ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Light pink to pink, film-coated capsule shaped tablet. One side of the tablet debossed with the number
"93". The other side of the tablet debossed with the number "7238".
4.
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).
Irbesartan/Hydrochlorothiazide Teva can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be
recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be
considered:
•
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg may be administered in patients whose
blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg
alone;
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg may be administered in patients
insufficiently controlled by irbesartan 300 mg or by Irbesartan/Hydrochlorothiazide Teva
150 mg/12.5 mg.
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg may be administered in patients
insufficiently controlled by Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Irbesartan/HydrochlorothiazideTeva may be administered with another
antihypertensive medicinal product (see section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Irbesartan/Hydrochlorothiazide Teva is
not recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients
with renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment:
Irbesartan/Hydrochlorothiazide Teva is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.
2
No dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in patients with mild to
moderate hepatic impairment (see section 4.3).
Elderly patients:
no dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in elderly
patients.
Paediatric patients:
Irbesartan/Hydrochlorothiazide Teva is not recommended for use in children and
adolescents due to a lack of data on safety and efficacy.
•
Hypersensitivity to the active substances, to any of the excipients (see section 6.1), or to other
sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)
•
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
•
Severe renal impairment (creatinine clearance < 30 ml/min)
•
Refractory hypokalaemia, hypercalcaemia
•
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
the combination of irbesartan and hydrochlorothiazide has
been rarely associated with symptomatic hypotension in hypertensive patients without other risk
factors for hypotension. Symptomatic hypotension may be expected to 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 initiating therapy with
Irbesartan/Hydrochlorothiazide Teva.
Renal artery stenosis - 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 angiotensin converting enzyme inhibitors or angiotensin-II
receptor antagonists. While this is not documented with Irbesartan/Hydrochlorothiazide Teva, a
similar effect should be anticipated.
Renal impairment and kidney transplantation:
when Irbesartan/Hydrochlorothiazide Teva is used in
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid
serum levels is recommended. There is no experience regarding the administration of
Irbesartan/Hydrochlorothiazide Teva in patients with a recent kidney transplantation.
Irbesartan/Hydrochlorothiazide Teva should not be used in patients with severe renal impairment
(creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur
in patients with impaired renal function. No dosage adjustment is necessary in patients with renal
impairment whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate
renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination
should be administered with caution.
Hepatic impairment:
thiazides should be used with caution in patients with impaired hepatic function
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with Irbesartan/Hydrochlorothiazide Teva 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
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of Irbesartan/Hydrochlorothiazide Teva is not recommended.
3
Metabolic and endocrine effects:
thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;
however at the 12.5 mg dose contained in the irbesartan and hydrochlorothiazide combination,
minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Electrolyte imbalance:
as for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia,
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps,
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea
or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
irbesartan 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 the irbesartan component of
Irbesartan/Hydrochlorothiazide Teva hyperkalaemia might 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 salts substitutes should be co-administered cautiously with
Irbesartan/Hydrochlorothiazide Teva (see section 4.5).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
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
hypomagnaesemia.
Lithium:
the combination of lithium and Irbesartan/Hydrochlorothiazide Teva is not recommended
(see section 4.5).
Anti-doping test:
hydrochlorothiazide contained in this medicinal product could produce a positive
analytic result in an anti-doping test.
General:
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 angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic
cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If
photosensitivity reaction occurs during treatment, 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.
4
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative anti-hypertensive treatments which have an established safety profile for use in
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Other antihypertensive agents:
the antihypertensive effect of Irbesartan/Hydrochlorothiazide Teva may
be increased with the concomitant use of other antihypertensive agents. Irbesartan and
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely
administered with other antihypertensive agents including calcium channel blockers and
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless
the volume depletion is corrected first (see section 4.4).
Lithium:
reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is
reduced by thiazides so the risk of lithium toxicity could be increased with irbesartan and
hydrochlorothiazide combinations. Therefore, the combination of lithium and
Irbesartan/Hydrochlorothiazide Teva is not recommended (see section 4.4). If the combination proves
necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium:
the potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide
on serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other
medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products
that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum
potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section
4.4).
Medicinal products affected by serum potassium disturbances:
periodic monitoring of serum
potassium is recommended when Irbesartan/Hydrochlorothiazide Teva is administered with medicinal
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs:
when angiotensin II antagonists are administered
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors,
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect
may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure, and an increase in
serum potassium, especially in patients with poor pre-existing renal function. The combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring renal function after initiation of concomitant therapy, and
periodically thereafter.
Additional information on irbesartan interactions:
in clinical studies, the pharmacokinetic of irbesartan
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan
5
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of
irbesartan.
Additional information on hydrochlorothiazide interactions:
when administered concurrently, the
following medicinal products may interact with thiazide diuretics:
Alcohol:
potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins):
dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4);
Colestyramine and Colestipol resins:
absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Irbesartan/Hydrochlorothiazide Teva should be taken at least one hour before
or four hours after these medications;
Corticosteroids, ACTH:
electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides:
thiazide induced hypokalaemia or hypomagnaesemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs:
the administration of a non-steroidal anti-inflammatory drug
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline):
the effect of pressor amines may be decreased, but not
sufficiently to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
the effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products:
dosage adjustments of antigout medicinal products may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics 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 or calcium sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Other interactions:
the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, beperiden) 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 medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
Pregnancy:
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3
and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
6
AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRAs therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to AIIRAs have
occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is
recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections
4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults.
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal
thiazide therapy. Since Irbesartan/Hydrochlorothiazide Teva contains hydrochlorothiazide, it is not
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment
should be carried out in advance of a planned pregnancy.
Lactation:
Because no information is available regarding the use of Irbesartan/Hydrochlorothiazide Teva during
breast-feeding, Irbesartan/Hydrochlorothiazide Teva is not recommended and alternative treatments
with better established safety profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, Irbesartan/Hydrochlorothiazide Teva 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.
Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition increases in blood urea
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in
the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness.
Table 1.
Adverse reactions in placebo-controlled trials and spontaneous reports*
System Organ Class
Frequency
Adverse Reaction
Common
Increases in blood urea nitrogen
(BUN), creatinine and creatine
7
Investigations
kinase
Uncommon
Decreases in serum potassium
and sodium
Cardiac disorders
Uncommon
Syncope, hypotension,
tachycardia, oedema
Nervous system disorders
Common
Dizziness
Uncommon
Orthostatic dizziness
Not known
Headache
Ear and labyrinth disorders
Not known
Tinnitus
Respiratory, thoracic and
mediastinal disorders
Not known
Cough
Gastrointestinal disorders
Common
Nausea/vomiting
Uncommon
Diarrhoea
Not known
Dyspepsia, dysgeusia
Common
Abnormal urination
Renal and urinary disorders
Not known
Impaired renal function
including isolated cases of renal
failure in patients at risk (see
section 4.4)
Musculoskeletal and connective
tissue disorders
Uncommon
Swelling extremity
Not known
Arthralgia, myalgia
Metabolism and nutrition
disorders
Not known
Hyperkalaemia
Vascular disorders
Uncommon
Flushing
General disorders and
administration site conditions
Common
Fatigue
Immune system disorders
Not known
Cases of hypersensitivity
reactions such as angioedema,
rash, urticaria
Hepatobiliary disorders
Not known
Hepatitis, abnormal liver
function
Uncommon Sexual dysfunction, libido
changes
* Frequency for adverse reactions detected by spontaneous reports is described as “not known”
Additional information on individual components:
in addition to the adverse reactions listed above for
the combination product, other adverse reactions previously reported with one of the individual
components may be potential adverse reactions with Irbesartan/Hydrochlorothiazide Teva. Tables 2
and 3 below detail the adverse reactions reported with the individual components of
Irbesartan/Hydrochlorothiazide Teva.
