Olmesartan HCT

Main information

  • Trade name:
  • Olmesartan/HCT Sandoz 20/25 olmesartan medoxomil/hydrochlorothiazide 20/25 mg film coated tablets blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • Olmesartan/HCT Sandoz 20/25 olmesartan medoxomil/hydrochlorothiazide 20/25 mg film coated tablets blister pack
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 221117
  • Last update:
  • 08-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

221117

Olmesartan/HCT Sandoz 20/25 olmesartan medoxomil/hydrochlorothiazide 20/25 mg film coated tablets

blister pack

ARTG entry for

Medicine Registered

Sponsor

Sandoz Pty Ltd

Postal Address

54 Waterloo Road,Macquarie Park, NSW, 2113

Australia

ARTG Start Date

5/02/2015

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. Olmesartan/HCT Sandoz 20/25 olmesartan medoxomil/hydrochlorothiazide 20/25 mg film coated tablets

blister pack

Product Type

Single Medicine Product

Effective date

26/07/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Indicated for the treatment of hypertension.,Treatment should not be initiated with this fixed dose combination.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

Al/Al

2 Years

Store below 25

degrees Celsius

Not recorded

Store in a Dry Place

Blister Pack

PVC/PVDC/Al

2 Years

Store below 25

degrees Celsius

Not recorded

Store in a Dry Place

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

Components

1. Olmesartan/HCT Sandoz 20/25 olmesartan medoxomil/hydrochlorothiazide 20/25 mg film coated tablets blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

20/25 mg film coated tablets are yellow film coated, oval shaped, biconvex

tablets debossed with L400 on one side and plain on other side.

Active Ingredients

Hydrochlorothiazide

25 mg

Olmesartan medoxomil

20 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 26.11.2017 at 01:26:23 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

Product Information

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PRODUCT INFORMATION

OLMESARTAN / HCT SANDOZ 20/12.5, 20/25, 40/12.5, 40/25 TABLETS

NAME OF THE MEDICINE

OLMESARTAN / HCT SANDOZ contains the active ingredients olmesartan medoxomil and

hydrochlorothiazide (HCTZ).

Olmesartan medoxomil is a prodrug, hydrolysed to olmesartan during absorption from the

gastrointestinal tract. Olmesartan is a selective AT

subtype angiotensin II receptor

antagonist. HCTZ is a thiazide diuretic.

Olmesartan medoxomil (CAS no. 144689-63-4) is described chemically as 2,3-dihydroxy-2-

butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[

p

o

-1H-tetrazol-5-ylphenyl) benzyl]

imidazole-5-carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C

and its structural formula is:

HCTZ (CAS no. 58-93-5) is described chemically as 6-chloro-3,4-dihydro-2

H

-1,2,4-

benzothiadiazine-7-sulfonamide 1,1-dioxide.

The empirical formula is C

and the structural formula is:

DESCRIPTION

Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a

molecular weight of 558.59. It is practically insoluble in water and sparingly soluble in

methanol.

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HCTZ is a white, or almost white, crystalline powder, with a molecular weight of 297.7.

HCTZ is very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol.

It dissolves in dilute solutions of alkali hydroxides.

OLMESARTAN / HCT SANDOZ is available for oral use as film-coated tablets containing

20/12.5 mg, 20/25 mg, 40/12.5 mg, or 40/25 mg olmesartan medoxomil/HCTZ.

OLMESARTAN / HCT SANDOZ tablets also contain the following inactive ingredients:

+cellulose - microcrystalline, lactose monohydrate, hyprolose, magnesium stearate,

hypromellose and OPADRY complete film coating system 03F82788 Yellow.

PHARMACOLOGY

Pharmacodynamics

OLMESARTAN / HCT SANDOZ is a combination of an angiotensin II receptor

antagonist, olmesartan medoxomil, and a thiazide diuretic, HCTZ. The combination of

these ingredients has an additive antihypertensive effect, reducing blood pressure to a

greater degree than either component alone.

Once daily dosing with OLMESARTAN / HCT SANDOZ provides an effective and smooth

reduction in blood pressure over the 24-hour dose interval.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting

enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-

angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and

release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan

medoxomil is an orally active angiotensin II receptor (type AT

) antagonist. It has more

than a 12,500-fold greater affinity for the AT

receptor than for the AT

receptor. It is

expected to block all actions of angiotensin II mediated by the AT

receptor, regardless of

the source or route of synthesis of angiotensin II. The selective antagonism of the

angiotensin II (AT

) receptors results in increases in plasma renin levels and angiotensin I

and II concentrations, and some decrease in plasma aldosterone concentrations.

Angiotensin II plays a significant role in the pathophysiology of hypertension via the type

1 (AT

) receptor.

In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in

arterial blood pressure. There has been no evidence of first-dose hypotension, of

tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of

therapy.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks

after the initiation of therapy, although a substantial proportion of the blood pressure lowering

effect is already observed after 2 weeks of treatment. When used together with HCTZ, the

reduction in blood pressure is additive and co-administration is well tolerated.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

HCTZ is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide

diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte

reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent

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amounts. The diuretic action of HCTZ reduces plasma volume, increases plasma renin

activity and increases aldosterone secretion, with consequent increases in urinary potassium

and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is

mediated by angiotensin II and therefore co-administration of an angiotensin II receptor

antagonist tends to reverse the potassium loss associated with thiazide diuretics. With HCTZ,

onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose,

whilst the action persists for approximately 6–12 hours.

The combination of olmesartan medoxomil and HCTZ produces additive reductions in blood

pressure, which generally increase with the dose of each component. In pooled placebo-

controlled studies, administration of the 20/12.5 mg, 20/25 mg, 40/12.5 mg, and 40/25 mg

combinations of olmesartan medoxomil/HCTZ resulted in mean placebo-subtracted

systolic/diastolic blood pressure reductions at trough ranging from 12/7 to 16/9 mmHg. Age

and gender had no clinically relevant effect on response to treatment with olmesartan

medoxomil/HCTZ combination therapy.

Administration of 12.5 mg and 25 mg HCTZ in patients insufficiently controlled by

olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hour

systolic/diastolic blood pressures measured by ambulatory blood pressure monitoring of 7/5

mmHg and 12/7 mmHg, respectively, compared with olmesartan medoxomil monotherapy

baseline. The additional mean systolic/diastolic blood pressure reductions at trough compared

with baseline, measured conventionally, were 11/10 mmHg and 16/11 mmHg, respectively.

The addition of 12.5 mg HCTZ in patients not achieving target blood pressure (≤130/85

mmHg) on olmesartan medoxomil 40 mg decreased systolic/diastolic blood pressure by an

additional 13/6 mmHg, and titration of the HCTZ dose to 25 mg in non-achievers at the lower

add-on dose resulted in a further blood pressure decrease of 9/5 mmHg. Conversely, addition

of olmesartan medoxomil 10–20 mg in patients with moderate to severe hypertension

insufficiently controlled by HCTZ 25 mg monotherapy provided mean systolic/diastolic blood

pressure reductions at trough of 21/18 mmHg compared with HCTZ monotherapy baseline.

The effectiveness of olmesartan medoxomil/HCTZ combination therapy was maintained over

long-term (1-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without

concomitant HCTZ therapy, did not result in rebound hypertension.

The effects of fixed dose combination of olmesartan medoxomil/HCTZ on mortality

and cardiovascular morbidity are currently unknown.

Pharmacokinetics

Absorption and distribution

Olmesartan medoxomil

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active

metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption

from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain

medoxomil moiety have been detected in plasma or excreta. The mean absolute

bioavailability of olmesartan from a tablet formulation was 25.6%.

The mean peak plasma concentration (C

) of olmesartan is reached within about 2 hours

after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations

increase approximately linearly with increasing single oral doses up to about 80 mg.

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Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan

medoxomil may be administered with or without food.

The mean volume of distribution after intravenous dosing is in the range of 16–29 litres.

