APO-VALSARTAN valsartan 320 mg tablets bottle

Main information

  • Trade name:
  • APO-VALSARTAN valsartan 320 mg tablets bottle
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • APO-VALSARTAN valsartan 320 mg tablets bottle
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 185856
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

185856

APO-VALSARTAN valsartan 320 mg tablets bottle

ARTG entry for

Medicine Registered

Sponsor

Apotex Pty Ltd

Postal Address

PO Box 280,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

5/04/2012

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. APO-VALSARTAN valsartan 320 mg tablets bottle

Product Type

Single Medicine Product

Effective date

11/11/2016

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Treatment of Hypertension.

Treatment of Heart failure (NYHA class II-IV) in patients receiving usual therapy (e.g. diuretics, digitalis) who are intolerant to ACE inhibitors.

To improve survival following myocardial infarction in clinically stable patients with clinical or radiological evidence of left ventricular failure and/or with left

ventricular systolic dysfunction (see Clinical Trials).

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Bottle

HDPE

24 Months

Store below 25

degrees Celsius

Not recorded

Protect from Moisture

Protect from Heat

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. APO-VALSARTAN valsartan 320 mg tablets bottle

Dosage Form

Tablet

Route of Administration

Oral

Visual Identification

Dark grey-violet, oval shaped, film-coated tablets, engraved 'APO' on one

side and 'VA320' on the other side.

Active Ingredients

Valsartan

320 mg

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

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 03:37:51 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Product Information – Australia

APO-Valsartan Tablets

Page 1 of 15

APO-VALSARTAN TABLETS

NAME OF THE MEDICINE

Chemical Name:

N-Pentanoyl-N- [2’ -(1 H-tetrazol-5-yl)biphenyl-4ylmethyl]-L-valine

Structural Formula:

Molecular Formula:

C24H29N5O3

Molecular Weight:

435.5

CAS Registry Number:

137862-53-4

DESCRIPTION

Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly

soluble in water.

Each tablet contains 40, 80, 160 or 320 mg of valsartan as the active ingredient.

It also contains the following inactive ingredients: powdered cellulose, calcium hydrogen phosphate

dehydrate, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose,

hydroxypropyl cellulose, macrogol 8000, titanium dioxide, yellow iron oxide, red iron oxide, purified

water. The 160 and 320 mg tablets also contain black iron oxide.

PHARMACOLOGY

Pharmacodynamics

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

formed from angiotensin I through the action of 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 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. Valsartan does not exhibit any partial agonist activity at the AT

receptor and has 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

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APO-Valsartan Tablets

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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 with 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.

most

patients

after

administration

single

oral

dose,

onset

antihypertensive activity occurs within 2 hours and the peak reduction in blood pressure is achieved

within 4-6 hours. The antihypertensive effect persists over 24 hours after dose 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.

Heart failure

Hemodynamics and plasma neurohormones were measured in NYHA class II-IV heart failure patients

with pulmonary capillary wedge pressure >15 mmHg in 2 short- term, chronic therapy studies. In one

study, which included patients chronically treated with ACE inhibitors, single and multiple doses of

valsartan given in combination with an ACE inhibitor improved hemodynamics including pulmonary

capillary wedge pressure (PCWP), pulmonary artery diastolic pressure (PAD) and systolic blood

pressure (SBP). Reductions were observed in plasma aldosterone (PA) and plasma norepinephrine

(PNE) levels after 28 days of treatment. In the second study, which included only patients untreated

with ACE inhibitors for at least 6 months prior to enrollment, valsartan significantly improved PCWP,

systemic vascular resistance (SVR), cardiac output (CO) and SBP after 28 days of treatment. In the

long-term Valsartan Heart Failure Trial, plasma norepinephrine and brain natriuretic peptide (BNP)

were significantly reduced from baseline in the valsartan group compared to placebo.

Pharmacokinetics

Absorption

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.

Distribution

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.

Metabolism

Valsartan does not undergo extensive biotransformation. Only approximately 25% of absorbed drug is

metabolised. The primary metabolite

is valeryl 4-hydroxy

valsartan,

which is pharmacologically

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

Excretion

Valsartan shows bi-exponential decay kinetics with a t1/2 α of about 1h and a t1/2 β 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

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APO-Valsartan Tablets

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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).

