ABISART

Main information

  • Trade name:
  • ABISART HCT 150/12.5
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ABISART HCT 150/12.5
    Australia
  • Language:
  • English

Other information

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization number:
  • 215943
  • Last update:
  • 09-10-2017

Public Assessment Report

Public Summary

Summary for ARTG Entry:

215943

ABISART HCT 150/12.5 irbesartan/hydrochlorothiazide 150/12.5 mg tablet bottle

ARTG entry for

Medicine Registered

Sponsor

Alphapharm Pty Ltd

Postal Address

PO Box R1462,ROYAL EXCHANGE, NSW, 1225

Australia

ARTG Start Date

29/11/2013

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. ABISART HCT 150/12.5

Product Type

Single Medicine Product

Effective date

19/09/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

ABISART HCT is 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

Bottle

HDPE

24 Months

Store below 25

degrees Celsius

Child resistant closure

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1.

Dosage Form

Tablet

Route of Administration

Oral

Visual Identification

A pink film-coated, oval, biconvex tablet debossed with "M" on one side of

the tablet and "I33" on the other side

Active Ingredients

Hydrochlorothiazide

12.5 mg

Irbesartan

150 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 07:52:48 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

ABISART

HCT

Irbesartan/Hydrochlorothiazide

PRODUCT INFORMATION

NAME OF THE MEDICINE

Active ingredient:

Irbesartan

Hydrochlorothiazide

Chemical name:

2-butyl-3-[(2'-(1

H

-tetrazol-5-yl)biphenyl-

4-yl)methyl]-1,3-diazaspiro

[4,4]

non-1-

en-4-one

6-chloro-3,4-dihydro-2

H

-1,2,4-

benzothiadiazine-7-sulphonamide 1, 1-

dioxide

Structural formula:

Molecular formula:

Molecular weight:

428.5

297.7

CAS registry no.:

138402-11-6

58-93-5

DESCRIPTION

ABISART HCT (irbesartan/hydrochlorothiazide) is an oral antihypertensive agent combining a nonpeptide

angiotensin II receptor (AT

subtype) antagonist, irbesartan, and a thiazide diuretic, hydrochlorothiazide.

Irbesartan is a white to almost-white crystalline powder. It is a relatively non-polar compound with a partition

coefficient (octanol-water) of 10.1 at a pH of 7.4. Irbesartan is practically insoluble in water and slightly soluble

in alcohol and methylene chloride.

Hydrochlorothiazide is a white crystalline powder. It is slightly soluble in water and freely soluble in sodium

hydroxide solution.

ABISART HCT 150/12.5 tablets contain 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide

ABISART HCT 300/12.5 tablets contain 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.

ABISART HCT 300/25 tablets contain 300 mg of irbesartan and 25 mg of hydrochlorothiazide.

The inactive ingredients in ABISART HCT tablets include: colloidal anhydrous silica, magnesium stearate,

sodium lauryl sulfate, microcrystalline cellulose, pregelatinized maize starch, povidone, lactose, croscarmellose

sodium, quinoline yellow aluminum lake, Opadry II complete film coating system 32F540072 pink (ARTG no

109229) (150/12.5 mg and 300/12.5 mg) and Opadry II complete film coating system 32F500006 purple (ARTG

no. 109227) (300/25 mg).

Abisart HCT – Product Information

PHARMACOLOGY

Pharmacodynamics

Irbesartan is a specific antagonist of angiotensin II receptors (AT

subtype). Angiotensin II is an important

component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium

homeostasis. Irbesartan does not require metabolic activation for its activity.

Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective

antagonism of the angiotensin II (AT

subtype) receptors localized on vascular smooth muscle cells and in the

adrenal cortex. It has no agonist activity at the AT

receptor and a much greater affinity (more than 8500-fold)

for the AT

receptor than for the AT

receptor (a receptor that has not been shown to be associated with

cardiovascular homeostasis).

Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (i.e., renin, angiotensin converting

enzyme [ACE]) or affect other hormone receptors or ion channels involved in the cardiovascular regulation of

blood pressure and sodium homeostasis.

Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic with diuretic, natriuretic and antihypertensive

effects. The mechanism of antihypertensive effect of thiazide diuretics, such as hydrochlorothiazide is not fully

known. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, increasing excretion of sodium

and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and

bicarbonate. Hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases

serum potassium. Co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss

associated with thiazide diuretics.

Pharmacokinetics

Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either

drug.

Absorption

oral

bioavailabilities

irbesartan

hydrochlorothiazide

measured

after

administration

irbesartan/hydrochlorothiazide

similar

bioavailabilities

irbesartan

hydrochlorothiazide

administered as separate entities. The absolute oral bioavailability for irbesartan has previously been shown to be

60-80% whilst the absolute oral bioavailability for hydrochlorothiazide is documented as 50-80%.