Table 2.
Adverse reactions reported with the use of irbesartan alone
System Organ Class
Frequency
Adverse Reaction
General disorders and
administration site conditions
Uncommon
Chest pain
Table 3.
Adverse reactions (regardless of relationship to medicinal product) reported with the use of
hydrochorothiazide alone
System Organ Class
Frequency
Adverse Reaction
Electrolyte imbalance
(including hypokalaemia and
hyponatraemia, see section 4.4),
hyperuricaemia, glycosuria,
hyperglycaemia, increases in
cholesterol and triglycerides
Investigations
Not known
8
Reproductive system and breast
disorders
Cardiac disorders
Not known
Cardiac arrhythmias
Blood and lymphatic system
disorders
Not known
Aplastic anaemia, bone marrow
depression,
neutopenia/agranulocytosis,
haemolytic anaemia, leucopenia,
thrombocytopenia
Nervous system disorders
Not known
Vertigo, paraesthesia, light-
headedness, restlessness
Eye disorders
Not known
Transient blurred vision,
xanthopsia
Respiratory, thoracic and
mediastinal disorders
Not known
Respiratory distress (including
pneumonitis and pulmonary
oedema)
Gastrointestinal disorders
Not known
Pancreatitis, anorexia,
diarrhoea, constipation, gastric
irritation, sialadenitis, loss of
appetite
Renal and urinary disorders
Not known
Interstitial nephritis, renal
dysfunction
Skin and subcutaneous tissue
disorders
Not known
Anaphylactic reactions, toxic
epidermal necrolysis,
necrotizing angitis (vasculitis,
cutaneous vasculitis), cutaneous
lupus erythematosus-like
reactions, reactivation of
cutaneous lupus erythematosus,
photosensitivity reactions, rash,
urticaria
Musculoskeletal and connective
tissue disorders
Not known
Weakness, muscle spasm
Vascular disorders
Not known
Postural hypotension
General disorders and
administration site conditions
Not known
Fever
Hepatobiliary disorders
Not known
Jaundice (intrahepatic
cholestatic jaundice)
Psychiatric disorders
Not known
Depression, sleep disturbances
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may
increase when titrating the hydrochlorothiazide.
No specific information is available on the treatment of overdose with irbesartan and
hydrochlorothiazide combinations. The patient should be closely monitored, and the treatment should
be symptomatic and supportive. Management depends on the time since ingestion and the severity of
the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated
charcoal may be useful in the treatment of overdose. 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 irbesartan overdose are expected to be hypotension and tachycardia;
bradycardia might also occur.
hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common
signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle
9
spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by
haemodialysis has not been established.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09D A04
Irbesartan/Hydrochlorothiazide Teva is a combination of an angiotensin-II receptor antagonist,
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an
additive antihypertensive effect, reducing blood pressure to a greater degree than either component
alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT
1
subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT
1
receptor, regardless of the source
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT
1
) receptors
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5).
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its
activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of 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 amounts. The
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity,
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss,
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone
system, co-administration of irbesartan tends to reverse the potassium loss associated with these
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at
about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg 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 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and
diastolic blood pressure (DBP) (13.3 and 8.3 mmHg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mmHg
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours
10
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
irbesartan/hydrochlorothiazide 150 mg/12.5 mg were 100 %. The trough to peak effects measured by
cuff during office visits were 68 % and 76 % for irbesartan/hydrochlorothiazide 150 mg/12.5 mg and
irbesartan/hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed
without excessive blood pressure lowering at peak and are consistent with safe and effective blood-
pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mmHg.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is 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 effect of irbesartan/hydrochlorothiazide was maintained
for over one year. Although not specifically studied with irbesartan/hydrochlorothiazide, rebound
hypertension has not been seen with either irbesartan or hydrochlorothiazide.
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.
There is no difference in response to irbesartan/hydrochlorothiazide, regardless of age or gender. As is
the case with other medicinal products that affect the renin-angiotensin system, black hypertensive
patients have notably less response to irbesartan monotherapy. When irbesartan is administered
concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive
response in black patients approaches that of non-black patients.
Efficacy and safety of irbesartan/hydrochlorothiazide as initial therapy for severe hypertension
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomised, double-blind,
active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomised in a 2:1 ratio to
either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systemically
force-titrated (before assessing the response to the lower dose) after one week to
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58 % males. The mean age of patients was 52.5 years, 13 % were ≥ 65 years of
age, and just 2 % were ≥ 75 years of age. Twelve percent (12 %) of patients were diabetic, 34 % were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5 % of
the participants.
The primary objective of this study was to compare the proportion of patients whose SeDBP was
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2 %) of patients on
the combination achieved trough SeDBP < 90 mmHg compared to 33.2 % of patients on irbesartan
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period,
there were no reported cases of syncope in either treatment group. There were 0.6 % and 0 % of
patients with hypotension and 2.8 % and 3.1 % of patients with dizziness as adverse reactions reported
in the combination and monotherapy groups, respectively.
5.2 Pharmacokinetic properties
11
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the
pharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for
their activity. Following oral administration of irbesartan/hydrochlorothiazide, the absolute oral
bioavailability is 60-80 % and 50-80 % for irbesartan and hydrochlorothiazide, respectively. Food
does not affect the bioavailability of irbesartan/hydrochlorothiazide. Peak plasma concentration occurs
at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of irbesartan is approximately 96 %, with negligible binding to cellular blood
components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68 %
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.
A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited
accumulation of irbesartan (< 20 %) is observed in plasma upon repeated once-daily dosing. In a
study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive
patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage
adjustment is necessary in female patients. Irbesartan AUC and C
max
values were also somewhat
greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years). However the
terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients.
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
Following oral or intravenous administration of
14
C irbesartan, 80-85 % of the circulating plasma
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide
(approximately 6 %).
In vitro
studies indicate that irbesartan is primarily oxidised by the cytochrome
P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are
eliminated by both biliary and renal pathways. After either oral or intravenous administration of
14
C
irbesartan, about 20 % of the radioactivity is recovered in the urine, and the remainder in the faeces.
Less than 2 % of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidneys. At least 61 % of the oral dose is eliminated
unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier,
and is excreted in breast milk.
Renal impairment:
in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment:
in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic
impairment.
5.3 Preclinical safety data
Irbesartan/hydrochlorothiazide:
the potential toxicity of the irbesartan/hydrochlorothiazide
combination after oral administration was evaluated in rats and macaques in studies lasting up to
6 months. There were no toxicological findings observed of relevance to human therapeutic use. The
following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products
12
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions
were observed):
•
kidney changes, characterized by slight increases in serum urea and creatinine, and
hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the
interaction of irbesartan with the renin-angiotensin system;
•
slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);
•
stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in
a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;
•
decreases in serum potassium due to hydrochlorothiazide and partly prevented when
hydrochlorothiazide was given in combination with irbesartan.
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the
renin-producing cells) and occur also with angiotensin converting enzyme inhibitors. These findings
appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in
humans.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at
doses that produced maternal toxicity. The effects of the irbesartan and hydrochlorothiazide
combination on fertility have not been evaluated in animal studies, as there is no evidence of adverse
effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when
administered alone. However, another angiotensin-II antagonist affected fertility parameters in animal
studies when given alone. These findings were also observed with lower doses of this other
angiotensin-II antagonist when given in combination with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not
been evaluated in animal studies.
Irbesartan:
there was no evidence of abnormal systemic or target organ toxicity at clinically relevant
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and
≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes,
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the
kidneys (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma
concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are
considered secondary to the hypotensive effects of the medicinal product which led to decreased renal
perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in
rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be
caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits,
abortion or early resorption was noted at doses causing significant maternal toxicity, including
mortality. No teratogenic effects were observed in the rat or rabbit.