Olmesartan is highly bound to plasma proteins (99.7%), but the potential for clinically

significant protein binding displacement interactions between olmesartan and other highly

bound co-administered drugs is low (as confirmed by the lack of a clinically significant

interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to

blood cells is negligible.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan crossed the

placental barrier in rats and was distributed to the foetus. Olmesartan was distributed to milk

at low levels in rats.

HCTZ

Following oral administration of olmesartan medoxomil and HCTZ in combination, the

median time to peak concentrations of HCTZ was 1.5 to 2 hours after dosing. HCTZ is 68%

protein bound in the plasma and its apparent volume of distribution is 0.83–1.14 L/kg.

Metabolism and elimination

Olmesartan medoxomil

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during

absorption, there is virtually no further metabolism of olmesartan.

Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared

with hepatic blood flow (approximately 90 L/h). Approximately 30% to 50% of the

systemically absorbed drug is excreted in the urine whilst the remainder is excreted in

faeces (via the bile).

The terminal elimination half-life of olmesartan varied between 10 and 15 hours after

multiple oral dosing. Steady state was reached after the first few doses and no further

accumulation was evident after 14 days of repeated dosing. Renal clearance was

approximately 0.5–0.7 L/h and was independent of dose.

HCTZ

HCTZ is not metabolised in man and is excreted almost entirely as unchanged drug in urine.

About 60% of the oral dose is eliminated as unchanged drug within 48 hours. Renal

clearance is about 250–300 mL/min. The terminal elimination half-life of HCTZ is 10–15

hours.

Pharmacokinetics in special populations

Elderly

In hypertensive patients, the AUC at steady state was increased by approximately 33% in

elderly patients (65–75 years old) and by approximately 31% (adjusted for gender and body

mass index) in very elderly patients (≥75 years old) compared with the younger age group

(See DOSAGE AND ADMINISTRATION).

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Paediatric

The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18

years of age.

Gender

Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in

women compared with men. AUC and C

were 10–15% higher in women than in men.

Female patients had approximately 20% smaller clearances of hydrochlorothiazide than male

patients.

Renal impairment

In patients with renal insufficiency, serum concentrations of olmesartan were elevated

compared to subjects with normal renal function. After repeated dosing, the AUC was

approximately tripled in patients with severe renal impairment (creatinine clearance

<30 mL/min)) (See DOSAGE AND ADMINISTRATION and PRECAUTIONS,

Renal insufficiency).

The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis

has not been studied.

Hepatic Impairment

Mean olmesartan AUC after single oral administration to patients with moderate hepatic

impairment (Child-Pugh score 7 - 9) was increased by about 48% compared with healthy

controls (total group), or by about 60% when compared with matched controls only.

Following repeated dosing, a similar increase in olmesartan mean AUC was observed in

patients with moderate hepatic impairment (Child-Pugh score 7 - 9) when compared with

matched healthy controls. Olmesartan mean C

values were similar in hepatically-

impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients

with severe hepatic impairment (Child-Pugh score 10 - 15) (See DOSAGE AND

ADMINISTRATION and PRECAUTIONS).

CLINICAL TRIALS

Olmesartan medoxomil

The antihypertensive effects of olmesartan have been demonstrated in seven placebo-

controlled studies at doses ranging from 2.5 to 80 mg for 6 to 12 weeks. Approximately

2,800 patients with essential hypertension were studied. The blood pressure lowering

effect of olmesartan tended to increase with time and to increase with dose up to the 40

mg dose. Olmesartan medoxomil 10 mg (n=521), 20 mg (n=513), and 40 mg (n=195)

once daily produced statistically significant reductions in peak and trough blood

pressure compared with placebo (n=543) at every time point from Week 2 to Week 12

(sSBP p<0.001 and sDBP p<0.001). The blood pressure lowering effect was maintained

throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-

peak ratios for systolic and diastolic response between 60 and 80%.

Product Information

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The blood pressure lowering effect of olmesartan, with and without HCTZ, was maintained

in patients treated for up to 1-year. There was no evidence of tachyphylaxis during long-

term treatment with olmesartan or rebound effect following abrupt withdrawal of olmesartan

medoxomil after 1-year of treatment.

The antihypertensive effect of olmesartan was similar in men and women and in patients older

and younger than 65 years. The effect was smaller in black patients (usually a low-renin

population), as has been seen with other ACE inhibitors, angiotensin receptor blockers and

beta-blockers. Olemsartan had an additional blood pressure lowering effect when added to

HCTZ.

Olmesartan medoxomil and HCTZ

In clinical trials, 1,230 patients were exposed to the combination of olmesartan medoxomil

(2.5 mg to 40 mg) and HCTZ (12.5 mg to 25 mg). These trials included one placebo-

controlled factorial trial (n=502) in mild-moderate hypertensives with combinations of

olmesartan medoxomil (10 mg, 20 mg, 40 mg or placebo) and HCTZ (12.5 mg, 25 mg or

placebo). The antihypertensive effect of the combination on trough blood pressure was

related to the dose of each component (see Table 1 below).

Table 1. Placebo-adjusted changes in sitting systolic and diastolic blood pressure (mmHg)

HCTZ dose

Olmesartan medoxomil dose

Placebo

10 mg

20 mg

40 mg

Placebo

12/5

13/7

12.5 mg

17/8

17/8

16/10

25 mg

14/5

19/11

22/11

24/14

Once daily dosing with 20 mg olmesartan medoxomil and 12.5 mg HCTZ, 40 mg olmesartan

medoxomil and 12.5 mg HCTZ or 40 mg olmesartan medoxomil and 25 mg HCTZ produce

mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) ranging

from 17/8 to 24/14 mmHg.

The onset of the antihypertensive effect occurred within 1-week and was near maximal at 4

weeks. The antihypertensive effect was independent of gender, but there were too few subjects

to identify response differences based on race or age greater than or less than 65 years. No

appreciable changes in trough heart rate were observed with combination therapy in the

placebo-controlled trial.

Use in the elderly

The antihypertensive effects of olmesartan medoxomil and HCTZ were investigated in a

randomised, double- blind, parallel group with losartan in elderly patients (65 years or older;

olmesartan medoxomil n=251 whom 69 were >75 years; losartan n=130 whom 48 were >75

years) with essential hypertension for 52 weeks. Patients were initiated on a starting dose of

20mg olmesartan. At 4 week intervals, the treatment was titrated to achieve target BP. The

results obtained for those on olmesartan medoxomil and HCTZ were similar to those in the

losartan group.

Product Information

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INDICATIONS

Treatment of hypertension.

Treatment should not be initiated with this fixed dose combination.

CONTRAINDICATIONS

OLMESARTAN / HCT SANDOZ is contraindicated in:

Patients who are hypersensitive to olmesartan medoxomil, sulfonamide derived drugs (e.g.

thiazides), or any other component of this medication

Pregnancy (see PRECAUTIONS, Use in pregnancy)

Patients with severe renal impairment (creatinine clearance <30 mL/min) (see

PRECAUTIONS, Renal impairment)

Patients with severe hepatic impairment (Child-Pugh score 10 - 15), cholestasis or biliary

obstruction (see PRECAUTIONS, Hepatic impairment)

Patients who are breastfeeding

Patients with refractory hypokalaemia, hypercalcaemia, hyponatraemia, and symptomatic

hyperuricaemia (see PRECAUTIONS, Electrolyte imbalance)

Patients with diabetes who are taking aliskiren (see INTERACTIONS WITH OTHER

MEDICINES)

PRECAUTIONS

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are

volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea

or vomiting. Such conditions should be corrected before the administration of olmesartan

medoxomil/HCTZ

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of

the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or

underlying renal disease, including renal artery stenosis), treatment with ACE inhibitors and

angiotensin receptor antagonists has been associated with acute hypotension, azotaemia,

oliguria or, rarely with acute renal failure and/or death. The possibility of similar effects

cannot be excluded with olmesartan medoxomil.

Renovascular hypertension

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

bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are

treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation

OLMESARTAN / HCT SANDOZ should not be used in patients with severe renal

impairment (creatinine clearance <30 mL/min) (see DOSAGE AND ADMINISTRATION).