Food does not affect the bioavailability of irbesartan and hydrochlorothiazide. Peak plasma concentrations occur

1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Distribution

Irbesartan is 90% protein-bound in the plasma, and has negligible binding to cellular components of blood. The

volume of distribution (V

) is 53-93 litres (0.72-1.24 Litres/Kg). Hydrochlorothiazide is 68% protein-bound in

the plasma, and its apparent volume of distribution is 0.83 - 1.141 Litres/Kg.

Metabolism

In plasma, unchanged irbesartan accounts for more than 80% of the circulating radioactivity following oral or

intravenous administration of

C irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation

and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan undergoes oxidation

primarily by the cytochrome P450 isoenzyme

CYP

2C9; isoenzyme

CYP

3A4 has negligible effect. It is not

metabolized by, nor does it substantially induce or inhibit most isoenzymes commonly associated with drug

metabolism (i.e.,

CYP

1A1,

CYP

1A2,

CYP

2A6,

CYP

2B6,

CYP

2D6, or

CYP

2E1). Irbesartan does not induce nor

inhibit isoenzyme

CYP

3A4.

Hydrochlorothiazide is not metabolized.

Abisart HCT – Product Information

Elimination

Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered

radioactivity after an oral or intravenous dose of

C irbesartan was recovered in urine with the remainder in the

faeces. Less than 2% of the dose was excreted in urine as unchanged irbesartan.

The terminal elimination half-life (t

) of irbesartan from plasma is 11 - 15 hours. The total body clearance of

intravenously administered irbesartan was 157 - 176 mL/min, of which 3.0-3.5 mL/min is renal clearance.

Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. Steady-state plasma concentrations

are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is

observed in plasma upon repeated once-daily dosing.

Hydrochlorothiazide is eliminated by the kidneys. The mean plasma half-life (t½) of hydrochlorothiazide from

plasma reportedly ranges from 5-15 hours.

Special Populations

In male and female hypertensive subjects,

higher (11-44%) plasma concentrations of irbesartan were observed in

females than in males, although, following multiple dosing, males and females did not show differences in either

accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.

In elderly (male and female)

normotensive subjects (65-80 years) with clinically normal renal and hepatic

function, the plasma AUC and peak plasma concentration (C

) of irbesartan are approximately 20%-50%

greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is

comparable. No significant age-related differences in clinical effect have been observed. The area under the

plasma concentration time curve (AUC) for hydrochlorothiazide was elevated in the elderly group following

multiple dosing consistent with previously published data.

In black and white normotensive subjects

, the plasma AUC and t

of irbesartan are approximately 20-25% greater

in blacks than in whites; the peak plasma concentrations (C

) of irbesartan are essentially equivalent.

In patients with renal impairment

(regardless of degree) and in haemodialysis patients, the pharmacokinetics of

irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with severe renal

impairment (creatinine clearance <20 mL/min), the elimination half-life of hydrochlorothiazide was reported to

increase to 21 hours.

In patients with hepatic insufficiency due to mild to moderate cirrhosis

, the pharmacokinetics of irbesartan are

not significantly altered.

A bioequivalence study on 32 subjects has been conducted comparing the generic irbesartan/hydrochlorothiazide

300/25 mg tablet with the originator irbesartan/hydrochlorothiazide 300/25 mg tablet. The generic and originator

geometric LS mean C

for irbesartan was 3.813 and 3.442 μg/mL respectively and hydrochlorothiazide was

223.1 and 210.5 μg/mL respectively. The C

ratio for irbesartan was 1.11 with the 90% confidence interval (CI)

between 103.80% - 118.22% and hydrochlorothiazide was 1.06 with the 90% CI between 101.06% - 111.10%.

The mean AUC

point estimate for irbesartan was 0.98 with the 90% CI between 91.82% – 104.20% and

hydrochlorothiazide was 1.01 with 90% CI between 97.73% - 105.41%. The T

of irbesartan for generic and

originator was 1.65 and 1.68 hr respectively and hydrochlorothiazide was 1.95 and 2.00 hr respectively.

CLINICAL TRIALS

Based on data from placebo-controlled clinical trials, the following effects were noted. The blood pressure

lowering effect of irbesartan in combination with hydrochlorothiazide was apparent after the first dose and

substantially present within 1-2 weeks, with the maximal effect occurring by 6-8 weeks. In long-term follow-up

studies, the blood pressure lowering effect of irbesartan/hydrochlorothiazide with dose-to-response addition of

adjunctive therapy was maintained for over one year.

Abisart HCT – Product Information

The combination of hydrochlorothiazide and irbesartan produced dose-related additive reductions in blood

pressure across their therapeutic dose ranges. The addition of 12.5mg hydrochlorothiazide to 300 mg irbesartan

once daily in patients not adequately controlled on 300 mg irbesartan alone resulted in further placebo-corrected

diastolic blood pressure reductions at trough (24 hours post dosing) of 6.1 mmHg. The combination of 300 mg

irbesartan and 12.5 mg hydrochlorothiazide resulted in an overall placebo-subtracted systolic/diastolic reductions

of up to 13.6/11.5 mmHg.

Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300/12.5 mg combination

may respond when uptitrated to 300/25 mg. In these patients, an incremental blood pressure lowering effect was

observed for both SBP and DBP (13.3 and 8.3 mm Hg, respectively).

Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide showed systolic/diastolic mean

placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9mmHg. Peak effects

occurred at 3-6 hours.

When assessed by ambulatory blood pressure monitoring, irbesartan 150 mg and hydrochlorothiazide 12.5 mg

tablets once daily produced consistent reduction in blood pressure over the 24 hours period with a mean 24-hour

placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. The observed trough-to-peak effects were

at least 68% of the corresponding placebo-subtracted peak diastolic and peak systolic responses.

In a clinical trial with patients not adequately controlled on 25 mg hydrochlorothiazide alone after 4 weeks’

treatment, the addition of irbesartan (with dose-to-response uptitration from 75 mg to 150 mg at 6 weeks)

produced

mean

systolic/diastolic

reductions

weeks

which

were

11.1/7.2

greater

than

hydrochlorothiazide alone.

Blood pressure was lowered to about the same extent in both standing and supine positions. Orthostatic effects

were infrequent, but may be expected to occur in patients who develop intercurrent sodium and/or volume-

depletion.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been

studied. Epidemiological studies have shown that long term treatment with hydrochlorothiazide reduces the risk

of cardiovascular mortality and morbidity.

The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender. The overall

antihypertensive response to the combination was similar for black and non-black patients.

After withdrawal of irbesartan, blood pressure gradually returned toward baseline. Rebound hypertension was

not observed with irbesartan or hydrochlorothiazide.

With hydrochlorothiazide, onset of diuresis occurred in 2 hours, and peak effect occurred at about 4 hours, while

the action persisted for approximately 6-12 hours.

INDICATIONS

ABISART HCT is indicated for the treatment of hypertension. Treatment should not be initiated with this fixed-

dose combination.

CONTRAINDICATIONS

ABISART HCT is contraindicated in patients who are hypersensitive to irbesartan, sulfonamide-derived drugs

(e.g., thiazides), or to any other component of the ABISART HCT formulation. In general, hypersensitivity

reactions are more likely to occur in patients with a history of allergy or bronchial asthma.

ABISART HCT is contraindicated in patients who are anuric.

Do not co-administer ABISART HCT with aliskiren-containing medicines in patients with diabetes or with

moderate to severe renal impairment.

Abisart HCT – Product Information

Do not co-administer ABISART HCT with ACE inhibitors in patients with diabetic nephropathy.

Pregnancy (See

PRECAUTIONS

Use in Pregnancy

PRECAUTIONS

Hypotension - Volume-Depleted Patients

Irbesartan and hydrochlorothiazide tablets have been rarely associated with hypotension in hypertensive patients

without other risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who

have been sodium and/or volume-depleted by vigorous diuretics therapy and/or dietary salt restriction, vomiting

and/or diarrhoea or haemodialysis. Volume and/or sodium depletion should be corrected before initiating therapy

with irbesartan/hydrochlorothiazide tablets. Thiazides may potentiate the action of other antihypertensive drugs

(see

INTERACTIONS WITH OTHER MEDICINES

Renal Impairment

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function during

therapy with irbesartan and hydrochlorothiazide may be anticipated in susceptible individuals. In patients whose

renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., hypertensive patients

with renal artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment with

drugs that affect this system has been associated with oliguria and/or progressive azotemia and (rarely) with acute

renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor

antagonist, including irbesartan and hydrochlorothiazide cannot be excluded.

There is no experience with irbesartan/hydrochlorothiazide tablets in patients with a recent renal transplant.

Irbesartan and hydrochlorothiazide therapy is not recommended for patients with severe renal disease (creatinine

clearance ≤30 mL/min) (see

CONTRAINDICATIONS - Anuric Patients

). Hydrochlorothiazide associated

precipitation of azotemia may occur in patients with impaired renal function. As experience is limited in patients

with a creatinine clearance >30 and <60mL/min, irbesartan/hydrochlorothiazide tablets should be administered

with caution to such patients.

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

Dual blockade of the RAAS by combining irbesartan/hydrochlorothiazide with an ACE inhibitor or with aliskiren

is not recommended since there is an increased risk of hypotension, hyperkalemia and changes in renal function

compared

monotherapy.

irbesartan/hydrochlorothiazide

combination

with

aliskiren

contraindicated

patients

with

diabetes

mellitus

with

moderate

severe

renal

impairment

(see

CONTRAINDICATIONS

The use of irbesartan/hydrochlorothiazide in combination with an ACE inhibitor is contraindicated in patients

with

diabetic

nephropathy

(see

CONTRAINDICATIONS

INTERACTIONS

WITH

OTHER

MEDICINES

Renal Artery Stenosis

See comments under

Renal Impairment

above.

Primary Aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through

inhibition of the renin-angiotensin system. Therefore the use of irbesartan and hydrochlorothiazide tablets is not

recommended.

Post-sympathectomy

The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.