Hydrochlorothiazide:
although equivocal evidence for a genotoxic or carcinogenic effect was found in
some experimental models, the extensive human experience with hydrochlorothiazide has failed to
show an association between its use and an increase in neoplasms.
6.
6.1 List of excipients
Tablet core:
13
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Film-coating for 150 mg/12.5 mg strength:
Hypromellose
Titanium Dioxide
Polyethylene Glycol 6000 (Macrogol)
Polyethylene Glycol 400 (Macrogol)
Iron Oxide Red
Iron Oxide Yellow
Iron Oxide Black
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
Aluminium – Aluminium blisters: This medicinal product does not require any special storage
conditions.
6.5
Nature and contents of container
White opaque PVC-PVdC - Aluminium blisters or Aluminium – Aluminium blisters. Pack sizes of 7,
14, 15, 20, 28, 30, 56, 60, 90, 98 and 100 film-coated tablets and perforated unit dose blister 50x1
film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
8.
9.
14
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
15
1.
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Light pink to pink, film-coated capsule shaped tablet. One side of the tablet debossed with the number
"93". The other side of the tablet debossed with the number "7239".
4.
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).
Irbesartan/Hydrochlorothiazide Teva can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be
recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be
considered:
•
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg may be administered in patients whose
blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg
alone;
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg may be administered in patients
insufficiently controlled by irbesartan 300 mg or by Irbesartan/Hydrochlorothiazide Teva
150 mg/12.5 mg.
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg may be administered in patients
insufficiently controlled by Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Irbesartan/HydrochlorothiazideTeva may be administered with another
antihypertensive medicinal product (see section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Irbesartan/Hydrochlorothiazide Teva is
not recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients
with renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment:
Irbesartan/Hydrochlorothiazide Teva is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.
16
No dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in patients with mild to
moderate hepatic impairment (see section 4.3).
Elderly patients:
no dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in elderly
patients.
Paediatric patients:
Irbesartan/Hydrochlorothiazide Teva is not recommended for use in children and
adolescents due to a lack of data on safety and efficacy.
•
Hypersensitivity to the active substances, to any of the excipients (see section 6.1), or to other
sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)
•
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
•
Severe renal impairment (creatinine clearance < 30 ml/min)
•
Refractory hypokalaemia, hypercalcaemia
•
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
the combination of irbesartan and hydrochlorothiazide has
been rarely associated with symptomatic hypotension in hypertensive patients without other risk
factors for hypotension. Symptomatic hypotension may be expected to 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 initiating therapy with
Irbesartan/Hydrochlorothiazide Teva.
Renal artery stenosis - 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 angiotensin converting enzyme inhibitors or angiotensin-II
receptor antagonists. While this is not documented with Irbesartan/Hydrochlorothiazide Teva, a
similar effect should be anticipated.
Renal impairment and kidney transplantation:
when Irbesartan/Hydrochlorothiazide Teva is used in
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid
serum levels is recommended. There is no experience regarding the administration of
Irbesartan/Hydrochlorothiazide Teva in patients with a recent kidney transplantation.
Irbesartan/Hydrochlorothiazide Teva should not be used in patients with severe renal impairment
(creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur
in patients with impaired renal function. No dosage adjustment is necessary in patients with renal
impairment whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate
renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination
should be administered with caution.
Hepatic impairment:
thiazides should be used with caution in patients with impaired hepatic function
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with Irbesartan/Hydrochlorothiazide Teva 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
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of Irbesartan/Hydrochlorothiazide Teva is not recommended.
17
Metabolic and endocrine effects:
thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;
however at the 12.5 mg dose contained in the irbesartan and hydrochlorothiazide combination,
minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Electrolyte imbalance:
as for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia,
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps,
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea
or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
irbesartan 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 the irbesartan component of
Irbesartan/Hydrochlorothiazide Teva hyperkalaemia might 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 salts substitutes should be co-administered cautiously with
Irbesartan/Hydrochlorothiazide Teva (see section 4.5).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
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
hypomagnaesemia.
Lithium:
the combination of lithium and Irbesartan/Hydrochlorothiazide Teva is not recommended
(see section 4.5).
Anti-doping test:
hydrochlorothiazide contained in this medicinal product could produce a positive
analytic result in an anti-doping test.
General:
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 angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic
cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If
photosensitivity reaction occurs during treatment, 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.
18
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative anti-hypertensive treatments which have an established safety profile for use in
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Other antihypertensive agents:
the antihypertensive effect of Irbesartan/Hydrochlorothiazide Teva may
be increased with the concomitant use of other antihypertensive agents. Irbesartan and
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely
administered with other antihypertensive agents including calcium channel blockers and
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless
the volume depletion is corrected first (see section 4.4).
Lithium:
reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is
reduced by thiazides so the risk of lithium toxicity could be increased with irbesartan and
hydrochlorothiazide combinations. Therefore, the combination of lithium and
Irbesartan/Hydrochlorothiazide Teva is not recommended (see section 4.4). If the combination proves
necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium:
the potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide
on serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other
medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products
that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum
potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section
4.4).
Medicinal products affected by serum potassium disturbances:
periodic monitoring of serum
potassium is recommended when Irbesartan/Hydrochlorothiazide Teva is administered with medicinal
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs:
when angiotensin II antagonists are administered
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors,
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect
may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure, and an increase in
serum potassium, especially in patients with poor pre-existing renal function. The combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring renal function after initiation of concomitant therapy, and
periodically thereafter.
Additional information on irbesartan interactions:
in clinical studies, the pharmacokinetic of irbesartan
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan
19
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of
irbesartan.
Additional information on hydrochlorothiazide interactions:
when administered concurrently, the
following medicinal products may interact with thiazide diuretics:
Alcohol:
potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins):
dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4);
Colestyramine and Colestipol resins:
absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Irbesartan/Hydrochlorothiazide Teva should be taken at least one hour before
or four hours after these medications;
Corticosteroids, ACTH:
electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides:
thiazide induced hypokalaemia or hypomagnaesemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs:
the administration of a non-steroidal anti-inflammatory drug
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline):
the effect of pressor amines may be decreased, but not
sufficiently to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
the effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products:
dosage adjustments of antigout medicinal products may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics 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 or calcium sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Other interactions:
the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, beperiden) 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 medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
Pregnancy:
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3
and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
20
AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRAs therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to AIIRAs have
occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is
recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections
4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults.
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal
thiazide therapy. Since Irbesartan/Hydrochlorothiazide Teva contains hydrochlorothiazide, it is not
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment
should be carried out in advance of a planned pregnancy.
Lactation:
Because no information is available regarding the use of Irbesartan/Hydrochlorothiazide Teva during
breast-feeding, Irbesartan/Hydrochlorothiazide Teva is not recommended and alternative treatments
with better established safety profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, Irbesartan/Hydrochlorothiazide Teva 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.
Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition increases in blood urea
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in
the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness.
Table 1.