Product Information

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No dosage adjustment is necessary in patients with mild (creatinine clearance 50 – 80

mL/min)to moderate (creatinine clearance 30 – <50 mL/min) renal impairment. In such

patients OLMESARTAN / HCT SANDOZ should be administered with caution and periodic

monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide

diuretic-associated azotaemia may occur in patients with impaired renal function. There is no

experience of the administration of olmesartan medoxomil/HCTZ in patients with recent

kidney transplantation.

The pharmacokinetics of OLMESARTAN / HCT SANDOZ or coadministered olmesartan

medoxomil and HCTZ have not been studied in patients with renal impairment.

Sprue-like Enteropathy

Severe, chronic diarrhoea with substantial weight loss has been reported in patients taking

olmesartan medoxomil months to years after drug initiation. Intestinal biopsies of patients often

demonstrated villous atrophy. If a patient develops these symptoms during treatment with

olmesartan medoxomil, exclude other etiologies. Consider discontinuation of OLMETEC

PLUS in cases where no other etiology is identified.

Hepatic impairment

OLMESARTAN / HCT SANDOZ should be used with caution in patients with impaired

hepatic function or progressive liver disease since minor alterations of fluid and electrolyte

balance during thiazide therapy may precipitate hepatic coma. Use of olmesartan

medoxomil in patients with severe hepatic impairment (Child-Pugh score 10 - 15),

cholestasis and biliary obstruction is contraindicated (see CONTRAINDICATIONS).

The pharmacokinetics of OLMESARTAN / HCT SANDOZ or coadministered olmesartan

medoxomil and HCTZ have not been studied in patients with hepatic impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive drugs

acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan

medoxomil and HCTZ is not recommended in such patients.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of

insulin or oral hypoglycaemic agents may be required (see INTERACTIONS WITH

OTHER MEDICINES). Latent diabetes mellitus may become manifest during thiazide

therapy.

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic

therapy. Hyperuricaemia may occur or frank gout may be precipitated in some patients

receiving thiazide therapy.

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Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes

should be performed at appropriate intervals.

Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (including

hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or

electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness,

restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and

gastrointestinal disturbances such as nausea or vomiting (see ADVERSE EFFECTS).

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy

with olmesartan medoxomil may reduce diuretic-induced hypokalaemia. The risk of

hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk

diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients

receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to antagonism

at the angiotensin-II receptors (AT

) through the olmesartan medoxomil component of

OLMESARTAN / HCT SANDOZ hyperkalaemia may occur, especially in the presence of

renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum

potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium

supplements or potassium-containing salt substitutes should be co-administered cautiously

with OLMESARTAN / HCT SANDOZ (see INTERACTIONS WITH OTHER

MEDICINES).

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced

hyponatraemia.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight

elevation of serum calcium in the absence of known disorders of calcium metabolism.

Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should

be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may

result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather; appropriate

therapy is water restriction, rather than administration of salt except in rare instances

when the hyponatraemia is life-threatening. In actual salt depletion, appropriate

replacement is the therapy of choice.

Metabolic acidosis may occur. Although a chloride deficit in a particular patient is

generally mild and usually does not require specific treatment, except under

extraordinary circumstances (as in liver disease or renal disease), chloride replacement

may be required in the treatment of metabolic alkalosis.

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 olmesartan medoxomil; some of these patients previously experienced

angioedema with other drugs including ACE inhibitors. OLMESARTAN / HCT

SANDOZ should be immediately discontinued in patients who develop angioedema,

and OLMESARTAN / HCT SANDOZ should not be re-administered.

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Photosensitivity

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

photosensitivity reaction occurs during treatment with OLMESARTAN / HCT

SANDOZ, it is recommended to stop the treatment. If a re-administration of the

diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or

to artificial UVA.

Ethnic differences

As with all other angiotensin receptor antagonists, the blood pressure lowering effect

of olmesartan medoxomil can be somewhat less in black patients than in non-black

patients, possibly because of a higher prevalence of low-renin status in the black

hypertensive population.

Lithium

The co-administration of OLMESARTAN / HCT SANDOZ and lithium is not recommended

(see Interactions with other medicines).

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause 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 weeks of 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 treatments 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.

Concomitant use of ACE inhibitors or angiotensin receptor antagonists and anti-

inflammatory drugs and thiazide diuretics

The use of ACE-inhibitors or angiotensin receptor antagonists, and an anti-inflammatory drug

(NSAID or COX-2 inhibitor), and a thiazide diuretic at the same time increases the risk of

renal impairment. This includes use with fixed-combination products containing more than

one class of drug. Concomitant use of all three classes of these medications should be

accompanied by increased monitoring of serum creatinine, particularly at the institution of the

treatment. The concomitant use of drugs from these three classes should be used with caution

particularly in elderly patients or those with pre-existing renal impairment.

Other

As with any anti-hypertensive agent, excessive blood pressure decrease in patients with

ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial

infarction or stroke.

Caution should be exercised in patients who have shown prior hypersensitivity to other

angiotensin II receptor antagonists. Hypersensitivity reactions to HCTZ may occur in

patients with or without a history of allergy or bronchial asthma, but are more likely in

patients with such a history.

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Exacerbation or activation of systemic lupus erythematosus has been reported with the use

of thiazide diuretics.

Carcinogenicity

The carcinogenic potential of olmesartan medoxomil and HCTZ in combination

has not been investigated.

Olmesartan medoxomil was not carcinogenic when administered by dietary administration to

rats for up to 2 years. The highest dose tested (2,000 mg/kg/day) corresponded to a relative

systemic exposure to olmesartan that was about 30 times that anticipated at the maximum

recommended human dose (MRHD) of 40 mg/day (based on AUC). Two carcinogenicity

studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-

month dietary administration study in the Hras2 transgenic mouse, at doses of up to

1,000 mg/kg/day (about 11 times anticipated clinical exposure to olmesartan at the MRHD,

based on AUC in Hras2), revealed no evidence of a carcinogenic effect of olmesartan

medoxomil.

Two-year feeding studies in mice and rats showed no evidence of carcinogenic potential for

HCTZ 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. There was equivocal evidence for

hepatocarcinogenicity in male mice treated with HCTZ at approximately 600 mg/kg/day.

Genotoxicity

Olmesartan medoxomil

Both olmesartan medoxomil and olmesartan tested negative in the

in vitro

Syrian hamster

embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames

(bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations

in cultured cells

in vitro

(Chinese hamster lung) and tested positive for thymidine kinase

mutations in the

in vitro

mouse lymphoma assay. Olmesartan medoxomil tested negative

in

vivo

for mutations in the intestine and kidney of a mutagenic susceptible mouse (MutaMouse)

and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2,000

mg/kg/day. Olmesartan not tested in this mouse model. On balance, the weight-of-evidence

indicates that olmesartan medoxomil does not pose a genotoxic risk at clinically relevant

doses.

HCTZ

HCTZ was negative in several different assays of gene mutation and chromosomal

aberration. However, positive test results were obtained in the

in vitro

CHO sister chromatid

exchange (clastogenicity) assay and the mouse lymphoma (mutagenicity) assay at HCTZ

concentrations of 43–1,200 µg/mL.

Olmesartan medoxomil and HCTZ

Olmesartan medoxomil/HCTZ in a ratio of 20:12.5 was negative in the bacterial reverse

mutation test up to the maximum recommended plate concentration for the standard assays.

As expected, positive clastogenicity responses were observed with either drug or the

combination (40:12.5, 20:12.5, 10:12.5) in Chinese hamster lung cells but no synergistic

clastogenicity was observed. However, the combination (20:12.5) was negative in the

in vivo

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mouse micronucleus test at oral doses (1,935/1,209 mg/kg) that were likely to achieve high

relative systemic exposure (>33–700-fold based on AUC) to both components.

Effects on fertility

The effects of olmesartan medoxomil and HCTZ in combination on fertility have not been

investigated.

Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as

high as 1,000 mg/kg/day (relative plasma exposure of 7-8 times that anticipated at the

MRHD based on AUC) in a study in which dosing was begun 2 (female) or 9 (male) weeks

prior to mating.

