.5 mg than with valsartan monotherapy (70.6%, 65.3% and 49.8%, respectively).

These efficacy results demonstrate that patients not adequately controlled with valsartan 320 mg benefit from

clinically relevant additional BP reductions when treated with the valsartan/HCT combinations.

No specific studies were performed to assess the efficacy of valsartan and hydrochlorothiazide Tablets in patients

inadequately controlled on hydrochlorothiazide alone, or to determine in direct comparison the difference

between valsartan and hydrochlorothiazide Tablets 160/25 mg and 320/25 mg.

INDICATIONS

Dilart HCT is indicated for the treatment of hypertension. Treatment should not be initiated with these

combinations.

CONTRAINDICATIONS

Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the

excipients of Dilart HCT; pregnancy; severe hepatic impairment; biliary cirrhosis and cholestasis; anuria; severe

renal impairment (creatinine clearance < 30 mL/min); refractory hypokalaemia, hyponatraemia, hypercalcaemia,

and symptomatic hyperuricaemia; concomitant use with aliskiren in patients with Type 2 diabetes mellitus (see

INTERACTIONS WITH OTHER MEDICINES).

PRECAUTIONS

Serum electrolyte changes

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium,

or other drugs that may increase potassium levels (heparin, etc.) should be used with caution. Thiazide diuretics

can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be

administered with caution in patients with conditions involving enhanced potassium loss, for example salt losing

nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia is accompanied by

clinical signs (e.g. muscular weakness, paresis, or ECG alterations), valsartan and hydrochlorothiazide tablets

should be discontinued. Correction of hypokalaemia and any coexisting hypomagnesaemia is recommended prior

to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. All

patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.

Regular monitoring of serum sodium concentrations is recommended. Treatment with thiazide diuretics,

including

hydrochlorothiazide,

been

associated

with

hyponatraemia

hypochloraemic

alkalosis.

Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been

observed

isolated

cases.

Thiazides,

including

hydrochlorothiazide,

increase

urinary

excretion

magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This

may result in hypercalcaemia.

Periodic determination of serum electrolytes should be performed at appropriate intervals.

Dilart HCT – Product Information

Sodium- and/or volume-depleted patients

In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics,

symptomatic

hypotension

occur

rare

cases

after

initiation

therapy

with

valsartan

hydrochlorothiazide tablets. Sodium and/or volume depletion should be corrected before starting treatment with

valsartan and hydrochlorothiazide tablets.

If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous

infusion of normal saline. Treatment can be continued once the blood pressure has stabilised.

Patients with severe chronic heart failure or other conditions with stimulation of the renin-

angiotensin-aldosterone-system

In patients whose renal function may depend on the activity of the renin-angiotensin aldosterone system (e.g.

patients with severe heart failure), treatment with angiotensin converting enzyme inhibitors has been associated

with oliguria and/or progressive azotaemia and in rare cases with acute renal failure. The use of valsartan and

hydrochlorothiazide tablets in patients with severe heart failure has not been established. Hence it cannot be

excluded that because of the inhibition of the renin-angiotensin-aldosterone system the use of valsartan and

hydrochlorothiazide tablets may as well be associated with impairment of the renal function. Valsartan and

hydrochlorothiazide tablets should not be used in these patients.

Renal artery stenosis

There is an increased risk of severe hypotension and renal insufficiency when patients with unilateral or bilateral

renal artery stenosis or stenosis to a solitary kidney are treated with agents that affect the renin-angiotensin-

aldosterone system. Dilart HCT should be used with caution, since blood urea and serum creatinine may increase

in such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive drugs acting through the

renin-angiotensin aldosterone system therefore use of valsartan and hydrochlorothiazide tablets in these patients

is not recommended.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with all other vasodilators, special caution is indicated when using valsartan and hydrochlorothiazide tablets

in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy

(HOCM).

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face,

lips, pharynx and/or tongue has been reported in patients treated with valsartan; some of these patients previously

experienced angioedema with other drugs including ACE inhibitors. Valsartan and hydrochlorothiazide tablets

should be immediately discontinued in patients who develop angioedema, and should not be re-administered.