Effect of Age and Disease on Pharmacokinetics

Elderly patients

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

elderly

than

young.

dosage

adjustment

necessary

(see

“DOSAGE

ADMINISTRATION”).

Children

The pharmacokinetics of valsartan have not been investigated in patients less than 18 years of age.

Heart failure

The average time to peak concentration and elimination half-life of valsartan in heart failure patients

are similar to that observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly

and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a

day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral

administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure

patients.

Impaired renal function

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.

Impaired hepatic function

About 70 % of the absorbed 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").

CLINICAL TRIALS

Hypertension

Treatment with Valsartan 320 mg

randomised,

double-blind,

multi-centre,

active-controlled,

parallel-group

study

patients

with

hypertension was designed to evaluate the efficacy and safety of once daily dose of valsartan 320 mg

(n=1873) compared to valsartan 160 mg (n=1884) after a 4 week run-in period with valsartan 160 mg

o.d. Blood pressure lowering effects of 4 weeks treatment were measured in patients aged 18-80

years with uncomplicated mild to moderate hypertension (mean sitting diastolic blood pressure

[MSDBP] ≥ 95 mmHg and ≤109 mmHg). Patients with severe or malignant hypertension, those who

were unable to cease all antihypertensive agents for 2 weeks and those who had a clinically significant

disorder that might affect study outcome or patients safety were excluded from participation in this

study.

The primary efficacy measure was change in trough MSDBP from baseline to endpoint, and the

secondary efficacy measure was changes in trough MSDBP from baseline to endpoint in patients not

adequately controlled with valsartan 160 mg.

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Results for both MSDBP and mean sitting diastolic blood pressure (MSSBP) are reported

in Tables 1 and 2.

Table 1

Between-treatment comparisons of MSDBP and MSSBP (mmHg) at

endpoint (study H2301 - overall ITT population)

Comparison

LSM difference in

change from

baseline (SE)

95% CI for LSM

difference

p-value

MSDBP

valsartan 320 mg vs. 160 mg

-1.18 (0.23)

(-1.63; -0.72)

<0.0001

MSSBP

valsartan 320 mg vs. 160 mg

-2.59 (0.40)

(-3.38; -1.81)

<0.0001

Note: Results were from an ANCOVA model containing centre, treatment and responder stratum

Table 2

Between-treatment comparison of MSDBP and MSSBP (mmHg) at

endpoint in non-responders (study H2301)

Comparison

LSM difference in

change from

baseline (SE)

95% CI for LSM

difference

p-value

MSDBP

valsartan 320 mg vs. 160 mg

-1.29 (0.32)

(-1.91; -0.66)

<0.0001

MSSBP

valsartan 320 mg vs. 160 mg

-2.46 (0.57)

(-3.58; -1.34)

<0.0001

Note: Results were from an ANCOVA model containing centre and treatment.

Heart failure

The Valsartan Heart Failure Trial was a randomised, controlled multinational clinical trial of valsartan

compared with placebo on morbidity and mortality in NYHA class II (62%), III (36%) and IV (2%) heart

failure patients receiving usual therapy with LVEF < 40% and left ventricular internal diastolic diameter

(LVIDD) >2.9 cm/m

. The study enrolled 5010 patients in 16 countries who were randomised to

receive either valsartan or placebo in addition to all other appropriate therapy including ACE inhibitors

(93%), diuretics (86%), digoxin (67%) and beta blockers (36%). The mean duration of follow-up was

nearly two years. The mean daily dose in the study was 254 mg. The study had two primary

endpoints: all-cause mortality (time to death) and heart failure morbidity (time to first morbid event)

defined as death, sudden death with resuscitation, hospitalisation for heart failure or administration of

intravenous inotropic or vasodilator drugs for four hours or more without hospitalisation.

In the trial population no statistically significant improvement in mortality was observed among

valsartan treated patients compared to those who received placebo. Morbidity was significantly

reduced by 13.2% with valsartan compared to placebo treatment. The primary benefit was a 27.5%

reduction in the risk for time to first heart failure hospitalisation. There was no evidence of additional

benefit from concurrent use of valsartan with ACE inhibitors. An increased rate of mortality was

observed in patients taking the triple combination of a beta-blocker, an ACE inhibitor and valsartan.