Adverse reactions in placebo-controlled trials and spontaneous reports*
System Organ Class
Frequency
Adverse Reaction
Common
Increases in blood urea nitrogen
(BUN), creatinine and creatine
21
Investigations
kinase
Uncommon
Decreases in serum potassium
and sodium
Cardiac disorders
Uncommon
Syncope, hypotension,
tachycardia, oedema
Nervous system disorders
Common
Dizziness
Uncommon
Orthostatic dizziness
Not known
Headache
Ear and labyrinth disorders
Not known
Tinnitus
Respiratory, thoracic and
mediastinal disorders
Not known
Cough
Gastrointestinal disorders
Common
Nausea/vomiting
Uncommon
Diarrhoea
Not known
Dyspepsia, dysgeusia
Common
Abnormal urination
Renal and urinary disorders
Not known
Impaired renal function
including isolated cases of renal
failure in patients at risk (see
section 4.4)
Musculoskeletal and connective
tissue disorders
Uncommon
Swelling extremity
Not known
Arthralgia, myalgia
Metabolism and nutrition
disorders
Not known
Hyperkalaemia
Vascular disorders
Uncommon
Flushing
General disorders and
administration site conditions
Common
Fatigue
Immune system disorders
Not known
Cases of hypersensitivity
reactions such as angioedema,
rash, urticaria
Hepatobiliary disorders
Not known
Hepatitis, abnormal liver
function
Uncommon Sexual dysfunction, libido
changes
* Frequency for adverse reactions detected by spontaneous reports is described as “not known”
Additional information on individual components:
in addition to the adverse reactions listed above for
the combination product, other adverse reactions previously reported with one of the individual
components may be potential adverse reactions with Irbesartan/Hydrochlorothiazide Teva. Tables 2
and 3 below detail the adverse reactions reported with the individual components of
Irbesartan/Hydrochlorothiazide Teva.
Table 2.
Adverse reactions reported with the use of irbesartan alone
System Organ Class
Frequency
Adverse Reaction
General disorders and
administration site conditions
Uncommon
Chest pain
Table 3.
Adverse reactions (regardless of relationship to medicinal product) reported with the use of
hydrochorothiazide alone
System Organ Class
Frequency
Adverse Reaction
Electrolyte imbalance
(including hypokalaemia and
hyponatraemia, see section 4.4),
hyperuricaemia, glycosuria,
hyperglycaemia, increases in
cholesterol and triglycerides
Investigations
Not known
22
Reproductive system and breast
disorders
Cardiac disorders
Not known
Cardiac arrhythmias
Blood and lymphatic system
disorders
Not known
Aplastic anaemia, bone marrow
depression,
neutopenia/agranulocytosis,
haemolytic anaemia, leucopenia,
thrombocytopenia
Nervous system disorders
Not known
Vertigo, paraesthesia, light-
headedness, restlessness
Eye disorders
Not known
Transient blurred vision,
xanthopsia
Respiratory, thoracic and
mediastinal disorders
Not known
Respiratory distress (including
pneumonitis and pulmonary
oedema)
Gastrointestinal disorders
Not known
Pancreatitis, anorexia,
diarrhoea, constipation, gastric
irritation, sialadenitis, loss of
appetite
Renal and urinary disorders
Not known
Interstitial nephritis, renal
dysfunction
Skin and subcutaneous tissue
disorders
Not known
Anaphylactic reactions, toxic
epidermal necrolysis,
necrotizing angitis (vasculitis,
cutaneous vasculitis), cutaneous
lupus erythematosus-like
reactions, reactivation of
cutaneous lupus erythematosus,
photosensitivity reactions, rash,
urticaria
Musculoskeletal and connective
tissue disorders
Not known
Weakness, muscle spasm
Vascular disorders
Not known
Postural hypotension
General disorders and
administration site conditions
Not known
Fever
Hepatobiliary disorders
Not known
Jaundice (intrahepatic
cholestatic jaundice)
Psychiatric disorders
Not known
Depression, sleep disturbances
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may
increase when titrating the hydrochlorothiazide.
No specific information is available on the treatment of overdose with irbesartan and
hydrochlorothiazide combinations. The patient should be closely monitored, and the treatment should
be symptomatic and supportive. Management depends on the time since ingestion and the severity of
the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated
charcoal may be useful in the treatment of overdose. 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 irbesartan overdose are expected to be hypotension and tachycardia;
bradycardia might also occur.
hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common
signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle
23
spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by
haemodialysis has not been established.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09D A04
Irbesartan/Hydrochlorothiazide Teva is a combination of an angiotensin-II receptor antagonist,
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an
additive antihypertensive effect, reducing blood pressure to a greater degree than either component
alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT
1
subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT
1
receptor, regardless of the source
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT
1
) receptors
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5).
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its
activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of 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 amounts. The
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity,
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss,
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone
system, co-administration of irbesartan tends to reverse the potassium loss associated with these
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at
about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg 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 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and
diastolic blood pressure (DBP) (13.3 and 8.3 mmHg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mmHg
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours
24
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
irbesartan/hydrochlorothiazide 150 mg/12.5 mg were 100 %. The trough to peak effects measured by
cuff during office visits were 68 % and 76 % for irbesartan/hydrochlorothiazide 150 mg/12.5 mg and
irbesartan/hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed
without excessive blood pressure lowering at peak and are consistent with safe and effective blood-
pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mmHg.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is 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 effect of irbesartan/hydrochlorothiazide was maintained
for over one year. Although not specifically studied with irbesartan/hydrochlorothiazide, rebound
hypertension has not been seen with either irbesartan or hydrochlorothiazide.
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.
There is no difference in response to irbesartan/hydrochlorothiazide, regardless of age or gender. As is
the case with other medicinal products that affect the renin-angiotensin system, black hypertensive
patients have notably less response to irbesartan monotherapy. When irbesartan is administered
concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive
response in black patients approaches that of non-black patients.
Efficacy and safety of irbesartan/hydrochlorothiazide as initial therapy for severe hypertension
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomised, double-blind,
active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomised in a 2:1 ratio to
either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systemically
force-titrated (before assessing the response to the lower dose) after one week to
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58 % males. The mean age of patients was 52.5 years, 13 % were ≥ 65 years of
age, and just 2 % were ≥ 75 years of age. Twelve percent (12 %) of patients were diabetic, 34 % were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5 % of
the participants.
The primary objective of this study was to compare the proportion of patients whose SeDBP was
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2 %) of patients on
the combination achieved trough SeDBP < 90 mmHg compared to 33.2 % of patients on irbesartan
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period,
there were no reported cases of syncope in either treatment group. There were 0.6 % and 0 % of
patients with hypotension and 2.8 % and 3.1 % of patients with dizziness as adverse reactions reported
in the combination and monotherapy groups, respectively.
5.2 Pharmacokinetic properties
25
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the
pharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for
their activity. Following oral administration of irbesartan/hydrochlorothiazide, the absolute oral
bioavailability is 60-80 % and 50-80 % for irbesartan and hydrochlorothiazide, respectively. Food
does not affect the bioavailability of irbesartan/hydrochlorothiazide. Peak plasma concentration occurs
at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of irbesartan is approximately 96 %, with negligible binding to cellular blood
components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68 %
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.
A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited
accumulation of irbesartan (< 20 %) is observed in plasma upon repeated once-daily dosing. In a
study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive
patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage
adjustment is necessary in female patients. Irbesartan AUC and C
max
values were also somewhat
greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years). However the
terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients.
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
Following oral or intravenous administration of
14
C irbesartan, 80-85 % of the circulating plasma
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide
(approximately 6 %).
In vitro
studies indicate that irbesartan is primarily oxidised by the cytochrome
P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are
eliminated by both biliary and renal pathways. After either oral or intravenous administration of
14
C
irbesartan, about 20 % of the radioactivity is recovered in the urine, and the remainder in the faeces.
Less than 2 % of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidneys. At least 61 % of the oral dose is eliminated
unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier,
and is excreted in breast milk.
Renal impairment:
in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment:
in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic
impairment.
5.3 Preclinical safety data
Irbesartan/hydrochlorothiazide:
the potential toxicity of the irbesartan/hydrochlorothiazide
combination after oral administration was evaluated in rats and macaques in studies lasting up to
6 months. There were no toxicological findings observed of relevance to human therapeutic use. The
following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products
26
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions
were observed):
•
kidney changes, characterized by slight increases in serum urea and creatinine, and
hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the
interaction of irbesartan with the renin-angiotensin system;
•
slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);
•
stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in
a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;
•
decreases in serum potassium due to hydrochlorothiazide and partly prevented when
hydrochlorothiazide was given in combination with irbesartan.