Dual blockade of the Renin-Angiotensin System (RAS)

Caution is required while co-administering angiotensin receptor antagonists (ARBs), including valsartan, with

other agents blocking the RAS such as ACE inhibitors or aliskiren (see INTERACTIONS WITH OTHER

MEDICINES).

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus

erythematosus.

Dilart HCT – Product Information

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of

cholesterol, triglycerides, and uric acid. Like other diuretics, hydrochlorothiazide, may raise the serum uric acid

level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia and precipitate gout in

susceptible patients.

Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of

known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations,

it should be used with caution in patients with hypercalcaemia. Marked hypercalcaemia unresponsive to thiazide

withdrawal or

12 mg/dL may be evidence of an underlying thiazide independent hypercalcaemic process.

Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphataemia have been

observed in a few patients on prolonged thiazide therapy. If hypercalcaemia occurs, further diagnostic

clarification is necessary.

Acute Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in acute

transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or

ocular pain and typically occur within hours to week of a drug initiation. Untreated acute-angle closure glaucoma

can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical

treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing

acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs

during treatment, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary,

it is recommended to protect exposed areas to the sun or to artificial UVA.

General

Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Use in patients with renal impairment

Renal function has a marked effect on the kinetics of hydrochlorothiazide (see PHARMACOKINETICS –

Renal Impairment). Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease.

Valsartan and hydrochlorothiazide tablets should be used with caution in patients with moderate renal impairment

(creatinine clearance > 30 mL/min). Periodic checks of serum potassium, creatinine and uric acid levels are

advisable.

Patients with severe renal impairment (creatinine clearance < 30 mL/min) should not take valsartan and

hydrochlorothiazide tablets (see CONTRAINDICATIONS).

Use in patients with hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis valsartan and hydrochlorothiazide

tablets should be used with caution (see PHARMACOKINETICS – Hepatic Impairment). Patients with severe

hepatic impairment, biliary cirrhosis or cholestasis should not take valsartan and hydrochlorothiazide tablets (see

CONTRAINDICATIONS).

Thiazides, like other diuretics, may precipitate electrolyte imbalance, hepatic encephalopathy and hepato-renal

syndrome when used to treat cirrhotic ascites.

Dilart HCT – Product Information

Effects on ability to drive and use machinery

When driving vehicles or operating machinery, it should be taken into account that occasionally dizziness may

occur during treatment of hypertension.

Children

The safety and efficacy of valsartan and hydrochlorothiazide tablets have not been established in children.

Carcinogenicity and Mutagenicity

combination

valsartan/hydrochlorothiazide

tested

mutagenicity,

clastogenicity,

carcinogenicity.

Valsartan

In animal studies there was no clear evidence of carcinogenic activity when valsartan was administered in the

diet to male and female mice at doses up to 160 mg/kg/day for two years, but systemic exposure (plasma AUC

value) at this dose level was lower than that achieved in humans. There was no clear evidence of carcinogenic

activity in male or female rats at up to 200 mg/kg/day with plasma concentrations approximately 3 times the

concentrations achieved in humans (based on AUC) at the maximum recommended dose (320/25 mg).

Genetic toxicology studies showed that valsartan does not cause gene mutation in bacteria or mammalian cells,

nor does it induce chromosomal damage in vitro or in vivo.

Hydrochlorothiazide

Two-year feeding studies in mice and rats showed no evidence of carcinogenic potential in female mice at doses

up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day.

However, there was equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide

alone at approximately 600 mg/kg/day.

Hydrochlorothiazide did not induce gene mutation in bacteria or chromosome damage in mammalian cells in

several in vitro and in vivo assays. However positive results were obtained in a mammalian cell assay for gene

mutation (mouse lymphoma cell assay) and in two other tests (sister chromatid exchange assay in Chinese

hamster ovary cells and nondisjunction assay in Aspergillus nidulans).

Effects on Fertility

The effects of valsartan and hydrochlorothiazide in combination and hydrochlorothiazide alone on fertility have

not been investigated.