Valsartan-treated patients showed significant improvement in NYHA class, and heart failure signs and

symptoms, including dyspnea, fatigue, oedema and rales compared to placebo. Patients on valsartan

had a better quality of life as demonstrated by change in the Minnesota Living with Heart Failure

Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan-treated

patients was significantly increased and LVIDD significantly reduced from baseline at endpoint

compared to placebo.

Post-myocardial infarction

Valsartan

Acute

myocardial

iNfarcTion

trial

(VALIANT)

randomised,

controlled,

multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs,

symptoms or radiological evidence of congestive heart failure and/or evidence of left ventricular

systolic dysfunction (manifested as an ejection fraction ≤ 40% by radionuclide ventriculography or ≤

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APO-Valsartan Tablets

Page 5 of 15

35% by echocardiography or ventricular contrast angiography). Patients with systolic blood pressure

below 100 mm Hg, serum creatinine above 221 mcmol/L (2.5 mg/dL), and significant right ventricular

myocardial infarction were excluded.

Patients were randomised within 12 hours to 10 days after the onset of myocardial infarction

symptoms to one of three treatment groups: valsartan given 4–8 days (median 6 days) after

myocardial infarction, captopril given 4–8 days (median 6 days) after myocardial infarction, or the

combination of both. Physicians were advised to titrate patients up to at least 80 mg valsartan twice

daily at 15 days after randomisation or at hospital discharge, and that the target maximum dose of 160

mg valsartan twice daily should be reached after 3 months. The mean treatment duration was two

years. The mean daily dose of valsartan in the monotherapy group was 217 mg. Baseline therapy

included acetylsalicylic acid (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%),

and statins (34%). The population studied was 69% male, 94% Caucasian, and 53% were 65 years of

age or older. The primary endpoint was time to all-cause mortality.

Valsartan was as effective as captopril in reducing all-cause mortality after myocardial infarction, as

summarised in the table below. Valsartan was also effective in prolonging the time to and reducing

cardiovascular mortality, hospitalisation for heart failure, recurrent myocardial infarction, resuscitated

cardiac arrest, and non-fatal stroke (secondary composite endpoint).

Efficacy results: primary and secondary endpoints from the VALIANT study

Valsartan

N=4,909

Captopril

N=4,909

Valsartan +

Captopri

l

N=4,885

Primary Endpoint

Number of deaths (%)

979 (19.9%)

958 (19.5%)

941 (19.3%)

Secondary Endpoints

Cardiovascular mortality

827 (16.8%)

830 (16.9%)

827 (16.9%)

Cardiovascular mortality, hospitalisation for heart

failure,

recurrent

non-fatal

myocardial

infarction (composite endpoint)

1529

(31.1%)

1567

(31.9%)

1518

(31.1%)

Cardiovascular mortality, hospitalisation for heart

failure,

recurrent

non-fatal

myocardial

infarction, non-fatal stroke and cardiac arrest with

resuscitation (composite endpoint)

1612

(32.8%)

1641

(33.4%)

1580

(32.3)

No statistically significant differences between the treatment groups were observed.

Since this was a trial with an active control (captopril), an additional analysis of all-cause mortality was

performed to estimate how valsartan would have performed versus placebo. Using the results of the

previous reference myocardial infarction trials – SAVE, AIRE, and TRACE – the estimated effect of

valsartan preserved 99.6% of the effect of captopril (97.5% CI = 60–139%). Combining valsartan with

captopril

further

benefit

over

captopril

alone,

therefore

this

combination

recommended. There was no difference in all-cause mortality based on age, gender, race, baseline

therapies or underlying disease.

INDICATIONS

Treatment of hypertension

Treatment of heart failure (NYHA class II-IV) in patients receiving usual therapy (e.g. diuretics,

digitalis) who are intolerant to ACE inhibitors.

To improve survival following myocardial infarction in clinically stable patients with clinical or

radiological evidence of left ventricular failure and/or with left ventricular systolic dysfunction

(see “

CLINICAL TRIALS

”).