No animal fertility studies are available for HCTZ.

Use in pregnancy (Category D)

Olmesartan medoxomil

Drugs that act directly on the renin-angiotensin system can cause foetal and neonatal

morbidity and death when administered to pregnant women. Several dozen cases have

been reported in the world literature of patients who were taking ACE inhibitors. When

pregnancy is detected, OLMESARTAN / HCT SANDOZ should be discontinued as

soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third

trimesters of pregnancy has been associated with foetal 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 foetal

function; oligohydramnios in this setting has been associated with foetal 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.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has

been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an

angiotensin II receptor antagonist only during the first trimester should be so informed. If

pregnancy occurs during therapy, OLMESARTAN / HCT SANDOZ must be discontinued

as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a

drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers

should be apprised of the potential hazards to their foetuses and serial ultrasound

examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, OLMESARTAN / HCT SANDOZ should be discontinued

unless it is considered life-saving for the mother. Contraction stress testing (CST), a

nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon

the week of pregnancy. Patients and physicians should be aware, however, that

oligohydramnios may not appear until after the foetus has sustained irreversible injury.

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Infants with histories of

in utero

exposure to an angiotensin II receptor antagonist should be

closely observed for hypotension, oliguria and hyperkalaemia. If oliguria occurs, attention

should be directed toward support of blood pressure and renal perfusion. Exchange

transfusion or dialysis may be required as means of reversing hypotension and/or

substituting for disordered renal function.

There is no clinical experience with the use of olmesartan medoxomil/HCTZ in

pregnant women. No teratogenic effects were observed when olmesartan medoxomil

was administered to pregnant rats at oral doses up to 1,000 mg/kg/day (7 times

clinical exposure to olmesartan at MRHD based on AUC) or pregnant rabbits at oral

doses up to 1 mg/kg/day (half the MRHD on a mg/m

basis; higher doses could not

be evaluated for effects on foetal development as they were lethal to the does). In

rats, significant decreases in pup birth weight and weight gain were observed at doses

≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear

auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes,

and separation of eyelids) and dose-dependent increases in the incidence of dilation

of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed adverse

effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the

MRHD of 40 mg/day.

Thiazide diuretics

Thiazides cross the placental barrier and appear in cord blood. They may cause foetal

electrolyte disturbances and possible other reactions that have occurred in adults. Cases of

neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal

thiazide therapy.

Use in lactation

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at

low concentration in the milk of lactating rats. Thiazides appear in human milk.

Because of the potential for adverse effects on the nursing infant, a decision should be made

whether to discontinue nursing or discontinue the drug.

Paediatric use

The safety and effectiveness of olmesartan medoxomil/HCTZ in children have not been

established.

Use in the elderly

Clinical Studies of olmesartan medoxomil/HCTZ of 415 subjects aged 65 and over

determined that the elderly do not respond differently from younger subjects. In general

dose selection for an elderly patient should be cautious, usually starting at the low end of

the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac

function and of concomitant diseases or other drug therapy.

Effect on laboratory tests

Olmesartan medoxomil

In post-marketing experience, increased blood creatinine levels and hyperkalaemia have

been reported.

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HCTZ

Laboratory adverse events reports with HCTZ include the following: Hyperglycaemia,

glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and

hypokalaemia), increases in cholesterol and triglycerides.

Effects on ability to drive and use machines

The effect of olmesartan medoxomil/HCTZ on the ability to drive and use machines

has not been specifically studied. However, it should be borne in mind that dizziness

or fatigue may occasionally occur in patients taking antihypertensive therapy.

INTERACTIONS WITH OTHER MEDICINES

Effects of other medicinal products on Olmesartan medoxomil/HCTZ

Colesevelam hydrochloride

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam

hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in

AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively,

were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam

hydrochloride. Consider administering olmesartan medoxomil 4 hours before the

colesevelam hydrochloride dose.

Medicinal products affecting potassium levels

The potassium-depleting effect of HCTZ may be potentiated by the co-administration of other

medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic

diuretics, laxatives, corticosteroids, ACTH, amphotericin, benzyl penicillin sodium or

salicylic acid derivatives).

Conversely, based on experience with the use of other drugs that affect the renin-angiotensin

system, concomitant use of potassium-sparing diuretics, potassium supplements, salt

substitutes containing potassium or other drugs that may increase serum potassium levels (e.g.

heparin) may lead to increases in serum potassium (see PRECAUTIONS).

If drugs which affect potassium levels are to be prescribed in combination with olmesartan

medoxomil/HCTZ, monitoring of potassium plasma levels is advised.

Other antihypertensive medications

The blood pressure lowering effect of olmesartan medoxomil/HCTZ can be increased by

concomitant use of other antihypertensive medications.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (including acetylsalicylic acid at doses >3 g/day and also COX-2 inhibitors) and

angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration.

The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of

acute renal failure. Monitoring of renal function at the beginning of treatment should be

recommended as well as regular hydration of the patient. Additionally, concomitant treatment

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can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their

partial loss of efficacy.

In some patients the administration of NSAIDs reduces the diuretic, natriuretic and

antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when

OLMESARTAN / HCT SANDOZ tablets and NSAIDs are used concomitantly, the patient

should be observed closely to determine if the desired effect of the diuretic is obtained.

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is

associated with increased risks of hypotension, hyperkalaemia, and changes in renal function

(including acute renal failure) compared to monotherapy. Closely monitor blood pressure,

renal function and electrolytes in patients on olmesartan medoxomil/HCTZ and other agents

that affect the RAS.

Do not co-administer aliskiren with olmesartan medoxomil/HCTZ in patients with diabetes

(see CONTRAINDICATIONS). Avoid use of aliskiren with olmesartan medoxomil/HCTZ in

patients with renal impairment (GFR <60 ml/min).

Colesevelam hydrochloride

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam

hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in

AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively,

were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam

hydrochloride. Consider administering olmesartan medoxomil 4 hours before the

colesevelam hydrochloride dose.

Other drugs

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in

bioavailability of olmesartan was observed. Co-administration of warfarin and digoxin had

no effect on the pharmacokinetics of olmesartan medoxomil.

Alcohol, barbiturates, narcotics or antidepressants

Potentiation of orthostatic hypotension may occur.

Baclofen, amifostine

Potentiation of antihypertensive effect may occur.

Cholestyramine and colestipol resins

Absorption of HCTZ is impaired in the presence of anionic exchange resins.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility

and stomach emptying rate.

Effects of Olmesartan medoxomil/HCTZ

on other medicinal products

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Lithium

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

concomitant administration of lithium with ACE inhibitors and angiotensin II antagonists.

Therefore, use of olmesartan medoxomil and lithium in combination is not recommended (see

PRECAUTIONS, Lithium). If use of the combination proves necessary, careful monitoring

of serum lithium levels is recommended.

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when olmesartan

medoxomil/HCTZ is administered with drugs affected by serum potassium disturbances (e.g.

digitalis glycosides and antiarrhythmics) and with the following torsades de pointes-inducing

medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing

factor to torsades de pointes:

Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)

Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine,

trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide,

haloperidol, droperidol)

Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin,

mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-

induced cardiac arrhythmias.

Antidiabetic drugs (oral agents and insulin)

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of

the antidiabetic drug may be required.

Metformin

Metformin should be used with caution because of the risk of lactic acidosis induced by

possible functional renal failure linked to HCTZ.

Beta-blockers and diazoxide

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)

The effect of non-depolarizing skeletal muscle relaxants may be potentiated by HCTZ.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)

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Dosage adjustment of uricosuric medications may be necessary since HCTZ may raise the

level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be

necessary. Co-administration of a thiazide may increase the incidence of hypersensitivity

reactions to allopurinol.

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium

supplements must be prescribed, serum calcium levels should be monitored and calcium

dosage adjusted accordingly.

Amantadine

Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their

myelosuppressive effects.