Fertility of male and female rats was not affected at oral doses of valsartan up to 200 mg/kg/day, with plasma

concentrations approximately 2 times the concentrations achieved in humans (based on AUC) at the maximum

recommended dose.

Use in Pregnancy (Category D)

Valsartan and hydrochlorothiazide tablets should not be used during pregnancy (see CONTRAINDICATIONS)

or in women planning to become pregnant. Physicians prescribing any agents acting on the RAAS should counsel

women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is

detected during therapy, valsartan and hydrochlorothiazide tablets should be discontinued as soon as possible.

Drugs that act on the renin-angiotensin-aldosterone system (RAAS) can cause fetal and neonatal morbidity and

death when administered to pregnant women. Several dozen cases have been reported in the world literature in

patients who were taking angiotensin converting enzyme inhibitors (a specific class of drugs acting on the RAAS).

Due to the mechanism of action of angiotensin II antagonists, a risk to the fetus cannot be excluded. The use of

drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) during the second and third trimesters

Dilart HCT – Product Information

of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,

anuria, reversible or irreversible renal failure and death. In addition, in retrospective data, first trimester use of

ACE inhibitors has been associated with a potential risk of birth defects. Intrauterine exposure to thiazide diuretics,

including hydrochlorothiazide, is associated with fetal or neonatal thrombocytopenia, and may be associated with

other adverse reactions that have occurred in adults. There have been reports of spontaneous abortion,

oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.

There was no evidence of teratogenicity in mice, rats and rabbits dose with the valsartan/hydrochlorothiazide

combination during organogenesis at up to 600/187.5, 200/62.5 and 100/3.125 mg/kg/day PO, respectively.

Fetotoxicity

observed

association

with

maternal

toxicity

rats

rabbits

valsartan/hydrochlorothiazide doses of 200/62.5 mg/kg/day and 100/3.125 mg/kg/day. Decreased fetal weights,

absent renal papillae and delayed ossification were observed in rats and increased late resorptions in rabbits.

No teratogenic effects were observed when valsartan alone was administered orally to mice and rats at a dose of

600 mg/kg/day and to rabbits at a dose of 10 mg/kg/day during the period of organogenesis. However, foetal

losses were observed at the highest dose level in rabbits, and foetal weight was reduced at 600 mg/kg/day in rats

and at 5 mg/kg/day in rabbits.

Administration of 600 mg/kg/day valsartan to rats prior to parturition and during lactation caused a decrease in

birth weight, a reduction in post-natal growth and survival, and a slight delay in physical development of the

offspring. A reduction of red blood cell parameters and evidence of changes in renal haemodynamics were

observed at 200-600 mg/kg/day.

Use in Lactation

It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats.

Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use valsartan

and hydrochlorothiazide tablets in breast-feeding mothers.

There are no studies with the valsartan/hydrochlorothiazide combination in lactating animals. A peri/postnatal

study in rats with valsartan showed reductions in post-natal growth and survival, and a slight delay in physical

development of the offspring when valsartan was administered to rats prior to parturition and during lactation at

600 mg/kg/day. No effects were observed at 200 mg/kg/day.

INTERACTIONS WITH OTHER MEDICINES

Valsartan-hydrochlorothiazide

The following drug interactions may occur due to both components (valsartan and/or hydrochlorothiazide) of

Dilart HCT:

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent

administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides. Since renal

clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with

valsartan and hydrochlorothiazide tablets Therefore, careful monitoring of serum lithium concentrations is

recommended during concomitant use.

Valsartan

In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following

drugs: cimetidine, warfarin, frusemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine,

glibenclamide.

As valsartan is not metabolised to a significant extent, clinically relevant drug-drug interactions in the form of

metabolic induction or inhibition of the cytochrome P450 system are not expected with valsartan. Although

Dilart HCT – Product Information

valsartan is highly bound to plasma proteins, in vitro studies have not shown any interaction at this level with a

range of molecules which are also highly protein-bound, such as diclofenac, frusemide, and warfarin.