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APO-Valsartan Tablets

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CONTRAINDICATIONS

Hypersensitivity to any of the components of valsartan;

Pregnancy (see

PRECAUTIONS

- Use in Pregnancy);

Severe hepatic impairment; biliary cirrhosis and cholestasis;

Concomitant use with aliskiren in patients with Type 2 diabetes mellitus (see “

INTERACTIONS

WITH OTHER MEDICINES

”).

PRECAUTIONS

Use in Special Patient Groups

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 may occur in rare cases after initiation of therapy with valsartan.

Sodium and/or volume depletion should be corrected before starting treatment with valsartan, for

example, by reducing the diuretic dose or treatment should be commenced under close medical

supervision.

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

intravenous infusion of normal saline. Treatment with valsartan can be continued once the blood

pressure has stabilised.

Renal artery stenosis

There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery

stenosis. Short-term administration of valsartan to twelve patients with renovascular hypertension

secondary

unilateral

renal

artery

stenosis

induce

significant

changes

renal

haemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, since other drugs that

affect

renin-angiotensin-aldosterone

system

(RAAS)

increase

blood

urea

serum

creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring of both parameters is

recommended as a safety measure.

Impaired renal function

In patients with severe renal impairment (creatinine clearance < 30 mL/min) the dose of valsartan

should not exceed 80 mg per day.

The use of angiotensin receptor antagonists (ARBs) including valsartan or angiotensin converting

enzyme inhibitors (ACEIs) with aliskiren should be avoided in patients with severe renal impairment

(see “INTERACTIONS WITH OTHER MEDICINES”).

As a consequence of inhibiting the renin-angiotensin-aldosterone system, increases of blood urea and

serum creatinine and changes in renal function including renal failure (very rarely) have been reported,

particularly in patients with pre-existing renal dysfunction or those with severe cardiac insufficiency. In

patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system

(e.g. patients with severe congestive heart failure) treatment with angiotensin converting enzyme

inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive

azotemia and (rarely) acute renal failure and/or death. It cannot be excluded that valsartan could

behave similarly.

Impaired hepatic function

In patients with mild to moderate hepatic impairment without cholestasis, valsartan should be used

with caution (see "PHARMACOKINETICS - Impaired hepatic function"). The daily dose of valsartan

should not exceed 80 mg. Patients with severe hepatic impairment, biliary cirrhosis or cholestasis

should not take valsartan (see “CONTRAINDICATIONS”).

Hepatic injury

Cases

clinically

significant

liver

disease

have

occurred

with

some

angiotensin

receptor

antagonists. Hepatitis has been reported rarely with valsartan.

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Heart failure/Post myocardial infarction

Use of valsartan in patients with heart failure or post-myocardial infarction commonly results in some

reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic

hypotension is not usually necessary provided dosing instructions are followed. Patients with more

complicated post- myocardial infarction courses may be at increased risk for hypotension and/or renal

dysfunction. Caution should be observed when initiating therapy in patients with heart failure or post-

myocardial infarction. An assessment of renal function should always be conducted in patients with

heart failure or post-myocardial infarction.

Concomitant therapy in patients with heart failure

An increase in the mortality rate among patients who received a combination of valsartan, ACE

inhibitors and beta blockers has been observed in clinical trials. Concurrent administration of ACE

inhibitors, beta blockers and valsartan is not recommended (see “CLINICAL TRIALS”).

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

inhibitors.

Valsartan 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 ARBs, including valsartan, with other agents blocking the

RAS such as ACEIs or aliskiren (see “INTERACTIONS WITH OTHER MEDICINES”).

Patients receiving potassium sparing diuretics or potassium containing products

If concomitant medication is considered necessary, monitoring of serum potassium is advised (see

"INTERACTIONS WITH OTHER MEDICINES").

Primary hyperaldosteronism

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

through the renin-angiotensin-aldosterone system therefore use of valsartan in these patients is not

recommended.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with all other vasodilators, special caution is indicated in patients suffering from haemodynamically

relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Elderly patients

In the controlled clinical trials of valsartan, 1214 (36.2%) of hypertensive patients treated with

valsartan were > 65 years and 265 (7.9%) were > 75 years. No overall difference in the efficacy or

safety of valsartan was observed in this patient population.