Abisart HCT – Product Information

Impaired Hepatic Function

Irbesartan/hydrochlorothiazide tablets should be used with caution in patients with impaired hepatic function or

progressive liver disease, since minor alterations in fluid and electrolyte balance may precipitate hepatic coma.

Fluid and Electrolyte Imbalance

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia

and hypochloremic alkalosis). Although hypokalemia may develop when thiazide diuretics are used alone,

especially with higher doses, concurrent therapy with irbesartan reduces the frequency of diuretic-induced

hypokalemia. Chloride deficit is generally mild and usually does not require treatment. Calcium excretion is

decreased

thiazides

which

cause

intermittent

slight

elevation

serum

calcium.

Marked

hypercalcemia suggests the possibility of 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.

Monitoring of laboratory parameters may be necessary in patients at risk of electrolyte imbalance.

Metabolic and Endocrine Effects

Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide

therapy. Insulin requirements in diabetic patients may be increased and latent diabetes mellitus may become

manifest during thiazide administration. Increases in cholesterol and triglyceride levels have been associated with

thiazide diuretic therapy, however, minimal or no effects were reported at the 12.5 mg hydrochlorothiazide dose

contained in irbesartan/hydrochlorothiazide tablets.

Monitoring of laboratory parameters may be necessary in patients at risk of metabolic disturbances.

Systemic Lupus Erythematosus

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

Secondary Acute Angle-Closure Glaucoma and/or Acute Myopia

Hydrochlorothiazide is a sulfonamide. Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic

reaction, which may result in secondary acute angle-closure glaucoma and/or acute myopia. Isolated cases of

acute angle-closure glaucoma without definite causal association have been reported with hydrochlorothiazide.

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 drug intake 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 (see

ADVERSE EFFECTS

Heart Failure

The safety of irbesartan in the presence of heart failure has not been fully defined. Sudden death has occurred in

some studies of patients with heart failure, and although such deaths may have reflected the natural history of the

underlying heart failure, caution is recommended when treating such patients with irbesartan.

Cardiac Arrhythmia

At this time, experience is limited with irbesartan in the treatment of patients with ventricular dysfunction or

cardiac arrhythmias; caution is advised.

Driving/Operating Machinery

The effects of irbesartan/hydrochlorothiazide tablets on ability to drive motor vehicles or operate machinery have

not been specifically studied, but based on its pharmacodynamic properties. Irbesartan/hydrochlorothiazide

Abisart HCT – Product Information

tablets is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into

account that occasionally dizziness or weariness may occur during treatment of hypertension.

Effects on Fertility

The effects of hydrochlorothiazide and the irbesartan/hydrochlorothiazide combination on fertility have not been

evaluated in animal studies. However, with irbesartan alone, fertility and reproductive performance were not

affected in studies of male and female rats at oral doses up to 650mg/kg/day (approximately 3[male] and 8[female]

fold higher exposure based on AUC, than that of humans at the maximum recommended clinical dose of

300mg/day.)

Use in Pregnancy (Category D)

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 in patients who

were

taking

angiotensin-converting

enzyme

inhibitors.

When

pregnancy

detected,

irbesartan/hydrochlorothiazide 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 have 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 renal 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. Nonetheless, when patients become pregnant, physicians should

have the patient discontinue the use of irbesartan/hydrochlorothiazide tablets as soon as possible.

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

hypotension, oliguria and hyperkalemia.

Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy

pregnant women is not recommended and exposes mother and foetus to unnecessary hazard, including foetal or

neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.

No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at doses as high

as 150/150mg/kg/day. When pregnant rats were treated with irbesartan alone from day 0 to day 20 of gestation,

at doses of 50 mg/kg/day and higher, transient effects (increased renal pelvic cavitation, hydroureter or

subcutaneous oedema) were noted in full term rat foetuses but not in young animals necropsied after six weeks

of age. In pregnant rabbits, at doses of 30mg/kg/day, maternal mortality, abortion and early foetal resorptions

were noted. No teratogenic effects were observed in the rat or the rabbit.

Use in Lactation

Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its metabolites are excreted

in human milk. Hydrochlorothiazide is excreted in human breast milk. Thiazides in high doses causing intense

diuresis can inhibit the milk production. The use of irbesartan and hydrochlorothiazide during breastfeeding is

not recommended.

Because of the potential risk to the infant, a decision should be made whether to discontinue breast feeding or to

discontinue the drug, taking into account the importance of irbesartan/hydrochlorothiazide tablets to the therapy

of the mother.

Abisart HCT – Product Information

Paediatric Use

Safety and effectiveness in paediatric patients have not been established.

Use in the Elderly

Among patients who received irbesartan/hydrochlorothiazide tablets in clinical studies, no overall differences in

efficacy or safety were observed between older patients (65 years or older) and younger patients.

Carcinogenicity

The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been evaluated in animal

studies. However, the carcinogenic potential of irbesartan was assessed in two 104 week studies in mice and rats.