Combination use of ACE inhibitors or angiotensin receptor antagonist, thiazide diuretics and anti-

inflammatory drugs (NSAIDs or COX-2 inhibitors)

When

angiotensin

antagonists

administered

simultaneously

with

NSAIDs,

attenuation

antihypertensive effect may occur.

Furthermore, the use of an ACE inhibiting drug (ACE-inhibitors) or angiotensin receptor antagonist, a thiazide

diuretic (including hydrochlorothiazide), and an anti-inflammatory drug (NSAID or COX-2 inhibitor) at the same

time increases the risk of renal impairment. Concomitant use of angiotensin II antagonists and NSAIDs in patients

who are elderly, volume-depleted (including those on diuretic therapy) or have compromised renal function may

lead to an increased risk of worsening renal function, including possible acute renal failure. This includes use in

fixed combination products containing more than one class of drug. Combined use of these medications should

be accompanied by increased monitoring of serum creatinine, particularly when initiating or modifying treatment.

Dual blockade of the renin-angiotensin system (RAS) with ARBs, ACEIs or aliskiren

The concomitant use of ARBs, including valsartan, with other agents acting on the RAS is associated with an

increased incidence of hypotension, hyperkalaemia, and changes in renal function compared to monotherapy. It

is recommended to monitor blood pressure, renal function and electrolytes in patients on valsartan and

hydrochlorothiazide tablets and other agents that affect the RAS (see PRECAUTIONS).

The concomitant use of ARBs including valsartan, or ACEIs, with aliskiren is contraindicated in patients with

Type 2 diabetes mellitus (see CONTRAINDICATIONS).

Potassium

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium,

or other drugs that may alter potassium levels (heparin, etc.) should be used with caution and with frequent

monitoring of potassium (see PRECAUTIONS – Serum electrolyte changes).

Hepatic transporters

Co-administration with inhibitors of the hepatic uptake transporter OATP1B1 (such as rifampicin, cyclosporin)

or hepatic efflux transporter MRP2 (e.g. ritonavir) may increase the systemic exposure to valsartan.

Hydrochlorothiazide

Other diuretics and antihypertensive agents

The antihypertensive effect may be increased with concomitant use of other antihypertensive drugs (e.g.

guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers). The thiazide component of

valsartan and hydrochlorothiazide tablets may enhance the hyperglycemic effect of beta-blockers and diazoxide.

Drugs used during surgery

Thiazides, including hydrochlorothiazide, potentiate the action of non-depolarising muscle relaxants (e.g. curare

derivatives).

Non-steroidal anti-inflammatory drugs

Concomitant administration of NSAIDs (e.g. salicylic acid derivatives indomethacin) including Selective

Cyclooxegase-2 Inhibitors (COX-2 Inhibitors) may weaken the diuretic and antihypertensive activity of the

thiazide component of valsartan and hydrochlorothiazide. Concurrent hypovolaemia may induce acute renal

failure. In patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised

renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of

Dilart HCT – Product Information

worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or

modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.

Antidiabetic agents

Thiazide diuretics, including hydrochlorothiazide, may increase blood glucose. It may prove necessary to readjust

the dosage of insulin and of oral antidiabetic agents.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects, favoring the onset of

digitalis-induced cardiac arrhythmias.

Hypokalaemic agents

The hypokalaemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics,

amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics. If these medicinal

products are to be prescribed with the hydrochlorothiazide-valsartan combination, monitoring of potassium

plasma levels is advised. These medicinal products may potentiate the effect of hydrochlorothiazide on serum

potassium (see PRECAUTIONS - Serum electrolyte changes).

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when valsartan and hydrochlorothiazide

tablets is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis

glycosides, antiarrhythmics) and the torsades de pointes inducing medicinal products (which include some

antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes.

Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as

antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs.

Allopurinol

Co-administration

thiazide

diuretics

(including

hydrochlorothiazide)

increase

incidence

hypersensitivity reactions to allopurinol.

Anticholinergic agents

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden),

apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic

drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.