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the
renin-producing cells) and occur also with angiotensin converting enzyme inhibitors. These findings
appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in
humans.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at
doses that produced maternal toxicity. The effects of the irbesartan and hydrochlorothiazide
combination on fertility have not been evaluated in animal studies, as there is no evidence of adverse
effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when
administered alone. However, another angiotensin-II antagonist affected fertility parameters in animal
studies when given alone. These findings were also observed with lower doses of this other
angiotensin-II antagonist when given in combination with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not
been evaluated in animal studies.
Irbesartan:
there was no evidence of abnormal systemic or target organ toxicity at clinically relevant
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and
≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes,
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the
kidneys (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma
concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are
considered secondary to the hypotensive effects of the medicinal product which led to decreased renal
perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in
rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be
caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits,
abortion or early resorption was noted at doses causing significant maternal toxicity, including
mortality. No teratogenic effects were observed in the rat or rabbit.
Hydrochlorothiazide:
although equivocal evidence for a genotoxic or carcinogenic effect was found in
some experimental models, the extensive human experience with hydrochlorothiazide has failed to
show an association between its use and an increase in neoplasms.
6.
6.1 List of excipients
Tablet core:
27
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Film-coating for 300 mg/12.5 mg strength:
Hypromellose
Titanium Dioxide
Polyethylene Glycol 6000 (Macrogol)
Polyethylene Glycol 400 (Macrogol)
Iron Oxide Red
Iron Oxide Yellow
Iron Oxide Black
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
Aluminium – Aluminium blisters: This medicinal product does not require any special storage
conditions.
6.5 Nature and contents of container
White opaque PVC-PVdC - Aluminium blisters or Aluminium – Aluminium blisters. Pack sizes of 7,
14, 15, 20, 28, 30, 56, 60, 90, 98 and 100 film-coated tablets and perforated unit dose blister 50x1
film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
8.
9.
28
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
29
1.
Irbesartan/Hydrocholorthiazide Teva 300 mg/25 mg film-coated tablets
2.
Each film-coated tablets contains 300 mg of irbesartan and 25 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Pink to dark pink, film-coated capsule shaped tablet. One side of the tablet debossed with the number
"93". The other side of the tablet debossed with the number "7469".
4.
Treatment of essential hypertension.
This fixed dose combination is indicated in adult patients whose blood pressure is not adequately
controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).
Irbesartan/Hydrochlorothiazide Teva can be taken once daily, with or without food.
Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may be
recommended.
When clinically appropriate direct change from monotherapy to the fixed combinations may be
considered:
•
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg may be administered in patients whose
blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg
alone;
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg may be administered in patients
insufficiently controlled by irbesartan 300 mg or by Irbesartan/Hydrochlorothiazide Teva
150 mg/12.5 mg.
•
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg may be administered in patients
insufficiently controlled by Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Irbesartan/HydrochlorothiazideTeva may be administered with another
antihypertensive medicinal product (see section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Irbesartan/Hydrochlorothiazide Teva is
not recommended for patients with severe renal dysfunction (creatinine clearance < 30 ml/min). Loop
diuretics are preferred to thiazides in this population. No dosage adjustment is necessary in patients
with renal impairment whose renal creatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).
Hepatic impairment:
Irbesartan/Hydrochlorothiazide Teva is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.
30
No dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in patients with mild to
moderate hepatic impairment (see section 4.3).
Elderly patients:
no dosage adjustment of Irbesartan/Hydrochlorothiazide Teva is necessary in elderly
patients.
Paediatric patients:
Irbesartan/Hydrochlorothiazide Teva is not recommended for use in children and
adolescents due to a lack of data on safety and efficacy.
•
Hypersensitivity to the active substances, to any of the excipients (see section 6.1), or to other
sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)
•
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
•
Severe renal impairment (creatinine clearance < 30 ml/min)
•
Refractory hypokalaemia, hypercalcaemia
•
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
the combination of irbesartan and hydrochlorothiazide has
been rarely associated with symptomatic hypotension in hypertensive patients without other risk
factors for hypotension. Symptomatic hypotension may be expected to 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 initiating therapy with
Irbesartan/Hydrochlorothiazide Teva.
Renal artery stenosis - 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 angiotensin converting enzyme inhibitors or angiotensin-II
receptor antagonists. While this is not documented with Irbesartan/Hydrochlorothiazide Teva, a
similar effect should be anticipated.
Renal impairment and kidney transplantation:
when Irbesartan/Hydrochlorothiazide Teva is used in
patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid
serum levels is recommended. There is no experience regarding the administration of
Irbesartan/Hydrochlorothiazide Teva in patients with a recent kidney transplantation.
Irbesartan/Hydrochlorothiazide Teva should not be used in patients with severe renal impairment
(creatinine clearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotemia may occur
in patients with impaired renal function. No dosage adjustment is necessary in patients with renal
impairment whose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate
renal impairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination
should be administered with caution.
Hepatic impairment:
thiazides should be used with caution in patients with impaired hepatic function
or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with Irbesartan/Hydrochlorothiazide Teva 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
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of Irbesartan/Hydrochlorothiazide Teva is not recommended.
31
Metabolic and endocrine effects:
thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;
however at the 12.5 mg dose contained in the irbesartan and hydrochlorothiazide combination,
minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Electrolyte imbalance:
as for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia,
hyponatraemia, and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps,
muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea
or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
irbesartan 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 the irbesartan component of
Irbesartan/Hydrochlorothiazide Teva hyperkalaemia might 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 salts substitutes should be co-administered cautiously with
Irbesartan/Hydrochlorothiazide Teva (see section 4.5).
There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
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
hypomagnaesemia.
Lithium:
the combination of lithium and Irbesartan/Hydrochlorothiazide Teva is not recommended
(see section 4.5).
Anti-doping test:
hydrochlorothiazide contained in this medicinal product could produce a positive
analytic result in an anti-doping test.
General:
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 angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive
agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic
cardiovascular disease could result in a myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of
allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). If
photosensitivity reaction occurs during treatment, 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.
32
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative anti-hypertensive treatments which have an established safety profile for use in
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Other antihypertensive agents:
the antihypertensive effect of Irbesartan/Hydrochlorothiazide Teva may
be increased with the concomitant use of other antihypertensive agents. Irbesartan and
hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely
administered with other antihypertensive agents including calcium channel blockers and
beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and
a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless
the volume depletion is corrected first (see section 4.4).
Lithium:
reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects
have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is
reduced by thiazides so the risk of lithium toxicity could be increased with irbesartan and
hydrochlorothiazide combinations. Therefore, the combination of lithium and
Irbesartan/Hydrochlorothiazide Teva is not recommended (see section 4.4). If the combination proves
necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium:
the potassium-depleting effect of hydrochlorothiazide is
attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide
on serum potassium would be expected to be potentiated by other medicinal products associated with
potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other
medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products
that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum
potassium. Adequate monitoring of serum potassium in patients at risk is recommended (see section
4.4).
Medicinal products affected by serum potassium disturbances:
periodic monitoring of serum
potassium is recommended when Irbesartan/Hydrochlorothiazide Teva is administered with medicinal
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs:
when angiotensin II antagonists are administered
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors,
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect
may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure, and an increase in
serum potassium, especially in patients with poor pre-existing renal function. The combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring renal function after initiation of concomitant therapy, and
periodically thereafter.
Additional information on irbesartan interactions:
in clinical studies, the pharmacokinetic of irbesartan
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan
33
have not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration of
irbesartan.