Of the 2511 patients with heart failure randomised to valsartan in the valsartan Heart Failure Trial,

45% (1141) were 65 years or older. No special precautions are required when using valsartan in

elderly patients with heart failure.

Children and adolescent

The safety and efficacy of valsartan in children and adolescents (below the age of 18 years) have not

been established.

Effects on ability to drive and use machines

As with other antihypertensive agents, it is advisable to exercise caution when driving or operating

machinery.

Mutagenesis, carcinogenesis and impairment of fertility

animal

studies,

there

clear

evidence

carcinogenic

activity

when

valsartan

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 concentrations

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Page 8 of 15

approximately 1.5 times the concentrations achieved in humans at the maximum recommended dose

(160 mg bid). Genetic toxicology studies showed that valsartan does not cause gene mutation in

bacterial or mammalian cells, nor does it induce chromosomal damage in vitro or in vivo. Fertility of

male and female rats was not affected at oral doses up to 200 mg/kg/day, with systemic exposure

similar to that in human patients at the maximum recommended dose.

Use in Pregnancy (Category D)

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).

There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction,

when pregnant women have inadvertently taken valsartan. As for any drug that also acts directly on

the RAAS, valsartan 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.

When pregnancy is detected, valsartan should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) during the

second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including

hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function.

Oligohydramnios

this

setting

been

associated

with

fetal

limb

contractures,

craniofacial

deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent

ductus arteriosus have also been reported, although it is not clear whether these occurrences were

due to exposure to the drug. In addition, in retrospective data, first trimester use of ACE inhibitors has

been associated with a potential risk of birth defects.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely

observed for hypotension, oliguria and hyperkalaemia.

No teratogenic effects were observed when valsartan 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, fetal losses were observed at the highest dose level in rabbits, and fetal 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 postnatal 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

Although valsartan is excreted in the milk of lactating rats, it is not known whether it is excreted in

human milk. A peri/postnatal study in rats showed reductions in postnatal 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 oral dose levels greater than 200 mg/kg/day. Thus, it is not advisable

to use Valsartan in lactating mothers.

INTERACTIONS WITH OTHER MEDICINES

Combination use of ACE inhibitors or angiotensin receptor antagonist, anti-inflammatory drugs (NSAIDs

or COX-2 inhibitors) and thiazide diuretics

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the

antihypertensive effect may occur.

The use of an ACE inhibiting drug (ACE-inhibitors) or angiotensin receptor antagonist, an anti-

inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic 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

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Page 9 of 15

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 other agents that affect the RAS (see “PRECAUTIONS”).

The concomitant use of ARBs including valsartan, or ACEIs, with aliskiren should be avoided in

patients with severe renal impairment (GFR < 30 mL/min) (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

potassium-sparing

diuretics

(e.g.

spironolactone,

triamterene,

amiloride),

potassium supplements or salt substitutes containing potassium may lead to increases in serum

potassium

heart

failure

patients,

lead

increases

serum

creatinine.

(see

"PRECAUTIONS - Use in Special Patient Groups").

Lithium salts:

Reversible

increases

serum

lithium

concentrations

toxicity

have

been

reported

during

concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists,

including valsartan. Therefore, careful monitoring of serum lithium levels is recommended during

concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased

further with valsartan.

Hepatic Transporters

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

cyclosporin) or hepatic efflux transporter M RP2 (e.g. ritonavir) may increase the systemic exposure to

valsartan.

No drug interactions of clinical significance have yet been found. Compounds which have been

studied in clinical trials include cimetidine,

warfarin, frusemide, digoxin, atenolol,

indomethacin,

hydrochlorothiazide, amlodipine and 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 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.

ADVERSE EFFECTS

The following summary of adverse reactions is based on clinical trials in hypertension, heart failure

and post-myocardial infarction treated with various doses of valsartan (10 mg - 320 mg daily). It also

includes post marketing reports. The incidence of reported AEs in clinical trials did not appear to be

related to dose or duration of treatment. Therefore, AEs occurring on all doses of valsartan were

pooled. As well, the incidence of AEs was not associated with gender, age or race.