Additional information

Concomitant administration of olmesartan medoxomil and HCTZ had no clinically

relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or

pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Co-administration of olmesartan medoxomil with pravastatin had no clinically relevant effects

on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes

1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4

in vitro

, and had no or minimal inducing effects

on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and

drugs metabolised by the above cytochrome P450 enzymes are expected.

ADVERSE EFFECTS

Olmesartan medoxomil and HCTZ

The safety profile of olmesartan medoxomil/HCTZ has been evaluated in 2,341

hypertensive patients. This experience included 941 patients treated for at least 6 months,

and 642 patients treated for at least 1-year.

Treatment with olmesartan medoxomil/HCTZ was well tolerated, with an incidence of

adverse events similar to placebo. Events generally were mild, transient and had no

relationship to the dose of olmesartan medoxomil/HCTZ.

In the clinical trials, the overall frequency of adverse events was not dose-related.

Analysis of gender, age and race groups demonstrated no differences between olmesartan

medoxomil/HCTZ and placebo-treated patients. The rate of withdrawals due to adverse

events in all trials of hypertensive patients was 2.0% of patients treated with olmesartan

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medoxomil/HCTZ and 2.0% of patients treated with placebo. The only adverse event

which was statistically significantly more frequent on olmesartan medoxomil/HCTZ than

on placebo was dizziness (2.9% versus 1.3%). The incidence of dizziness was not dose

related.

Incidence of adverse events reported in all clinical trials with a greater than or equal to 1%

incidence is shown in Table 2:

Table 2. Clinical adverse effects (all causalities) occurring in ≥1% of patients

Body system

Adverse event

Number (%) patients with adverse event

Olmesartan

medoxomil/

HCTZ

(n=2,341)

Olmesartan

medoxomil

(n=2,847)

HCTZ

(n=444)

Placebo

(n=466)

Ear and labyrinth disorders

Vertigo

30 (1.3)

30 (1.1)

5 (1.1)

4 (0.9)

Gastrointestinal disorders

Diarrhoea

30 (1.3)

53 (1.9)

4 (0.9)

4 (0.9)

Dyspepsia

17 (0.7)

36 (1.3)

4 (0.9)

6 (1.3)

Nausea

22 (0.9)

39 (1.4)

1 (0.2)

4 (0.9)

General disorders and administration site conditions

Chest pain

15 (0.6)

30 (1.1)

4 (0.9)

4 (0.9)

Fatigue

31 (1.3)

38 (1.3)

1 (0.2)

5 (1.1)

Influenza like illness

50 (2.1)

60 (2.1)

6 (1.4)

9 (1.9)

Oedema peripheral

12 (0.5)

34 (1.2)

2 (0.5)

6 (1.3)

Infections and infestations

Bronchitis

98 (4.2)

100 (3.5)

21 (4.7)

20 (4.3)

Gastroenteritis

20 (0.9)

37 (1.3)

2 (0.5)

3 (0.6)

Influenza

23 (1.0)

36 (1.3)

3 (0.7)

6 (1.3)

Nasopharyngitis

49 (2.1)

70 (2.5)

10 (2.3)

13 (2.8)

Sinusitis

34 (1.5)

40 (1.4)

4 (0.9)

15 (3.2)

Upper respiratory tract

infection

43 (1.8)

80 (2.8)

2 (0.5)

14 (3.0)

Urinary tract infection

41 (1.8)

42 (1.5)

6 (1.4)

3 (0.6)

Viral infection

4 (0.9)

12 (0.4)

1 (0.2)

5 (1.1)

Investigations

ALT increased

19 (0.8)

36 (1.3)

3 (0.7)

4 (0.9)

AST increased

17 (0.7)

31 (1.1)

2 (0.5)

4 (0.9)

Blood creatinine increased

15 (0.6)

26 (0.9)

4 (0.9)

5 (1.1)

Blood glucose increased

21 (0.9)

18 (0.6)

5 (1.1)

12 (2.6)

Blood potassium decreased

8 (0.3)

2 (0.1)

5 (1.1)

0 (0.0)

Blood uric acid increased

31 (1.3)

11 (0.4)

4 (0.9)

6 (1.3)

Gamma GT increased

20 (0.9)

48 (1.7)

3 (0.7)

8 (1.7)

Musculoskeletal and connective tissue disorders

Arthralgia

32 (1.4)

56 (2.0)

6 (1.4)

7 (1.5)

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Back pain

72 (3.1)

102 (3.6)

10 (2.3)

8 (1.7)

Pain in limb

11 (0.5)

33 (1.2)

5 (1.1)

7 (1.5)

Spinal disorder

11 (0.5)

14 (0.5)

4 (0.9)

7 (1.5)

Nervous system disorders

Dizziness

69 (2.9)

79 (2.7)

10 (2.3)

6 (1.3)

Headache

80 (3.4)

141 (5.0)

16 (3.6)

30 (6.4)

Psychiatric disorders

Anxiety

4 (0.2)

11 (0.4)

2 (0.5)

5 (1.1)

Insomnia

16 (0.7)

30 (1.1)

1 (0.2)

9 (1.9)

Respiratory, thoracic and mediastinal disorders

Cough

31 (1.3)

42 (1.5)

1 (0.2)

5 (1.1)

Pharyngitis

34 (1.5)

43 (1.5)

7 (1.6)

4 (0.9)

Adverse events reported across all clinical trials with olmesartan medoxomil/HCTZ

(including trials with active as well as placebo control, irrespective of causality or

incidence relative to placebo) include the events listed below. Frequencies are defined as:

common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very

rare (<1/10,000).

Cardiovascular:

Uncommon: palpitations

Central nervous system:

Uncommon: Syncope

General:

Uncommon: weakness

Investigations:

Uncommon: Blood potassium decreased, blood potassium

increased, blood urea increased

Metabolism and nutrition:

Uncommon: Hyperuricaemia, hypertriglyceridaemia

Skin and appendages:

Uncommon: Rash, eczema

Vascular disorders:

Uncommon: Hypotension, orthostatic hypotension

Laboratory parameters

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

rarely associated with olmesartan medoxomil/HCTZ.

Creatinine, blood urea nitrogen:

Increases in blood urea nitrogen (BUN) and serum

creatinine of >50% were observed in 1.3% of patients. No patients were discontinued

from clinical trials of olmesartan medoxomil/HCTZ due to increased BUN or creatinine.

Haemoglobin and haematocrit:

A greater than 20% decrease in haemoglobin and

haematocrit was observed in 0.0% and 0.4% (n=1 patient), respectively, of olmesartan

medoxomil/HCTZ patients, compared with 0.0% and 0.0%, respectively, in placebo-treated

patients. No patients were discontinued due to anaemia.

Use in elderly

Olmesartan medoxomil/HCTZ has been evaluated for safety in 415 patients aged 65 years

or older of whom, 105 were aged 75 years or older. Overall the incidence of adverse

events in the elderly is comparable to that of the adult population. The number of

withdrawals due to olmesartan medoxomil/HCTZ-related adverse effects was low (8/415;

1.9%).

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Adverse events reported with olmesartan medoxomil /HCTZ combination therapy in the

elderly with a greater than 1% incidence are shown in table 3:

Table 3. Clinical adverse effects (all causalities) occurring in ≥1% of elderly patients

Number (%) patients with adverse event

Body System

Adverse event

20 mg OM

+ HCTZ

(n = 99)

40 mg OM

+ HCTZ

(n = 316)

20 mg OM

(n = 742)

40 mg OM

(n = 464)

Gastrointestinal disorders

Diarrhoea

4 (1.3%)

7 (0.9%)

5 (1.1%)

Infections and infestations

Bronchitis

5 (5.1%)

6 (1.9%)

3 (0.4%)

7 (1.5%)

Bronchitis acute

2 (2.0%)

2 (0.6%)

8 (1.1%)

2 (0.4%)

Influenza

1 (0.3%)

9 (1.2%)

2 (0.4%)

Nasopharyngitis

2 (2.0%)

5 (1.6%)

16 (2.2%)

2 (0.4%)

Rhinitis

9 (1.2%)

2 (0.4%)

Urinary tract infection

3 (0.9%)

10 (1.3%)

7 (1.5%)

Musculoskeletal and connective tissue disorders

Arthralgia

1 (1.0%)

2 (0.6%)

10 (1.3%)

4 (0.9%)

Back pain

4 (4.0%)

3 (0.9%)

8 (1.1%)

1 (0.2%)

Nervous system disorders

Dizziness

9 (2.8%)

9 (1.2%)

8 (1.7%)

Headache

3 (3.0%)

3 (0.9%)

13 (1.8%)

13 (2.8%)

Respiratory, thoracic and mediastinal disorders

Cough

1 (1.0%)

3 (0.9%)

8 (1.1%)

6 (1.3%)

The most common adverse events considered to be treatment related in elderly patients on 20

mg olmesartan medoxomil with HCTZ were headache (2.0%) and cough (1.0%). The most

common adverse event considered to be treatment related in elderly patients on 40 mg

olmesartan medoxomil with HCTZ was dizziness (1.3%).