Additional information on hydrochlorothiazide interactions:
when administered concurrently, the
following medicinal products may interact with thiazide diuretics:
Alcohol:
potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins):
dosage adjustment of the antidiabetic
medicinal product may be required (see section 4.4);
Colestyramine and Colestipol resins:
absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Irbesartan/Hydrochlorothiazide Teva should be taken at least one hour before
or four hours after these medications;
Corticosteroids, ACTH:
electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides:
thiazide induced hypokalaemia or hypomagnaesemia favour the onset of
digitalis-induced cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs:
the administration of a non-steroidal anti-inflammatory drug
may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline):
the effect of pressor amines may be decreased, but not
sufficiently to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
the effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products:
dosage adjustments of antigout medicinal products may be necessary as
hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or
sulfinpyrazone may be necessary. Co-administration of thiazide diuretics 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 or calcium sparing medicinal products (e.g. vitamin D therapy) must be
prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Other interactions:
the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by
thiazides. Anticholinergic agents (e.g. atropine, beperiden) 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 medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
Pregnancy:
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3
and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
34
AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRAs therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to AIIRAs have
occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is
recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections
4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental
perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults.
Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal
thiazide therapy. Since Irbesartan/Hydrochlorothiazide Teva contains hydrochlorothiazide, it is not
recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment
should be carried out in advance of a planned pregnancy.
Lactation:
Because no information is available regarding the use of Irbesartan/Hydrochlorothiazide Teva during
breast-feeding, Irbesartan/Hydrochlorothiazide Teva is not recommended and alternative treatments
with better established safety profiles during breast-feeding are preferable, especially while nursing a
newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, Irbesartan/Hydrochlorothiazide Teva 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.
Irbesartan/hydrochlorothiazide combination:
Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide
(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patients
experienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue
(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition increases in blood urea
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed in
the trials.
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness.
Table 1.
Adverse reactions in placebo-controlled trials and spontaneous reports*
System Organ Class
Frequency
Adverse Reaction
Common
Increases in blood urea nitrogen
(BUN), creatinine and creatine
35
Investigations
kinase
Uncommon
Decreases in serum potassium
and sodium
Cardiac disorders
Uncommon
Syncope, hypotension,
tachycardia, oedema
Nervous system disorders
Common
Dizziness
Uncommon
Orthostatic dizziness
Not known
Headache
Ear and labyrinth disorders
Not known
Tinnitus
Respiratory, thoracic and
mediastinal disorders
Not known
Cough
Gastrointestinal disorders
Common
Nausea/vomiting
Uncommon
Diarrhoea
Not known
Dyspepsia, dysgeusia
Common
Abnormal urination
Renal and urinary disorders
Not known
Impaired renal function
including isolated cases of renal
failure in patients at risk (see
section 4.4)
Musculoskeletal and connective
tissue disorders
Uncommon
Swelling extremity
Not known
Arthralgia, myalgia
Metabolism and nutrition
disorders
Not known
Hyperkalaemia
Vascular disorders
Uncommon
Flushing
General disorders and
administration site conditions
Common
Fatigue
Immune system disorders
Not known
Cases of hypersensitivity
reactions such as angioedema,
rash, urticaria
Hepatobiliary disorders
Not known
Hepatitis, abnormal liver
function
Uncommon Sexual dysfunction, libido
changes
* Frequency for adverse reactions detected by spontaneous reports is described as “not known”
Additional information on individual components:
in addition to the adverse reactions listed above for
the combination product, other adverse reactions previously reported with one of the individual
components may be potential adverse reactions with Irbesartan/Hydrochlorothiazide Teva. Tables 2
and 3 below detail the adverse reactions reported with the individual components of
Irbesartan/Hydrochlorothiazide Teva.
Table 2.
Adverse reactions reported with the use of irbesartan alone
System Organ Class
Frequency
Adverse Reaction
General disorders and
administration site conditions
Uncommon
Chest pain
Table 3.
Adverse reactions (regardless of relationship to medicinal product) reported with the use of
hydrochorothiazide alone
System Organ Class
Frequency
Adverse Reaction
Electrolyte imbalance
(including hypokalaemia and
hyponatraemia, see section 4.4),
hyperuricaemia, glycosuria,
hyperglycaemia, increases in
cholesterol and triglycerides
Investigations
Not known
36
Reproductive system and breast
disorders
Cardiac disorders
Not known
Cardiac arrhythmias
Blood and lymphatic system
disorders
Not known
Aplastic anaemia, bone marrow
depression,
neutopenia/agranulocytosis,
haemolytic anaemia, leucopenia,
thrombocytopenia
Nervous system disorders
Not known
Vertigo, paraesthesia, light-
headedness, restlessness
Eye disorders
Not known
Transient blurred vision,
xanthopsia
Respiratory, thoracic and
mediastinal disorders
Not known
Respiratory distress (including
pneumonitis and pulmonary
oedema)
Gastrointestinal disorders
Not known
Pancreatitis, anorexia,
diarrhoea, constipation, gastric
irritation, sialadenitis, loss of
appetite
Renal and urinary disorders
Not known
Interstitial nephritis, renal
dysfunction
Skin and subcutaneous tissue
disorders
Not known
Anaphylactic reactions, toxic
epidermal necrolysis,
necrotizing angitis (vasculitis,
cutaneous vasculitis), cutaneous
lupus erythematosus-like
reactions, reactivation of
cutaneous lupus erythematosus,
photosensitivity reactions, rash,
urticaria
Musculoskeletal and connective
tissue disorders
Not known
Weakness, muscle spasm
Vascular disorders
Not known
Postural hypotension
General disorders and
administration site conditions
Not known
Fever
Hepatobiliary disorders
Not known
Jaundice (intrahepatic
cholestatic jaundice)
Psychiatric disorders
Not known
Depression, sleep disturbances
The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) may
increase when titrating the hydrochlorothiazide.
No specific information is available on the treatment of overdose with irbesartan and
hydrochlorothiazide combinations. The patient should be closely monitored, and the treatment should
be symptomatic and supportive. Management depends on the time since ingestion and the severity of
the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated
charcoal may be useful in the treatment of overdose. 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 irbesartan overdose are expected to be hypotension and tachycardia;
bradycardia might also occur.
hypochloremia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common
signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle
37
spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by
haemodialysis has not been established.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09D A04
Irbesartan/Hydrochlorothiazide Teva is a combination of an angiotensin-II receptor antagonist,
irbesartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an
additive antihypertensive effect, reducing blood pressure to a greater degree than either component
alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT
1
subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT
1
receptor, regardless of the source
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT
1
) receptors
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at
the recommended doses in patients without risk of electrolyte imbalance (see sections 4.4 and 4.5).
Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also
degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its
activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of 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 amounts. The
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity,
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss,
and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone
system, co-administration of irbesartan tends to reverse the potassium loss associated with these
diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at
about 4 hours, while the action persists for approximately 6-12 hours.
The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions in
blood pressure across their therapeutic dose ranges. The addition of 12.5 mg 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 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, an
incremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) and
diastolic blood pressure (DBP) (13.3 and 8.3 mmHg, respectively).
Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide gave systolic/diastolic
mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mmHg
in patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed by
ambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mg
hydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hours
38
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
irbesartan/hydrochlorothiazide 150 mg/12.5 mg were 100 %. The trough to peak effects measured by
cuff during office visits were 68 % and 76 % for irbesartan/hydrochlorothiazide 150 mg/12.5 mg and
irbesartan/hydrochlorothiazide 300 mg/12.5 mg, respectively. These 24-hour effects were observed
without excessive blood pressure lowering at peak and are consistent with safe and effective blood-
pressure lowering over the once-daily dosing interval.
In patients not adequately controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan
gave an added placebo-subtracted systolic/diastolic mean reduction of 11.1/7.2 mmHg.
The blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide is 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 effect of irbesartan/hydrochlorothiazide was maintained
for over one year. Although not specifically studied with irbesartan/hydrochlorothiazide, rebound
hypertension has not been seen with either irbesartan or hydrochlorothiazide.
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.