Pressor amines

The effect of pressor amines (e.g. noradrenaline) may be decreased.

Cholestyramine and colestipol resins

Single doses of cholestyramine or colestipol resins reduced the absorption of hydrochlorothiazide by up to 85

and 43 percent respectively.

Corticosteroids, ACTH

Electrolyte depletion, particularly hypokalaemia, may be increased.

Dilart HCT – Product Information

Treatments for gout

Co-administration

thiazide

diuretics,

including

hydrochlorothiazide,

increase

incidence

hypersensitivity reactions to allopurinol. Thiazides may also increase serum uric acid levels, and the dose of

uricosuric agents such as probenacid or sulfinpyrazone may need to be increased.

Tetracyclines

Concomitant administration of tetracyclines and thiazide diuretics increases the risk for tetracycline induced

increase in urea. This interaction is probably not applicable to doxycycline.

Alcohol, anaesthetics and sedatives

Potentiation of orthostatic hypotension may occur.

Iodine contrast media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses

of the iodine product. Patients should be rehydrated before the administration.

Other interactions

Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the risk of adverse effects

caused by amantadine, and may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide,

methotrexate) and potentiate their myelosuppressive effects.

There

have

been

reports

literature

hemolytic

anemia

occurring

with

concomitant

hydrochlorothiazide and methyldopa.

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may

potentiate the rise in serum calcium.

Concomitant treatment with cyclosporin may increase the risk of hyperuricemia and gout-type complications.

Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia. Such

patients should therefore be advised about the possibility of hyponatremic reactions, and should be monitored

accordingly.

ADVERSE EFFECTS

Valsartan and hydrochlorothiazide tablets has been evaluated for safety in more than 5700 patients. Adverse

experiences have generally been mild and transient in nature.

The following table of adverse experiences is based on five controlled trials involving a total of 7616 patients

(study Protocols 201, 301, 19, C2301 and C2302). Of the 7616 patients receiving valsartan in combination with

hydrochlorothiazide, 4372 received one of the marketed doses. All adverse experiences showing an incidence of

1% or more in the valsartan and hydrochlorothiazide tablets group are included in the following table, irrespective

of their causal association with the study drug.

Valsartan and

hydrochlorothiazide tablets

n=4372

%

Placebo

n=262

%

Infections and infestations

Nasopharyngitis

Upper respiratory tract infection

Nervous system disorders

Headache NOS

14.5

Dizziness (excl. vertigo)

Dilart HCT – Product Information

Musculoskeletal & connective tissue disorders

Back pain

Arthralgia

Gastrointestinal disorders

Diarrhoea NOS

General disorders & administration site

conditions

Fatigue

Respiratory, thoracic & mediastinal disorders

Cough

† Includes combinations of valsartan 80 mg / HCT 12.5 mg, valsartan 160 mg /HCT 12.5 mg, valsartan 160mg /HCT 25 mg, 320

mg/12.5 mg and 320 mg/25 mg.

‡ Nasopharyngitis including pharyngitis + rhinitis HCT = Hydrochlorothiazide; NOS = Not otherwise specified;

Other adverse experiences with a frequency below 1% included abdominal pain, abdominal pain upper, alopecia,

anaemia, anxiety, arrhythmia, arthritis, asthenia, bilirubin increase, bronchitis, bronchitis acute, chest pain,

dehydration, dizziness postural, dyspepsia, dyspnoea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis,

haemorrhage, hyperhidrosis, hypoaesthesia, hypokalaemia, hyponatraemia, hypotension, influenza, insomnia,

muscle spasms, muscle strain, muscular weakness, nausea, nasal congestion, neck pain, oedema, oedema

peripheral, otitis media, pain in extremity, palpitations, paraesthesia, pharyngolaryngeal pain, pollakiuria, pyrexia,

serum uric acid increased, sinus congestion, sinusitis, somnolence, ligament sprain, syncope, tachycardia, tinnitus,

urinary tract infection, vertigo, viral infection, vision blurred, vision disturbance. It is unknown whether these

effects were causally related to the therapy.