No carcinogenic potential was observed in either species at doses of up to 500mg/kg/day (male rats) and

1000mg/kg/day (mice and female rats). The AUC based exposure levels were 3 - 6 fold higher in mice, 3 fold

higher in male rats and 25 fold higher in female rats than that of humans at the maximum recommended clinical

dose of 300mg/day. With hydrochlorothiazide two-year feeding studies in mice and rats uncovered no evidence

of carcinogenic potential in female mice at doses up to approximately 600mg/kg/day, or in male and female rats

doses

approximately

100mg/kg/day.

studies,

however,

uncovered

equivocal

evidence

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

Genotoxicity

The irbesartan/hydrochlorothiazide combination was not genotoxic in a series of assays for gene-mutagenic

activity in bacterial and mammalian cells, and for clastogenic effects

in vitro

in vivo.

Hydrochlorothiazide

alone was not genotoxic in a gene-mutation assay in bacterial cells, or in tests for clastogenic activity

in vitro

in vivo.

However, positive results were obtained in a mammalian cell assay for gene mutation (mouse lymphoma

cell assay), and in two other tests (sister chromatid exchange assay in Chinese hamster ovary cells and

nondisjunction assay in

Aspergillus nidulans).

Effect on Laboratory Tests

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

rarely associated with administration of irbesartan/hydrochlorothiazide tablets.

Creatinine, Blood Urea Nitrogen

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3 and 1.1 percent

respectively, of patients with essential hypertension treated with irbesartan/hydrochlorothiazide tablets alone. No

patient

discontinued

taking

irbesartan/hydrochlorothiazide

tablets

increased

BUN.

patient

discontinued taking irbesartan/hydrochlorothiazide tablets due to a minor increase in creatinine.

Haemoglobin

Mean decreases of approximately 0.2g/dL occurred in patients treated with irbesartan/hydrochlorothiazide tablets

alone, but were rarely of clinical importance. This compared to a mean of 0.4g/dL in patients receiving placebo.

No patients were discontinued due to anaemia.

Liver Function Tests

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential

hypertension treated with irbesartan/hydrochlorothiazide tablets alone, one patient was discontinued due to

elevated liver enzymes.

Serum Electrolytes

double-blind clinical trials

various

doses of irbesartan

hydrochlorothiazide,

incidence of

hypertensive patients who developed hypokalemia (serum potassium <3.5 mmol/L) was 7.5% versus 6.0% for

placebo; the incidence of hyperkalemia (serum potassium >5.7mmol/L) was < 1.0% versus 1.7% for placebo. No

Abisart HCT – Product Information

patient discontinued due to increases or decreases in serum potassium. Overall, the combination of irbesartan and

hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic

response to hydrochlorothiazide. (See

PRECAUTIONS- Fluid and Electrolyte Imbalance)

INTERACTIONS WITH OTHER MEDICINES

Based on

in vitro

data, no interactions with irbesartan would be expected to occur with drugs whose metabolism

is dependent upon cytochrome P450 isoenzymes

CYP

1A1,

CYP

1A2,

CYP

2A6,

CYP

2B6,

CYP

2D6,

CYP

2E1 or

CYP

3A4. Irbesartan is primarily metabolised by

CYP

2C9, however, during clinical interaction studies, no

significant

pharmacokinetic

pharmacodynamic

interactions

were

observed

when

irbesartan

administered with warfarin (a drug metabolised by

CYP

2C9).

Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetics of irbesartan is

not affected by coadministration with nifedipine or hydrochlorothiazide.

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of

potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium or other medicinal

products that may increase kalaemia with irbesartan may lead to increases in serum potassium, sometimes severe,

and requires close monitoring of serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the

frequency of this effect.

Alcohol, barbiturates or narcotics

Potentiation of thiazide diuretic - induced orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin)

Thiazides may elevate blood glucose levels thus, dosage adjustments of antidiabetic agents may be necessary.

Antigout medication

Dosage adjustments of antigout medication may be needed since hydrochlorothiazide may raise the blood level

of uric acid.

Cardiac glycosides (e.g., digoxin) and other antiarrhythmic drugs (e.g., sotalol)

Diuretic-induced hypokalemia may accentuate cardiac arrhythmias.

Calcium salts –

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

drug (e.g., Vitamin D therapy) is prescribed, serum calcium levels should be monitored and calcium dosage

adjusted accordingly.

Cholestyramine resin and colestipol HCl –

May delay or decrease absorption of hydrochlorothiazide. Irbesartan/hydrochlorothiazide tablets should be taken

at least one hour before or four hours after these medications.

Lithium

Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. Increases in serum

lithium concentrations and lithium toxicity have also been reported with concomitant use of irbesartan. Co-

administration with irbesartan hydrochlorothiazide should be approached with caution and frequent monitoring

of serum lithium levels in patients receiving irbesartan and lithium.

Abisart HCT – Product Information

Inhibitors of Endogenous Prostaglandin Synthesis (i.e., NSAIDs) –

In some patients, these agents can reduce the effects of thiazide diuretics.