Frequencies are defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000,

<1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000).

Adverse reaction summary from clinical trials and post-marketing reports

Infections and infestations

Common: Viral infections

Uncommon: Upper respiratory tract infection, pharyngitis, sinusitis

Very rare: Rhinitis

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Blood and lymphatic system disorders

Common: Neuropenia

Very rare: Trombocytopenia

Immune system disorders

Very rare: Hypersensitivity including serum sickness

Metabolism and nutrition disorders

Common: Hyperkalaemia*

Psychiatric disorders

Uncommon: Insomnia, libido decrease

Nervous system disorders

Common: Postural dizziness

Uncommon: Syncope*

Rare: Dizziness

Very rare: Headache

Ear and labyrinth disorders

Uncommon: Vertigo

Cardiac disorders

Uncommon: Cardiac failure*

Vascular disorder

Common: Orthostatic hypotension*

Uncommon: Hypotension*

Very rare: Vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon: Cough

Gastrointestinal disorders

Uncommon: Diarrhoea, abdominal pain

Very rare: Nausea

Skin and subcutaneous tissue disorders

Very rare: Angioneurotic oedema**, rash, pruritus

Musculoskeletal and connective tissue disorders

Uncommon: Back pain

Very rare: Arthralgia, myalgia

Renal and urinary disorders

Very rare: Renal impairment

**##

, acute renal failure**, renal insufficiency**

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General disorders and administration site conditions

Uncommon: Fatigue, asthenia, oedema

*

reported in post-myocardial infarction indication; # reported in heart failure indication

** Reported as uncommon in post-myocardial infarction ## reported more frequently in heart failure

indication (common: dizziness, renal impairment, hypotension; uncommon: headeache, nausea)

Hypertension

In placebo-controlled trials in which 2542 patients with hypertension were treated with various doses of

valsartan (10 mg – 320 mg), the study drug showed an overall incidence of adverse events (AEs)

comparable with that of placebo.

A 6-month open-label extension trial involving 642 patients with hypertension treated with valsartan

320 mg showed an overall incidence of AEs comparable with that observed in placebo-controlled

trials.

All adverse events with an incidence of 1% or more in the Valsartan treatment group are

included in the following table, irrespective of their causal association with the study drug.

Valsartan

(n=2542)

Placebo

(n=1007)

Nervous system

Headache

13.6

Dizziness

Infections and infestations

Viral infection

Respiratory system:

Upper respiratory tract infection

Coughing

Rhinitis

Sinusitis

Pharyngitis

Gastrointestinal tract:

Diarrhoea

Abdominal pain

Nausea

Body as a whole:

Fatigue

Musculoskeletal system:

Back pain

Arthralgia

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.

Cardiovascular

palpitations

Gastrointestinal

constipation, dry mouth, dyspepsia and flatulence

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Musculoskeletal

muscle cramps

Neurologic and psychiatric

anxiety, paraesthesia and somnolence

Respiratory

dyspnoea

Urogenital

impotence

Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia and

vomiting.

Heart Failure

adverse

experience

profile

valsartan

heart

failure

patients

consistent

with

pharmacology of the drug and the health status of the patients. In the Valsartan Heart Failure Trial

(Val-HeFT), comparing valsartan in total daily doses up to 320 mg (n=2506) to placebo (n=2494),

9.9% of valsartan patients discontinued for adverse events vs. 7.3% of placebo patients.

Table 3 below includes adverse reactions from double blind short term heart failure trials, including the

first 4 months of the ValHeFT, and drug-related adverse events with an incidence greater than 1% and

more frequent in valsartan treated patients than in placebo treated patients. All patients received

standard drug therapy for heart failure, frequently as multiple medications which could include

diuretics, digitalis, beta-blockers, or ACE inhibitors.

Post-myocardial infarction

In the double-blind, randomised, active-controlled, parallel-group valiant trial comparing the efficacy

and safety of long-term treatment with valsartan, captopril and their combination in high-risk patients

after myocardial infarction, the safety profile of valsartan was consistent with the pharmacology of the

drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated

in the post-myocardial infarction setting.