Post-marketing data

Very rare cases of angioedema, rash, pruritus, and other hypersensitivity/allergic reactions including serum

sickness, and vasculitis have been reported. Very rare cases of impaired renal function, and myalgia have also

been reported. Several cases of hydrochlorothiazide-induced pulmonary oedema with granulocytic infiltration

and IgG deposition in alveolar membranes have been reported. Non-cardiogenic pulmonary oedema may be an

immunologically

mediated

rare

idiosyncratic

reaction

hydrochlorothiazide.

Very

rare

cases

thrombocytopenia have been reported.

Laboratory findings

A greater than 20% decrease in serum potassium was observed in 3.7% of patients receiving valsartan and

hydrochlorothiazide tablets as compared to placebo (3.1%) (see PRECAUTIONS – Serum electrolyte changes).

Elevations in creatinine and blood urea nitrogen (BUN) occurred in 1.9% and 14.7% respectively, of patients

taking valsartan and hydrochlorothiazide tablets and 0.4% and 6.3% respectively, given placebo in controlled

clinical trials.

Neutropenia was observed in 0.1 % of patients treated with valsartan and hydrochlorothiazide tablets versus 0.4 %

of patients treated with placebo.

Additional information on the individual components

Valsartan

Other adverse experiences that occurred in controlled clinical trials of patients treated with valsartan (>0.2% of

valsartan patients) are listed below. It cannot be determined whether these events were causally related to

valsartan.

Blood and lymphatic system:

decrease in haemoglobin, decrease in haematocrit

Body as a whole:

oedema, allergic reactions and asthenia

Cardiovascular:

palpitations

Dilart HCT – Product Information

Dermatologic:

pruritus and rash

Gastrointestinal:

abdominal

pain,

constipation,

diarrhoea,

mouth,

dyspepsia

flatulence

Infections and infestations:

viral infections, pharyngitis, sinusitis, upper respiratory tract infection

Metabolism and nutrition:

increase of serum potassium

Musculoskeletal:

back pain, muscle cramps, arthralgia and myalgia

Neurologic and psychiatric:

anxiety, insomnia, paraesthesia and somnolence, neuralgia, libido decrease

Respiratory:

dyspnoea

Special Senses:

vertigo

Urogenital:

impotence

Other reported events seen less frequently in clinical trials included other hypersensitivity reactions including

serum sickness, vasculitis, thrombocytopenia, acute renal failure, chest pain, syncope, anorexia, vomiting,

dizziness, headache, nausea, rhinitis and angioedema.

During the post-marketing period of valsartan there have been reports of dermatitis bullous, elevated liver

enzymes and very rare reports of hepatitis. There have also been very rare cases of bleeding. Rare cases of

rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those

contained in valsartan and hydrochlorothiazide tablets. The following adverse reactions have been reported in

patients treated with thiazide diuretics alone, including hydrochlorothiazide:

Very common

Mainly at higher doses, hypokalaemia, blood lipids increased.

Common

Hyponatraemia, hypomagnesaemia, hyperuricaemia, urticaria and other forms of rash, loss of appetite, mild

nausea and vomiting, postural hypotension, which may be aggravated by alcohol, anesthetics or sedatives,

impotence, electrolyte and metabolic disorders (see PRECAUTIONS).

Rare

Hypercalcaemia, hyperglycaemia, glycosuria and worsening of diabetic metabolic state, photosensitisation,

abdominal distress, constipation, diarrhoea, and gastrointestinal discomfort, intrahepatic cholestasis or jaundice,

cardiac arrhythmias, headache, dizziness or lightheadedness, sleep disturbances, depression, paraesthesia,

disturbances of vision, and thrombocytopenia, sometimes with purpura.

Very rare

Hypochloraemic alkalosis, necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-

like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone

marrow depression, haemolytic anaemia, hypersensitivity reactions, respiratory distress including pneumonitis

and pulmonary oedema.

Dilart HCT – Product Information

Adverse drug reactions from post-marketing experiences

The following adverse drug reactions have been identified based on post-marketing experiences. Because these

reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate

their frequencies. Therefore the frequency assigned is “not known”.