Other diuretics and antihypertensive medications –

thiazide

component

irbesartan/hydrochlorothiazide

tablets

potentiate

actions

other

antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. Hydrochlorothiazide may

interact with diazoxide; blood glucose, serum uric acid levels and blood pressure should be monitored.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and

thiazide diuretics –

Concomitant use of a renin-angiotensin system inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist),

and an anti-inflammatory drug (NSAID, including COX-2 inhibitor) alone or with a thiazide diuretic may

increase the risk of renal impairment, including possible acute renal failure. These effects are usually reversible.

This includes use in fixed-combination products containing more than one class of drug. The combination of

these agents should be administered with caution, especially in the elderly, volume-depleted and in patients with

pre-existing renal impairment. Renal function (serum creatinine) should be monitored after initiation of

concomitant

therapy,

periodically

thereafter.

antihypertensive

effect

angiotensin

receptor

antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

The use of ABISART HCT in combination with an ACE inhibitor is contraindicated in patients with diabetic

nephropathy (see

CONTRAINDICATIONS

INTERACTIONS WITH OTHER MEDICINES

Renin inhibitor

combination

irbesartan/hydrochlorothiazide

with

aliskiren-containing

medicinal

products

contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended

in other patients (see

CONTRAINDICATIONS

Angiotensin-Converting Enzyme inhibitors (ACE inhibitors)

The use of ABISART HCT in combination with an ACE inhibitor is contraindicated in patients with diabetic

nephropathy and is not recommended in other patients.

Drugs used during surgery

The effects of nondepolarizing muscle relaxants (e.g., tubocurarine), preanaesthetics and anaesthetics used in

surgery may be potentiated by hydrochlorothiazide; dosage adjustments may be required. Preanesthetic and

anaesthetic agents should be given in reduced dosage, and if possible, hydrochlorothiazide therapy discontinued

one week prior to surgery.

Carbamazepine

Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic

hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics

should be used.

Pressor amines (e.g., noradrenaline)

Due to the thiazide component there is a possible decreased response to pressor amines but not sufficient to

preclude their use.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalemia can occur with thiazide use.

Abisart HCT – Product Information

Other interactions

The hypoglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents

(e.g., atropine) may increase the bioavailability of thiazide type diuretics by decreasing gastrointestinal motility

and stomach emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides

may reduce the renal excretion of cytotoxic drugs (e.g., cyclophosphamide, methotrexate) and potentiate their

myelosuppressive effects.

ADVERSE EFFECTS

The combination of irbesartan and hydrochlorothiazide has been evaluated for safety in approximately 2750

subjects in clinical studies, including 1540 hypertensive patients treated for over 6 months and over 960 patients

treated for one year or more. Adverse events in patients receiving irbesartan/hydrochlorothiazide tablets were

generally mild and transient with no relationship to dose. The incidence of adverse events was not related to age,

gender, or race.

In placebo-controlled clinical studies, including 898 irbesartan/hydrochlorothiazide-treated patients (usual

duration of treatment 2 to 3 months), discontinuations due to any clinical or laboratory adverse event were 3.6

percent for irbesartan/hydrochlorothiazide-treated patients and 6.8 percent for placebo-treated patients (p=0.023).

Adverse events occurring in at least 1% of patients treated with irbesartan/hydrochlorothiazide, in placebo

controlled trials are shown in the table below.

The incidences of the same adverse events in the placebo, irbesartan and hydrochlorothiazide control groups are

also shown.

Adverse Events in Placebo-Controlled Hypertension Trials

Incidence Percentage (%) of Patients

BODY SYSTEM/EVENT

Irbesartan/

hydrochlorothiazide

n = 898

Irbesartan

n = 400

Hydrochlorothiazide

n = 380

Placebo

n = 236

General

Chest pain

Fatigue

Influenza

6.5*

Cardiovascular

Oedema

Tachycardia

Dermatological

Rash

Gastrointestinal

Abdominal Pain

Anorectal Disorder

Diarrhoea

Dyspepsia/Heartburn

Nausea/Vomiting

3.2*

Immunology/Sensitivity disorder

Allergy

Musculoskeletal/Connective Tissue

Musc/Skeletal Pain

Muscle Cramp

Musculoskeletal Trauma

9.7*

Nervous System

Anxiety/Nervousness

Dizziness

Dizziness Orthostatic

Headache

11.0*

9.3*

11.6

16.1

Renal/Genitourinary

Abnormal Urination

Abisart HCT – Product Information

Respiratory

Cough

Pharyngitis

Rhinitis

Sinus Abnormality

Upper Respiratory Infection

* Statistically significant difference compared with placebo, p<0.05

Adverse reactions (clinical events probably or possibly related to therapy as determined by the clinical

investigator)

that

occurred

more

than

hypertensive

patients

when

they

were

taking

irbesartan/hydrochlorothiazide and no additional study medications in premarketing clinical trials involving 2700

subjects, and that were not reported in the above tabulation of adverse events, are listed in the following section.

These adverse reactions have been classified using standard terminology and are categorized by body system.