There is no difference in response to irbesartan/hydrochlorothiazide, regardless of age or gender. As is
the case with other medicinal products that affect the renin-angiotensin system, black hypertensive
patients have notably less response to irbesartan monotherapy. When irbesartan is administered
concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive
response in black patients approaches that of non-black patients.
Efficacy and safety of irbesartan/hydrochlorothiazide as initial therapy for severe hypertension
(defined as SeDBP ≥ 110 mmHg) was evaluated in a multicenter, randomised, double-blind,
active-controlled, 8-week, parallel-arm study. A total of 697 patients were randomised in a 2:1 ratio to
either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systemically
force-titrated (before assessing the response to the lower dose) after one week to
irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.
The study recruited 58 % males. The mean age of patients was 52.5 years, 13 % were ≥ 65 years of
age, and just 2 % were ≥ 75 years of age. Twelve percent (12 %) of patients were diabetic, 34 % were
hyperlipidemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5 % of
the participants.
The primary objective of this study was to compare the proportion of patients whose SeDBP was
controlled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2 %) of patients on
the combination achieved trough SeDBP < 90 mmHg compared to 33.2 % of patients on irbesartan
(p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment
group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for
irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).
The types and incidences of adverse events reported for patients treated with the combination were
similar to the adverse event profile for patients on monotherapy. During the 8-week treatment period,
there were no reported cases of syncope in either treatment group. There were 0.6 % and 0 % of
patients with hypotension and 2.8 % and 3.1 % of patients with dizziness as adverse reactions reported
in the combination and monotherapy groups, respectively.
5.2 Pharmacokinetic properties
39
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the
pharmacokinetics of either medicinal product.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for
their activity. Following oral administration of irbesartan/hydrochlorothiazide, the absolute oral
bioavailability is 60-80 % and 50-80 % for irbesartan and hydrochlorothiazide, respectively. Food
does not affect the bioavailability of irbesartan/hydrochlorothiazide. Peak plasma concentration occurs
at 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Plasma protein binding of irbesartan is approximately 96 %, with negligible binding to cellular blood
components. The volume of distribution for irbesartan is 53-93 litres. Hydrochlorothiazide is 68 %
protein-bound in the plasma, and its apparent volume of distribution is 0.83-1.14 l/kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.
A less than proportional increase in oral absorption at doses beyond 600 mg was observed; the
mechanism for this is unknown. The total body and renal clearance are 157-176 and 3.0-3.5 ml/min,
respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma
concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited
accumulation of irbesartan (< 20 %) is observed in plasma upon repeated once-daily dosing. In a
study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive
patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage
adjustment is necessary in female patients. Irbesartan AUC and C
max
values were also somewhat
greater in elderly subjects (≥ 65 years) than those of young subjects (18-40 years). However the
terminal half-life was not significantly altered. No dosage adjustment is necessary in elderly patients.
The mean plasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.
Following oral or intravenous administration of
14
C irbesartan, 80-85 % of the circulating plasma
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide
(approximately 6 %).
In vitro
studies indicate that irbesartan is primarily oxidised by the cytochrome
P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. Irbesartan and its metabolites are
eliminated by both biliary and renal pathways. After either oral or intravenous administration of
14
C
irbesartan, about 20 % of the radioactivity is recovered in the urine, and the remainder in the faeces.
Less than 2 % of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not
metabolized but is eliminated rapidly by the kidneys. At least 61 % of the oral dose is eliminated
unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier,
and is excreted in breast milk.
Renal impairment:
in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of
hydrochlorothiazide was reported to increase to 21 hours.
Hepatic impairment:
in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic
impairment.
5.3 Preclinical safety data
Irbesartan/hydrochlorothiazide:
the potential toxicity of the irbesartan/hydrochlorothiazide
combination after oral administration was evaluated in rats and macaques in studies lasting up to
6 months. There were no toxicological findings observed of relevance to human therapeutic use. The
following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazide
combination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal products
40
alone and/or were secondary to decreases in blood pressure (no significant toxicologic interactions
were observed):
•
kidney changes, characterized by slight increases in serum urea and creatinine, and
hyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the
interaction of irbesartan with the renin-angiotensin system;
•
slight decreases in erythrocyte parameters (erythrocytes, haemoglobin, haematocrit);
•
stomach discoloration, ulcers and focal necrosis of gastric mucosa were observed in few rats in
a 6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, and
irbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;
•
decreases in serum potassium due to hydrochlorothiazide and partly prevented when
hydrochlorothiazide was given in combination with irbesartan.
Most of the above mentioned effects appear to be due to the pharmacological activity of irbesartan
(blockade of angiotensin-II-induced inhibition of renin release, with stimulation of the
renin-producing cells) and occur also with angiotensin converting enzyme inhibitors. These findings
appear to have no relevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in
humans.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination at
doses that produced maternal toxicity. The effects of the irbesartan and hydrochlorothiazide
combination on fertility have not been evaluated in animal studies, as there is no evidence of adverse
effect on fertility in animals or humans with either irbesartan or hydrochlorothiazide when
administered alone. However, another angiotensin-II antagonist affected fertility parameters in animal
studies when given alone. These findings were also observed with lower doses of this other
angiotensin-II antagonist when given in combination with hydrochlorothiazide.
There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazide
combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not
been evaluated in animal studies.
Irbesartan:
there was no evidence of abnormal systemic or target organ toxicity at clinically relevant
doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and
≥ 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes,
haemoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the
kidneys (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma
concentrations of urea and creatinine) were induced by irbesartan in the rat and the macaque and are
considered secondary to the hypotensive effects of the medicinal product which led to decreased renal
perfusion. Furthermore, irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in
rats at ≥ 90 mg/kg/day, in macaques at ≥ 10 mg/kg/day). All of these changes were considered to be
caused by the pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits,
abortion or early resorption was noted at doses causing significant maternal toxicity, including
mortality. No teratogenic effects were observed in the rat or rabbit.
Hydrochlorothiazide:
although equivocal evidence for a genotoxic or carcinogenic effect was found in
some experimental models, the extensive human experience with hydrochlorothiazide has failed to
show an association between its use and an increase in neoplasms.
6.
6.1 List of excipients
Tablet core:
41
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Film coating for 300 mg/25 mg strength:
Hypromellose
Titanium Dioxide
Polyethylene Glycol 6000 (Macrogol)
Polyethylene Glycol 400 (Macrogol)
Iron Oxide Red
Indigotine (Indigo carmine aluminium lake FD&C blue #2)
Iron Oxide Black
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
White opaque PVC-PVdC - Aluminium blisters: 1 year.
Aluminium – Aluminium blisters: 18 months.
6.4 Special precautions for storage
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
Aluminium – Aluminium blisters: This medicinal product does not require any special storage
conditions.
6.5 Nature and contents of container
White opaque PVC-PVdC - Aluminium blisters or Aluminium – Aluminium blisters. Pack sizes of 7,
14, 15, 20, 28, 30, 56, 60, 90, 98 and 100 film-coated tablets and perforated unit dose blister 50x1
film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
8.
9.
42
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
43
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
44
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13.
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllő
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG
United Kingdom
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
45
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 dated 28
May 2009 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management plan
Not applicable.
The application is based on a reference medicinal product for which no safety concerns requiring
specific risk minimization activities have been identified.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
46
ANNEX III
LABELLING AND PACKAGE LEAFLET
47
A. LABELLING
48
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg irbesartan and 12.5 mg hydrochlorothiazide
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
15 film-coated tablets
20 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50x1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Swallow tablets whole.
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
49
EXP
9.
SPECIAL STORAGE CONDITIONS
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg
50
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg irbesartan and 12.5 mg hydrochlorothiazide
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
15 film-coated tablets
20 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50x1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Swallow tablets whole.
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
52
EXP
9.