Frequency not known: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle

spasm, asthenia, acute angle-closure glaucoma.

DOSAGE AND ADMINISTRATION

The recommended dose of Dilart HCT is one tablet per day. When clinically appropriate either Dilart HCT

80/12.5,160/12.5 or 320/12.5 may be used.

Dilart HCT 160/12.5 mg may be administered in patients whose blood pressure is not adequately controlled after

4 weeks of treatment by valsartan 160 monotherapy. Treatment with Dilart HCT 160/25 mg is limited to those

patients who do not show adequate blood pressure reduction with Dilart HCT 160/12.5 mg after at least 4 weeks

of treatment.

Dilart HCT 320/12.5 mg may be administered in patients whose blood pressure is not adequately controlled after

4 weeks of treatment by valsartan 320 monotherapy. Treatment with Dilart HCT 320/25 mg is limited to those

patients with more severe hypertension who do not show adequate blood pressure reduction with Dilart HCT

320/12.5 mg after at least 4 weeks of treatment.

Dilart

should

administered

consistently

with

without

food

(see

PHARMACOLOGY

-

Pharmacokinetics).

Renal or Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate renal

impairment (creatinine clearance > 30 mL/min). In patients with mild to moderate hepatic impairment without

cholestasis the daily dose of valsartan should not exceed 80 mg (see PRECAUTIONS).

Patients with severe renal or hepatic impairment, biliary cirrhosis or cholestasis must not take Dilart HCT (see

CONTRAINDICATIONS).

OVERDOSAGE

Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness,

circulatory collapse and/or shock. In addition, the following signs and symptoms may occur due to an overdose

hydrochlorothiazide

component:

dizziness,

nausea,

somnolence,

hypovolaemia,

hypotension

electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

If the ingestion is recent, a sufficient amount of activated charcoal should be administered. Otherwise, the usual

treatment would be intravenous infusion of normal saline solution.

Valsartan cannot be eliminated by means of haemodialysis because it is strongly bound to plasma proteins. The

degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

Contact the Poisons Information Centre on 13 11 26 for advice on management.

PRESENTATION AND STORAGE CONDITIONS

Dilart HCT 80/12.5

A light orange, film-coated, oval, biconvex tablet debossed with VH 1 on one side

of the tablet and M on other side. Blister packs of 7, 14, 28*, 30 or 56 and Bottles

of 7, 14, 28, 30, 56, 100 and 500.

Dilart HCT – Product Information

Dilart HCT 160/12.5

A reddish, film-coated, oval, biconvex tablet debossed with VH 2 on one side of

the tablet and M on other side. Blister packs of 7, 14, 28*, 30 or 56 and Bottles of

7, 14, 28, 30, 56, 100 and 500.

Dilart HCT 160/25

A brown, film-coated, oval, biconvex tablet debossed with VH 3 on one side of the

tablet and M on other side. Blister packs of 7, 14, 28, 30 or 56 and Bottles of 7,

14, 28, 30, 56, 100 and 500.

Dilart HCT 320/12.5

A pink, film-coated, oval, biconvex tablet debossed with VH 4 on one side of the

tablet and M on other side. Blister packs of 7, 14, 28*, 30 or 56 and Bottles of 7,

14, 28, 30, 56, 100 and 500.

Dilart HCT 320/25

A yellow, film-coated, oval, biconvex tablet debossed with VH 5 on one side of the

tablet and M on other side. Blister packs of 7, 14, 28*, 30 or 56 and Bottles of 7,

14, 28, 30, 56, 100 and 500.

* Available in Australia

Store below 25°C. Keep in the original package.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30-34 Hickson Road

Millers Point NSW 2000

www.alphapharm.com.au

ABN 93 002 359 739

POISON SCHEDULE OF MEDICINE

Schedule 4(Prescription Only Medicine)

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS (THE ARTG)

26/08/2014

DATE OF MOST RECENT AMENDMENT

17/03/2015

DilartHCT_pi\Mar15/00