They are listed in order of decreasing frequency according to the following definitions:

common:

those adverse reactions occurring on one or more occasions in at least 1/100 but less than 1/10 patients;

uncommon:

adverse reactions occurring in at least 1/1000 but less than 1/100 patients;

rare

: those adverse reactions occurring in less than 1/1000 patients.

Cardiovascular

Uncommon

: bradycardia; disturbance of cardiac rhythm; subjective disturbance of cardiac

rhythm; disturbance of ventricular rhythm; ECG abnormality; flushing; hypotension; orthostatic hypotension;

syncope.

Dermatologic

Uncommon

: pruritus, skin discomfort

Endocrine/Metabolic

Common -

sexual dysfunction;

Uncommon -

diabetes; gout; hot flashes; libido changes.

Gastrointestinal: Uncommon -

constipation; decreased appetite; abdominal distention; dry mouth; epigastric

pain; flatulence; gastroesophageal reflux

.

General: Uncommon -

cold sensation; hyperhidrosis; malaise; weakness; weight gain.

Musculoskeletal/Connective Tissue: Uncommon -

abnormal reflexes; muscle ache; myalgia; extremity swelling;

extremity weakness.

Nervous System: Uncommon -

coordination disturbance; depression; emotional lability/disturbance; numbness;

paresthesia; sleep disturbance; somnolence; vertigo.

Respiratory: Uncommon -

dry nasopharynx; dyspnea; wheezing.

Special Senses: Uncommon -

abnormal hearing; taste disturbance; vision disturbance.

Other clinical adverse reactions reported with the use of irbesartan or hydrochlorothiazide alone include:

Cardiovascular:

subjective rhythm disturbance, flushing, ECG abnormality, cardiac murmur, cardiac rhythm

disturbance, orthostatic hypotension, atrial rhythm disturbance, conduction disorder, myocardial infarction.

Dermatologic:

facial erythema, dermatitis, acne, scalp-hair abnormality.

Endocrine/Metabolic/Electrolyte Imbalance:

breast disorder, hyperglycaemia, glycosuria, hyperuricaemia,

electrolyte imbalance (including hyponatraemia and hypokalaemia).

Gastrointestinal:

abnormal stool, increased appetite, oral lesion, dysphagia, oesophagitis

,

anorexia, gastric

irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis

,

xanthopsia

.

Abisart HCT – Product Information

General:

weakness, weight gain, warmth sensation, pain.

Haematopoietic:

leucopenia,

neutropenia/agranulocytosis,

thrombocytopenia,

anaemia,

aplastic

anaemia,

haemolytic anaemia.

Immunology/ Sensitivity Disorder:

upper extremity oedema, head/neck oedema, photosensitivity reactions,

fever, urticaria, necrotizing angiitis, (vasculitis, cutaneous vasculitis), respiratory distress (including pneumonitis

and pulmonary oedema), anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal/Connective Tissue:

arthritis, stiffness lower extremity, muscle spasm, weakness.

Nervous System

: stress related disorder, tremor, disturbing dreams, restlessness.

Renal/Genitourinary:

urination abnormality, renal dysfunction, interstitial nephritis.

Respiratory:

epistaxis.

Special Senses:

eye disturbance -other, eyelid abnormality, visual field abnormality, medication bad taste, eye

disorders

(transient

blurred

vision,

secondary

acute

angle-closure

glaucoma

and/or

acute

myopia)

(see

PRECAUTIONS – Secondary Acute Angle-Closure Glaucoma and/or Acute Myopia

Post-marketing Experience

As with other angiotensin-II receptor antagonists, rare cases of hypersensitivity reactions (urticaria, angioedema)

have been reported. The following have also been reported during post-marketing surveillance: vertigo, asthenia,

hyperkalemia, thrombocytopenia, myalgia, jaundice, elevated liver function tests, hepatitis, arthralgia, tinnitus

and impaired renal function including occasional cases of renal failure in patients at risk.

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

DOSAGE AND ADMINISTRATION

ABISART HCT should not be initiated as first-line therapy. The daily dose can be administered with or without

food.

Replacement Therapy

The combination may be substituted for the titrated components at the same dose level.

Dose Titration by Clinical Effect

When clinically appropriate, direct change from monotherapy to the fixed combinations may be considered:

ABISART HCT 150/12.5 mg may be administered to patients whose blood pressure is not adequately

controlled with hydrochlorothiazide or irbesartan 150 mg alone.

ABISART HCT 300/12.5 mg may be administered to patients insufficiently controlled by irbesartan

300 mg or by ABISART HCT 150/12.5 mg.

ABISART HCT 300/25 mg may be administered to patients insufficiently controlled by ABISART

HCT 300/12.5 mg.

Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended. When

necessary, ABISART HCT may be administered with another antihypertensive drug.

Abisart HCT – Product Information

Patients with Intravascular Volume Depletion

In severely volume-depleted and/or sodium-depleted patients, such as those treated vigorously with diuretics, the

condition should be corrected prior to administration of irbesartan/hydrochlorothiazide.