Serious adverse events (SAEs) were primarily cardiovascular and generally related to the underlying

disease as reflected in the primary efficacy endpoint of all-cause mortality. Nonfatal SAEs with

suspected study drug relationship observed with an incidence of ≥0.1% are included in Table 3 below.

The percentage of permanent discontinuations due to adverse events was 5.8% in valsartan treated

patients and 7.7% in captopril-treated patients. Permanent discontinuation for hypotension or renal

adverse events occurred in 1.4% and 1.1%, respectively, of valsartan treated patients, and in 0.8%

and 0.8%, respectively, of captopril-treated patients.

Post-marketing experience

Elevated liver enzymes and very rare reports of hepatitis. Angioedema and rash have been reported

rarely. Pruritus and other hypersensitivity/allergic reactions including serum sickness and vasculitis

have been reported very rarely. There have been very rare cases of bleeding and thrombocytopenia.

Very rare cases of impaired renal function have also been reported.

Rare cases of rhabdomyolysis

have been reported in patients receiving angiotensin II receptor blockers. Dermatitis bullous and

hyponatraemia of unknown incidence have been reported.

Laboratory Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely

associated with administration of valsartan.

Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking valsartan and 0.6% given

placebo in controlled trials of hypertensive patients. In heart failure patients, increases in serum

creatinine greater than 50% were observed in 3.9% of valsartan treated patients compared to 0.9% of

placebo treated patients. In post-myocardial infarction patients, doubling of serum creatinine was

observed in 4.2% of valsartan-treated patients, 4.8% of valsartan plus captopril-treated patients, and

3.4% of captopril-treated patients.

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Blood urea nitrogen: In heart failure trials, increases in blood urea nitrogen (BUN) greater than 50%

were observed in 16.6% of patients treated with valsartan compared to 6.3% of patients treated with

placebo.

Haematocrit and haemoglobin: Greater than 20% decreases in haemoglobin and haematocrit were

observed in 0.4% and 0.8% respectively, of valsartan patients compared with 0.1% and 0.1% in

placebo-treated patients. One valsartan patient discontinued treatment for microcytic anaemia.

Liver function tests: Occasional elevations (greater than 150%) of liver function values were reported in

patients treated with valsartan. Three patients (< 0.1%) treated with valsartan discontinued treatment

for elevated liver function values. Elevated liver enzymes have also been reported in post-marketing

surveillance.

Neutropenia: Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of

patients treated with placebo.

Serum potassium: In patients with hypertension, increases in serum potassium greater than 20% were

observed in 4.4% of patients treated with valsartan compared to 2.9% of placebo- treated patients. No

patients treated with valsartan discontinued therapy for hyperkalaemia. In heart failure patients,

increases in serum potassium greater than 20% were observed in 10.0% of valsartan treated patients

compared to 5.1% of placebo treated patients.

DOSAGE AND ADMINISTRATION

Dosage in Adults Only

Hypertension

The recommended dose of valsartan is 80 mg once daily, irrespective of race, age or gender. The

maximum antihypertensive effect is seen after 4 weeks. In patients whose blood pressure is not

adequately controlled, the daily dose may be increased to 160 mg. If additional blood pressure

reduction is required, a diuretic may be added or the dose can be increased further to a maximum of

320 mg. Valsartan may also be administered with other antihypertensive agents.

Heart failure

The recommended starting dose of valsartan is 40 mg twice daily. Titration upwards to 80 mg and 160

mg twice daily should be done to the highest dose tolerated by the patient. Consideration should be

given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical

trials is 320 mg in divided doses.

An assessment of renal function should always be conducted in patients with heart failure.

Valsartan has not been demonstrated to reduce mortality in patients with cardiac failure. No additional

benefit on morbidity has been demonstrated from the concurrent use of valsartan and ACE inhibitors.

Concurrent use of valsartan and an ACE inhibitor is not recommended.

Post-mycardial infarction

Therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20

mg twice daily, valsartan therapy should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the

next few weeks. The starting dose is provided by the 40 mg divisible tablet.

Achievement of the target dose of 160 mg twice daily should be based on the patient’s tolerability to

valsartan during titration. If symptomatic hypotension or renal dysfunction occurs, consideration should

be given to a dosage reduction. Evaluation of post-myocardial infarction patients should always

include assessment of renal function.