Post-marketing experience

The following adverse reactions have been reported in post-marketing experience:

Body as a whole:

Angioedema; asthenic conditions, such as asthenia,

fatigue, lethargy, malaise

Gastrointestinal:

Abdominal pain; nausea; vomiting

Liver and biliary system disorders:

Hepatic enzymes increased

Metabolic and nutritional disorders:

Hyperkalaemia

Musculoskeletal:

Rhabdomyolysis; myalgia

Nervous systems disorders:

Headache

Respiratory, thoracic and

mediastinal disorders:

Cough

Skin and appendages:

Alopecia; rash; pruritus; urticaria

Urogenital system:

Acute renal failure; increased blood creatinine levels

Additional information on individual components

Undesirable effects previously reported with either of the individual components may be

potential undesirable effects with olmesartan medoxomil/HCTZ, even if not observed in

clinical trials with this product.

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Olmesartan medoxomil

In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment-

emergent adverse events was similar on olmesartan medoxomil and on placebo. In long-

term (2-year) treatment, the incidence of withdrawals due to adverse events on olmesartan

medoxomil 20 mg once daily was 3%.

In placebo-controlled monotherapy studies, the only adverse drug reaction that was

unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil

and 0.9% on placebo).

The following adverse events have been reported across all clinical trials with olmesartan

medoxomil irrespective of causality or incidence relative to placebo. They are listed under

body system and ranked under headings of frequency using the conventions described

above:

Cardiovascular:

Uncommon: Tachycardia; Rare: Hypotension

Central nervous system:

Common: Dizziness; Uncommon: Vertigo

Gastro-intestinal:

Common: Abdominal pain, diarrhoea, dyspepsia, gastroenteritis,

nausea

General:

Common: Chest pain, fatigue, headache, influenza-like

symptoms, peripheral oedema, pain

Musculoskeletal:

Common: Arthritis, back pain, skeletal pain;

Uncommon: Arthralgia, myalgia

Myo/endo/pericardial and

valve disorders:

Uncommon: Angina pectoris

Respiratory system:

Common: Bronchitis, cough, pharyngitis, rhinitis, sinusitis

Skin and appendages:

Uncommon: Rash

Urinary system:

Common: Haematuria, urinary tract infection

Laboratory parameters

In placebo-controlled monotherapy studies the incidence was somewhat higher on olmesartan

medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for

raised creatine phosphokinase (1.3% versus 0.7%).

Laboratory adverse events reported across all clinical trials with olmesartan medoxomil

(including trials without a placebo control), irrespective of causality or incidence relative to

placebo, included:

Metabolic and nutritional:

Common: Increased creatine phosphokinase,

hyperglycaemia, hypertriglyceridaemia,

hyperuricaemia;

Rare: Hyperkalaemia

Liver and biliary:

Common: Liver enzyme elevations

Post-marketing experience

The following adverse reactions have been reported in post-marketing experience:

Body as whole:

Angioedema; asthenic conditions, such as asthenia,

fatigue, lethargy, malaise, anaphylactic reactions,

peripheral oedema

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Gastrointestinal:

Abdominal pain; nausea; vomiting;

diarrhoea; sprue-like enteropathy

Liver and biliary system disorders:

Hepatic enzymes increased

Metabolic and nutritional

disorders:

Hyperkalaemia

Musculoskeletal:

Rhabdomyolysis; myalgia

Nervous systems disorders:

Headache

Respiratory, thoracic and

mediastinal disorders:

Cough

Skin and appendages

Alopecia; rash; pruritus; urticaria.

Urogenital system

Acute renal failure; increased blood creatinine levels

ROADMAP/ORIENT

Two post marketing studies were conducted to determine the effects of olmesartan on renal

disease in diabetic patients. In both of these studies, cardiovascular events were exploratory

secondary efficacy endpoints. Cardiovascular deaths occurred in higher proportions of patients

treated with olmesartan than placebo, but the risk of non-fatal myocardial infarction was lower

with olmesartan.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study

in 4447 patients with type 2 diabetes, normoalbuminuria and at least one additional

cardiovascular risk factor, investigated whether treatment with olmesartan could prevent or

delay the onset of microalbuminuria. This is not an approved indication in Australia. During

the median follow-up duration of 3.2 years, patients received either olmesartan 40 mg or

placebo once daily in addition to other antihypertensive agents, except ACE inhibitors or

angiotensin receptor blockers (ARBs).

In this study, cardiovascular events were exploratory secondary efficacy endpoints. The

endpoints were classed as cardiovascular (CV) morbidity endpoints and CV mortality

endpoints. The CV morbidity endpoints included acute coronary syndrome (ACS), congestive

heart failure (CHF), silent myocardial infarction (MI), coronary revascularisation

(percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft

[CABG]), stroke, peripheral vascular disease (PVD), new-onset atrial fibrillation (AF), and

transient ischaemic attack (TIA). The CV Mortality endpoints includes: sudden cardiac death,

fatal MI, fatal stroke, CHF death, death post PTCA or CABG, recent MI on autopsy. The study

was not designed to formally compare the treatment groups in relation to these endpoints.

Cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients

(4.2%) with placebo. There was a finding of increased cardiovascular mortality in the

olmesartan group, compared with the placebo group (15 patients (0.7%) vs 3 patients

(0.1%)) (HR 4.9, 95%CI (1.4, 17.1), exploratory p value =0.0115). Conversely, a smaller

proportion of patients had a non-fatal myocardial infarction in the olmesartan group compared

with the placebo group (17 patients (0.8%) vs 26 patients (1.2%)), (HR 0.64, 95% CI (0.35,

1.18)) and the same proportions of patients in each treatment group were reported with non-

cardiovascular mortality (11 patients (0.5%) vs 12 patients (0.5%)). Non-fatal stroke was

reported in 14 patients (0.6%) in the olmesartan group and 8 patients (0.4%)) in the placebo

group. Overall mortality with olmesartan was numerically increased compared with placebo

(26 patients (1.2%) vs 15 patients (0.7%)), which was mainly driven by a higher number of

fatal cardiovascular events (sudden cardiac death (7 (0.3%) vs 1 (0.0%)) and fatal myocardial

infarction (5 (0.2%) vs 0 (0.0%)).

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The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy

Trial (ORIENT) primarily investigated the suppressive effect of olmesartan on the progression

of diabetic nephropathy in 577 randomized Japanese and Chinese type 2 diabetic patients with

overt nephropathy. This is not an approved indication in Australia. During a median follow-up

of 3.1 years, patients received either olmesartan or placebo in addition to other

antihypertensive agents including ACE inhibitors. The once daily dose of olmesartan was

uptitrated from 10 mg to 20 mg to 40 mg, subject to tolerability and safety. Not all patients

received the 40 mg dose. The study (undertaken in Japan and in Hong Kong) was not

designed to formally compare the treatment groups in relation to cardiovascular endpoints.

The composite cerebro/cardiovascular endpoint, an exploratory secondary efficacy endpoint,

occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%).