Elderly Patients

No dosage reduction is generally necessary for daily dosage of irbesartan 150 mg/hydrochlorothiazide 12.5 mg

in the elderly.

Patients with Renal Impairment

No dosage reduction is generally necessary for daily dosage of irbesartan 150 mg/hydrochlorothiazide 12.5 mg

in patients with mild-to-moderate renal impairment (creatinine clearance >30mL/min).

Patients with Hepatic Impairment

No dosage reduction is thought to be necessary in patients with mild to moderate hepatic impairment as the

pharmacokinetics of neither irbesartan nor hydrochlorothiazide are affected by hepatic impairment. Due to the

hydrochlorothiazide component, ABISART HCT should be used with caution in patients with severe hepatic

impairment (see

PRECAUTIONS – Impaired Hepatic Function).

OVERDOSAGE

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. No specific

information is available on the treatment of overdosage with irbesartan/hydrochlorothiazide tablets. The patient

should be closely monitored, and the treatment should be symptomatic and supportive, including fluid and

electrolyte replacement. Irbesartan is not removed from the body by hemodialysis.

The most common signs and symptoms observed in adults exposed to hydrochlorothiazide are those caused by

electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive

diuresis. If a cardiac glycoside (e.g., digoxin) or other antiarrhythmic drugs (e.g., sotalol) has also been

administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is

removed by haemodialysis has not been established.

For information on the management of overdosage, contact the Poison Information Centre on 13 11 26 (Australia).

PRESENTATION AND STORAGE CONDITIONS

ABISART HCT

150/12.5 mg tablet

Pink film-coated, oval, biconvex tablet debossed with “M” on one side of the tablet

and “I33” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles of 7, 14, 30, 90 tablets.

ABISART HCT

300/12.5 mg tablet

Pink film-coated, oval, biconvex tablet debossed with “M” on one side of the tablet

and “I34” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles of 7, 14, 30, 90 tablets.

ABISART HCT

300/25 mg tablet

Reddish-brown film-coated, oval, biconvex tablet debossed with “M” on one side

of the tablet and “I35” on the other side.

PCTFE (Aclar)/Al blisters or PVC/PVDC blisters of 3, 5, 7, 14, 28, 30, 56, 98

tablets and HDPE bottles of 7, 14, 30, 90 tablets

Abisart HCT – Product Information

Some strengths, pack sizes and/or pack types may not be marketed.

Storage

ABISART HCT tablets should be stored below 25°C.

NAME AND ADDRESS OF THE SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30-34 Hickson Road

Millers Point NSW 2000

ABN 93 002 359 739

www.mylan.com.au

POISON SCHEULE OF MEDICINE

S4 – Prescription Only Medicine

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS (THE ARTG)

14/08/2012

DATE OF MOST RECENT AMENDMENT

07/09/2017

Abisart HCT_pi\JUL17/00

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

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP  75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

Sciegen Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Irbesartan Tablets, USP 75 Mg, 150 Mg, and 300 Mg Due to The Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in The Active Pharmaceutical Ingredient (API)

ScieGen Pharmaceuticals, Inc. is voluntarily recalling listed lots, within expiry, of Irbesartan Tablets, USP 75 mg, 150 mg, and 300 mg dosage forms to the consumer level. These products are being recalled due to the presence of an impurity, N-nitrosodiethylamine (NDEA) contained in the API Irbesartan, USP manufactured by Aurobindo Pharma Limited. This impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a...

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

29-10-2018

Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Aurobindo Pharma Limited Issues Voluntary Recall of Irbesartan Drug Substance due to the Detection of Trace Amounts of NDEA (NNitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

Aurobindo Pharma Limited is voluntarily recalling 22 Batches of the drug substance Irbesartan due to the presence of an impurity, N-nitrosodiethylamine (NDEA). The impurity, which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC).

FDA - U.S. Food and Drug Administration

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

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

12-10-2018

Irbesartan Zentiva (Zentiva k.s.)

Irbesartan Zentiva (Zentiva k.s.)

Irbesartan Zentiva (Active substance: Irbesartan) - Centralised - Transfer Marketing Authorisation Holder - Commission Decision (2018)6772 of Fri, 12 Oct 2018 European Medicines Agency (EMA) procedure number: EMEA/H/C/785T/79

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

1-8-2018

Aprovel (Sanofi Clir SNC)

Aprovel (Sanofi Clir SNC)

Aprovel (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)5198 of Wed, 01 Aug 2018

Europe -DG Health and Food Safety

23-7-2018

Irbesartan Zentiva (Sanofi-Aventis groupe)

Irbesartan Zentiva (Sanofi-Aventis groupe)

Irbesartan Zentiva (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)4892 of Mon, 23 Jul 2018

Europe -DG Health and Food Safety

17-7-2018

Karvea (Sanofi-Aventis groupe)

Karvea (Sanofi-Aventis groupe)

Karvea (Active substance: Irbesartan) - Centralised - Yearly update - Commission Decision (2018)4781 of Tue, 17 Jul 2018

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