Valsartan may be used in patients treated with other post-myocardial infarction therapies, e.g.

thrombolytics, acetylsalicylic acid, beta blockers, and statins.

Valsartan should be administered consistently with or without food (see “Pharmacokinetics”).

No initial dosage adjustment is required in the elderly.

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Use in patients with renal impairment

For patients with severe renal impairment, a maximum daily dose of 80 mg per day is

recommended. (see “PRECAUTIONS” and “Pharmacokinetics”).

Use in patients with mild to moderate hepatic impairment

A daily dose of 80 mg should not be exceeded. (see “PRECAUTIONS” and “Pharmacokinetics”).

Patients with severe hepatic impairment, biliary cirrhosis or cholestasis should not take valsartan (see

CONTRAINDICATIONS”).

Dosage in children and adolescents (below the age of 18 years)

The safety and efficacy of valsartan in children and adolescents (below the age of 18 years) have not

been established.

OVERDOSAGE

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

consciousness, circulatory collapse and/or shock. The patient should always be given a sufficient

amount of activated charcoal. Otherwise, the usual treatment would be intravenous infusion of normal

saline solution. Valsartan is not removed by haemodialysis.

Contact the Poisons Information Centre on 13 11 26 (Australia) for advice on the management of

overdosage.

PRESENTATION AND STORAGE CONDITIONS

APO-Valsartan 40 mg tablets

Yellow, modified, capsule shaped, film-coated tablets, engraved ‘APO’ on one side and ‘VA’ scored ‘40’

on the other side

Blister Pack (Clear PVC/PE/PVDC/Aluminium silver foil) of 7, 14, 28, 30 & 56 tablets

AUST R number 185806.

Bottles (white, round HDPE bottle with blue child-resistant cap) of 28 tablets and (white, round HDPE

bottle with blue PP Lift N Peel cap) 100 & 500 tablets

AUST R number 185853.

APO-Valsartan 80 mg tablets

Pale red, round, biconvex, film-coated tablets, engraved ‘APO’ on one side and ‘VA’ over ‘80’ on the

other side.

Blister Pack (Clear PVC/PE/PVDC/Aluminium silver foil) of 7, 14, 28, 30 & 56 tablets

AUST R number 185814.

Bottles (white, round HDPE bottle with blue child-resistant cap) of 28 tablets and (white, round HDPE

bottle with blue PP Lift N Peel cap) 100 & 500 tablets

AUST R number 185854.

APO-Valsartan 160 mg tablets

Yellow, modified, capsule shaped, film-coated tablets, engraved ‘APO’ on one side and ‘VA160’ on the

other side.

Blister Pack (Clear PVC/PE/PVDC/Aluminium silver foil) of 7, 14, 28, 30 & 56 tablets

AUST R number 185821.

Bottles (white, round HDPE bottle with blue child-resistant cap) of 28 tablets and (white, round HDPE

bottle with blue PP Lift N Peel cap) 100 & 500 tablets

AUST R number 185855.

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APO-Valsartan Tablets

Page 15 of 15

APO-Valsartan 320 mg tablets

Dark grey-violet, oval shaped, film-coated tablets, engraved ‘APO’ on one side and ‘VA320’ on the other

side.

Blister Pack (Clear PVC/PE/PVDC/Aluminium silver foil) of 7, 14, 28, 30 & 56 tablets

AUST R number 185826.

Bottles (white, round HDPE bottle with blue child-resistant cap) of 28 tablets and (white, round HDPE

bottle with blue PP Lift N Peel cap) 100 & 500 tablets

AUST R number 185856.

Not all strengths, pack types and/or pack sizes may be available.

Storage

Store below 25°C. Protect from heat and moisture.

NAME AND ADDRESS OF THE SPONSOR

Apotex Pty Ltd

16 Giffnock Avenue

Macquarie Park NSW 2113

Australia

APO and APOTEX are registered trademarks of Apotex Inc.

POISON SCHEDULE OF THE MEDICINE

S4 – Prescription Only Medicine.

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG) : 29 March 2012

Date of most recent amendment: 16-Jun-2014