This composite endpoint included cardiovascular death, non-fatal stroke, and non-fatal

myocardial infarction as well as additional individual endpoints. Cardiovascular death was

reported in 10 patients (3.5%) receiving olmesartan compared with 3 patients (1.1%) receiving

placebo. Sudden death occurred in 5 patients (1.8%) in the olmesartan group compared with 2

patients (0.7%) in the placebo group. Overall mortality, non-fatal stroke and non-fatal

myocardial infarction were reported, however, in lower proportions of patients treated with

olmesartan compared with placebo (overall mortality 19 patients (6.7%) vs 20 patients (7.0%),

non-fatal stroke 8 patients (2.8%) vs 11 patients (3.9%) and non-fatal myocardial infarction 3

patients (1.1%) vs 7 patients (2.5%) (olmesartan vs placebo, respectively)).

Use in elderly patients

Olmesartan medoxomil has been evaluated for safety in 1646 patients aged 65 years or older

of whom, 454 were aged 75 years or older. Overall the incidence of adverse events in the

elderly is comparable to that of the adult population. The number of withdrawals due to

olmesartan medoxomil-related adverse effects was very low (6/1206; 0.5%) compared to the

placebo (1/85; 1.2%) or losartan (0/184; 0.0%)

The most common adverse events considered to be treatment related in elderly patients

were headache (1.5%) and dizziness (1.1%) on 40mg olmesartan medoxomil.

HCTZ

HCTZ may cause or exacerbate volume depletion, which may lead to electrolyte imbalance

(see PRECAUTIONS).

Adverse events reported with the use of HCTZ alone include:

Blood and lymphatic system:

Leukopenia, neutropenia/agranulocytosis,

thrombocytopenia, aplastic anaemia, haemolytic anaemia,

bone marrow depression

.

Cardiovascular:

Cardiac arrhythmias

Central nervous system:

Restlessness, light-headedness, vertigo, paraesthesiae

Eye:

Xanthopsia, transient blurred vision

Gastrointestinal system:

Anorexia, loss of appetite, gastric irritation, diarrhoea,

constipation, sialadenitis, pancreatitis

General:

Fever

Hepatobiliary:

Jaundice (intrahepatic cholestatic jaundice)

Musculoskeletal:

Muscle spasm, weakness

Psychiatric:

Sleep disturbances, depression

Product Information

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Version 01

Respiratory system:

Respiratory distress (including pneumonitis and pulmonary

oedema)

Skin and appendages:

Photosensitivity reactions, rash, cutaneous lupus

erythematosus-like reactions, reactivation of cutaneous

lupus, erythematosus, urticaria, necrotising angiitis

(vasculitis, cutaneous vasculitis),anaphylactic reactions,

toxic epidermal necrolysis

Urinary system:

Renal failure, renal dysfunction, interstitial nephritis

Vascular:

Postural hypotension

DOSAGE AND ADMINISTRATION

Adults

OLMESARTAN / HCT SANDOZ is administered once daily, with or without food, in

patients whose blood pressure is not adequately controlled by olmesartan medoxomil or

HCTZ alone.

OLMESARTAN / HCT SANDOZ is registered in combinations of 20/12.5 mg, 20/25 mg,

40/12.5 mg and 40/25 mg.

Dosing should be individualised and dependent on the patient’s condition. Depending on the

blood pressure response, the dose may be titrated after 4 weeks.

If blood pressure is not adequately controlled on olmesartan medoxomil alone, HCTZ may be

added with a starting dose of 12.5 mg. Should blood pressure still remain inadequately

controlled either up-titration of HCTZ to 25 mg or olmesartan to 40 mg dose may be

advisable.

If blood pressure is not adequately controlled on HCTZ alone, olmesartan medoxomil may be

added with a starting dose of 20 mg with up-titration to 40 mg should blood pressure still

remain inadequately controlled.

Doses of OLMESARTAN / HCT SANDOZ above 40/25 mg are not recommended.

Special populations

Elderly

No dosage adjustment is necessary.

If up-titration to the maximum dose of 40 mg daily is required, blood pressure should

be closely monitored.

Renal insufficiency

No adjustment of dosage is necessary for patients with mild (creatinine clearance of 50 – 80

mL/min) to moderate (creatinine clearance of 30–<50 mL/min) renal impairment. When

OLMESARTAN / HCT SANDOZ is used in such patients, periodic monitoring of renal

function is advised (see PRECAUTIONS). OLMESARTAN / HCT SANDOZ is

contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min)

(see CONTRAINDICATIONS).

Product Information

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Intravascular volume depletion

For patients with possible depletion of intravascular volume, particularly those with

impaired renal function, OLMESARTAN / HCT SANDOZ should be administered under

close medical supervision.

If a patient becomes volume depleted whilst taking OLMESARTAN / HCT SANDOZ,

blood pressure and renal function should be closely monitored until the situation resolves.

Hepatic insufficiency

No adjustment of dosage is necessary for patients with mild (Child-Pugh score 5 - 6) to

moderate (Child-Pugh score 7 - 9) hepatic impairment. Close monitoring of blood pressure

and renal function is advised in hepatically-impaired patients who are already receiving

diuretics and/or other antihypertensive agents. There is no experience of olmesartan

medoxomil in patients with severe (Child-Pugh score 10 - 15) hepatic impairment (see

PRECAUTIONS, hepatic impairment).

OLMESARTAN / HCT SANDOZ should not be used in patients with severe hepatic

impairment, cholestasis and biliary obstruction (see CONTRAINDICATIONS).

If up-titration of the olmesartan medoxomil component to the maximum dose of 40 mg daily

is required, blood pressure should be closely monitored.

Children and adolescents

The safety and efficiency of OLMESARTAN / HCT SANDOZ in children have not been

established.

OVERDOSAGE

No specific information is available on the effects or treatment of OLMESARTAN / HCT

SANDOZ overdosage. The patient should be closely monitored, and the treatment should be

symptomatic and supportive. Management depends upon the time since ingestion and the

severity of the symptoms. Activated charcoal may be useful in the treatment of overdosage.

Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the

patient should be placed in a supine position, with salt and volume replacements given

quickly.

The most likely manifestations of olmesartan medoxomil overdosage are expected to be

hypotension and tachycardia; bradycardia might also occur. Overdosage with HCTZ is

associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration

resulting from excessive diuresis. The most common signs and symptoms of overdosage are

nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate

cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain

anti- arrhythmic drugs.

No information is available regarding the dialysability of olmesartan or HCTZ.

For further advice on the management of an overdose contact the Poisons Information

Centre (on 131126 in Australia).

Product Information

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PRESENTATION AND STORAGE CONDITIONS

OLMESARTAN / HCT SANDOZ 20/12.5 film coated tablets contain 20 mg of olmesartan

medoxomil and 12.5 mg of hydrochlorothiazide. They are yellow film coated, round, biconvex

tablets debossed with ‘346’ on one side and ‘L’ on other side.

OLMESARTAN / HCT SANDOZ 20/25 film coated tablets contain 20 mg of olmesartan

medoxomil and 25 mg of hydrochlorothiazide. They are yellow film coated, Oval shape,

biconvex tablets debossed with ‘L400’ on one side and plain on other side.

OLMESARTAN / HCT SANDOZ 40/12.5 film coated tablets contain 40 mg of olmesartan

medoxomil and 12.5 mg of hydrochlorothiazide. They are yellow film coated, oval shape,

biconvex tablets debossed with ‘L347’ on one side and plain on other side.

OLMESARTAN / HCT SANDOZ 40/25 film coated tablets contain 40 mg of olmesartan

medoxomil and 25 mg of hydrochlorothiazide. They are yellow film coated, oval shape,

biconvex tablets debossed with ‘L348’ on one side and plain on other side.

OLMESARTAN / HCT SANDOZ tablets (all strengths) are available in

Aluminium/Aluminium blister packs or PVC/PVDC/Al blister packs containing 30 film-

coated tablets.

Store below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Sandoz Pty Ltd

ABN 60 075 449 553

54 Waterloo Road

Macquarie Park NSW 2114

Australia

POISON SCHEDULE OF THE MEDICINE

Prescription only medicine (S4)

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS (ON ARTG)

05 February 2015

DATE OF MOST RECENT AMENDMENT

: 06/01/2017

9-11-2018

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Sandoz Inc. is voluntarily recalling one lot of Losartan Potassium Hydrochlorothiazide Tablets, USP 100mg/25mg to the consumer level. This product is being recalled due to the trace amount of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Losartan, USP manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. Sandoz Inc. Losartan Potassium Hydrochlorothiazide product is manufactured by Lek Pharmaceuticals dd, Ljubljana, Slovenia. This impurity, which is a substance that occurs naturally in ...

FDA - U.S. Food and Drug Administration

30-10-2018

Small increased risk of certain types of skin cancer associated with the use of hydrochlorothiazide

Small increased risk of certain types of skin cancer associated with the use of hydrochlorothiazide

There is a small increased risk of developing basal cell carcinoma and squamous cell carcinoma in long-term use of blood pressure medicine containing hydrochlorothiazide. This follows from a review of new studies and available data undertaken by the European Medicines Agency, EMA.

Danish Medicines Agency

28-8-2018

Accord Healthcare Inc. Issues Voluntary Nationwide Recall of Hydrochlorothiazide Tablets USP 12.5 Mg Due to Labeling Mix-up

Accord Healthcare Inc. Issues Voluntary Nationwide Recall of Hydrochlorothiazide Tablets USP 12.5 Mg Due to Labeling Mix-up

A 100 count bottle of Hydrochlorothiazide Tablets USP 12.5 mg has been found to contain 100 Spironolactone Tablets USP 25 mg. Since the individual lot, PW05264, of the product is involved in a potential mix-up of labeling, Accord is recalling this individual lot from the market.

FDA - U.S. Food and Drug Administration

22-8-2018

UPDATED: Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Valsartan/Amlodipine/HCTZ, Valsartan/Amlodipine and Valsartan Tablets

UPDATED: Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Valsartan/Amlodipine/HCTZ, Valsartan/Amlodipine and Valsartan Tablets

Torrent Pharmaceuticals Limited is voluntarily recalling ALL LOTS within expiry of Valsartan/Amlodipine/HCTZ, Valsartan/Amlodipine and Valsartan tablets to the consumer level due to the detection of trace amounts of an unexpected impurity found in an active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals. The impurity detected in the API is N-nitrosodimethylamine (NDMA), which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industr...

FDA - U.S. Food and Drug Administration

18-8-2018

Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Valsartan / Amlodipine / HCTZ Tablets

Torrent Pharmaceuticals Limited Issues Voluntary Nationwide Recall of Valsartan / Amlodipine / HCTZ Tablets

Torrent Pharmaceuticals Limited is voluntarily recalling 14 lots of Valsartan/Amlodipine/HCTZ tablets to the consumer level due to the detection of trace amounts of an unexpected impurity found in an active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceuticals. The impurity detected in the API is N-nitrosodimethylamine (NDMA), which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, and has been classified as a probabl...

FDA - U.S. Food and Drug Administration

17-7-2018

Teva Pharmaceuticals USA Issues Voluntary Nationwide Recall of Valsartan and Valsartan Hydrochlorothiazide Tablets

Teva Pharmaceuticals USA Issues Voluntary Nationwide Recall of Valsartan and Valsartan Hydrochlorothiazide Tablets

Teva Pharmaceuticals USA today confirmed a voluntary recall to the consumer / user level of 29 lots of single and 51 lots of combination valsartan medicines distributed under the Actavis label in the U.S. due to the detection of trace amounts of an unexpected impurity found in an active pharmaceutical ingredient (API) manufactured by Zhejiang Huahai Pharmaceutical. The impurity detected in the API is N- nitrosodimethylamine (NDMA), which is a substance that occurs naturally in certain foods, drinking wat...

FDA - U.S. Food and Drug Administration

13-7-2018

Prinston Pharmaceutical Inc Issues Voluntary Nationwide Recall of Valsartan and Valsartan HCTZ Tablets Due to Detection of a Trace Amount of Unexpected Impurity, N-Nitrosodimethylamine (NDMA) in The Products

Prinston Pharmaceutical Inc Issues Voluntary Nationwide Recall of Valsartan and Valsartan HCTZ Tablets Due to Detection of a Trace Amount of Unexpected Impurity, N-Nitrosodimethylamine (NDMA) in The Products

Prinston Pharmaceutical Inc. dba Solco Healthcare LLC. is recalling all lots of Valsartan Tablets, 40 mg, 80mg, 160mg, and 320mg; and Valsartan-Hydrochlorothiazide Tablets, 80mg/12.5mg, 160mg/12.5mg, 160mg/25mg, 320mg/12.5mg, and 320mg/25mg to the retail level. This product recall is due to the detection of a trace amount of an unexpected impurity, N-nitrosodimethylamine (NDMA), made by the manufacturer – Zhejiang Huahai Pharmaceutical Co. Ltd. -- that is used in the manufacture of the subject product ...

FDA - U.S. Food and Drug Administration

8-3-2012

Review concluded regarding general reimbursement for Valsartan/Hydrochlorothiazide "Actavis"

Review concluded regarding general reimbursement for Valsartan/Hydrochlorothiazide "Actavis"

We have completed our review of an application for general reimbursement for Valsartan/Hydrochlorothiazide "Actavis". The product is neither eligible for general nor general conditional reimbursement.

Danish Medicines Agency

22-10-2018

Irbesartan / Hydrochlorothiazide Teva (Teva B.V.)

Irbesartan / Hydrochlorothiazide Teva (Teva B.V.)

Irbesartan / Hydrochlorothiazide Teva (Active substance: irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018) 6974 of Mon, 22 Oct 2018

Europe -DG Health and Food Safety

2-10-2018

CoAprovel (Sanofi Clir SNC)

CoAprovel (Sanofi Clir SNC)

CoAprovel (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)6465 of Tue, 02 Oct 2018

Europe -DG Health and Food Safety

24-9-2018

Karvezide (Sanofi-Aventis groupe)

Karvezide (Sanofi-Aventis groupe)

Karvezide (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)6222 of Mon, 24 Sep 2018

Europe -DG Health and Food Safety

29-8-2018

Rasilez HCT (Noden Pharma DAC)

Rasilez HCT (Noden Pharma DAC)

Rasilez HCT (Active substance: aliskiren hemifumarate / hydrochlorothiazide) - Centralised - Renewal - Commission Decision (2018)5769 of Wed, 29 Aug 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/964/R/87

Europe -DG Health and Food Safety

4-7-2018

Ifirmacombi (Krka d. d., Novo mesto)

Ifirmacombi (Krka d. d., Novo mesto)

Ifirmacombi (Active substance: Irbesartan / hydrochlorothiazide) - Centralised - Yearly update - Commission Decision (2018)4340 of Wed, 04 Jul 2018

Europe -DG Health and Food Safety

27-6-2018

Copalia HCT (Novartis Europharm Limited)

Copalia HCT (Novartis Europharm Limited)

Copalia HCT (Active substance: amlodipine besylate / valsartan / hydrochlorothiazide) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)4082 of Wed, 27 Jun 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1159/T/67

Europe -DG Health and Food Safety

27-6-2018

Dafiro HCT (Novartis Europharm Limited)

Dafiro HCT (Novartis Europharm Limited)

Dafiro HCT (Active substance: amlodipine besylate / valsartan / hydrochlorothiazide) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)4084 of Wed, 27 Jun 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1160/T/68

Europe -DG Health and Food Safety

11-6-2018

Exforge HCT (Novartis Europharm Limited)

Exforge HCT (Novartis Europharm Limited)

Exforge HCT (Active substance: amlodipine besylate / valsartan / hydrochlorothiazide) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)3752 of Mon, 11 Jun 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/1068/T/66

Europe -DG Health and Food Safety

25-5-2018

Webinar: Changes to the regulation of autologous human cells and tissue products

Webinar: Changes to the regulation of autologous human cells and tissue products

Webinar providing an overview of the changes to the regulation of autologous HCT

Therapeutic Goods Administration - Australia