SPECIAL STORAGE CONDITIONS
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg
53
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
54
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg irbesartan and 25 mg hydrochlorothiazide
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
15 film-coated tablets
20 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50x1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Swallow tablets whole.
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
55
EXP
9.
SPECIAL STORAGE CONDITIONS
White opaque PVC-PVdC - Aluminium blisters: Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg
56
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg film-coated tablets
irbesartan/hydrochlorothiazide
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
57
B. PACKAGE LEAFLET
58
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablets
irbesartan / hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan/Hydrochlorothiazide Teva is and what it is used for
2. Before you take Irbesartan/Hydrochlorothiazide Teva
3. How to take Irbesartan/Hydrochlorothiazide Teva
4. Possible side effects
5.
How to store Irbesartan/Hydrochlorothiazide Teva
6.
Further information
1.
WHAT IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA IS AND WHAT IT IS
USED FOR
Irbesartan/Hydrochlorothiazide Teva is a combination of two active substances, irbesartan and
hydrochlorothiazide. Irbesartan belongs to a group of medicines known as angiotensin-II receptor
antagonists. Angiotensin-II is a substance produced in the body that binds to receptors in blood
vessels causing them to tighten. This results in an increase in blood pressure. Irbesartan prevents the
binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure
to lower. Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes
increased urine output and so causes a lowering of blood pressure.
The two active ingredients in Irbesartan/Hydrochlorothiazide Teva work together to lower blood
pressure further than if either was given alone.
Irbesartan/Hydrochlorothiazide Teva is used in the treatment of high blood pressure in adults
(essential hypertension), when treatment with irbesartan or hydrochlorothiazide alone did not provide
adequate control of your blood pressure.
2.
BEFORE YOU TAKE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Do not take
Irbesartan/Hydrochlorothiazide Teva
-
If you are allergic (hypersensitive) to irbesartan and hydrochlorothiazide, or any of the other
ingredients of Irbesartan/Hydrochlorothiazide Teva or to medicines chemically related to
sulfonamide (ask your doctor or pharmacist for further clarification).
-
If you are more than 3 months pregnant (it is also better to avoid Irbesartan/Hydrochlorothiazide
Teva in early pregnancy – see pregnancy section).
-
If you have severe liver or kidney problems.
-
If you have difficulty in producing urine.
-
If you have a condition which is associated with persistently high calcium or low potassium
levels in your blood.
Irbesartan/Hydrochlorothiazide Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan/Hydrochlorothiazide Teva
59
-
If you have any further questions, ask your doctor or pharmacist.
Tell your doctor if any of the following apply to you:
-
If you suffer from kidney problems, including kidney transplantation.
-
If you suffer from heart problems.
-
If you suffer from liver problems.
-
If you suffer from diabetes.
-
If you suffer from lupus erythematosus (also known as lupus or SLE).
-
If your suffer from primary aldosteronism (a condition related to high production of the
hormone aldosterone, which causes sodium retention and, in turn, an increase in blood
pressure).
You must tell your doctor if you think you are (or might become) pregnant.
Irbesartan/Hydrochlorothiazide Teva is not recommended in early pregnancy, and must not be taken if
you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage
(see pregnancy section).
You should also tell your doctor:
-
If you are on a low-salt diet.
-
If you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle
pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an
excessive effect of hydrochlorothiazide (contained in Irbesartan/Hydrochlorothiazide Teva).
-
If you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such
as redness, itching, swelling, blistering) occurring more quickly than normal
-
If you are going to have an operation (surgery) or be given anaesthetics
Hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping test.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiaizde Teva may
have an effect on other medicines. Preparations containing lithium should not be taken with
Irbesartan/Hydrochlorothiaizde Teva without close supervision by your doctor.
You may need to have blood checks if you take:
-
Potassium supplements.
-
Salt substitutes containing potassium.
-
Potassium sparing medicines or other diuretics (water tablets).
-
Medicines for the treatment of gout.
-
Therapeutic vitamin D supplements.
-
Medicines to control heart rhythm.
-
Medicines for diabetes (oral agents or insulins).
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure,
steroids, medicines to treat cancer, pain killers, arthritis medicines, or colestyramine and colestipol
resins for lowering blood cholesterol.
Taking
Irbesartan/Hydrochlorothiazide Teva with food and drink
Irbesartan/Hydrochlorothiazide Teva can be taken with or without food.
Due to the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiazide Teva, if you drink alcohol
while on treatment with this medicine, you may have an increased feeling of dizziness on standing up,
specially when getting up from a sitting position.
Pregnancy and breast-feeding
60
-
If you get excessive diarrhoea or vomiting.
-
Some laxatives.
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Irbesartan/Hydrochlorothiazide Teva before you become pregnant or as soon
as you know you are pregnant and will advise you to take another medicine instead of
Irbesartan/Hydrochlorothiazide Teva. Irbesartan/Hydrochlorothiazide Teva is not recommended in
early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding.
Irbesartan/Hydrochlorothiazide Teva is not recommended for mothers who are breast-feeding, and
your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is
newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Irbesartan/Hydrochlorothiazide Teva is unlikely to affect your ability to drive or use machines.
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If
you experience these, talk to your doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Always take Irbesartan/Hydrochlorothiazide Teva exactly as your doctor has told you. You should
check with your doctor or pharmacist if you are not sure.
Dosage
The usual dose of Irbesartan/Hydrochlorothiazide Teva is one or two tablets a day.
Irbesartan/Hydrochlorothiazide Teva will usually be prescribed by your doctor when your previous
treatment for high blood pressure did not provide appropriate blood pressure reduction. Your doctor
will instruct you how to switch from the previous treatment to Irbesartan/Hydrochlorothiazide Teva.
Method of administration
Irbesartan/Hydrochlorothiazide Teva is for oral use. Swallow the tablets with a sufficient amount of
fluid (e.g. one glass of water). You can take Irbesartan/Hydrochlorothiazide Teva with or without
food. Try to take your daily dose at about the same time each day. It is important that you continue to
take Irbesartan/Hydrochlorothiazide Teva until your doctor tells you otherwise.
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment.
If you take more Irbesartan/Hydrochlorothiazide Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take
Irbesartan/Hydrochlorothiazide Teva
Irbesartan/Hydrochlorothiazide Teva should not be given to children under 18 years of age. If a child
swallows some tablets, contact your doctor immediately.
If you forget to take Irbesartan/Hydrochlorothiazide Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
61
Like all medicines, Irbesartan/Hydrochlorothiazide Teva can cause side effects, although not
everybody gets them. Some of these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan/Hydrochlorothiazide Teva and contact
your doctor immediately.
The frequency of the side effects listed below is defined using the following convention:
Common: affects 1 to 10 users in 100
Uncommon: affects 1 to 10 users in 1,000
Not known: frequency cannot be estimated from the available data.
Side effects reported in clinical studies for patients treated with the combination of irbesartan and
hydrochlorothiazide were:
•
Common: nausea/vomiting, abnormal urination, fatigue and dizziness (including when getting
up from a lying or sitting position) and blood tests may show raised levels of an enzyme that
measures the muscle and heart function (creatine kinase) or raised levels of substances that
measure kidney function (blood urea nitrogen, creatinine).
•
Uncommon: diarrhoea, low blood pressure, fainting, heart rate increased, flushing, swelling and
sexual dysfunction (problems with sexual performance). Blood tests may show lowered levels
of potassium and sodium in your blood.
Some undesirable effects have been reported since the marketing of the combination of irbesartan and
hydrochlorothiazide but the frequency for them to occur is not known. These undesirable effects are:
headache, ringing in the ears, cough, taste disturbance, indigestion, pain in joints and muscles, liver
function abnormal and impaired kidney function, increased level of potassium in your blood and
allergic reactions such as rash, hives, swelling of the face, lips, mouth, tongue or throat.
As for any combination of two active substances, side effects associated with each individual
component cannot be excluded. In patients taking irbesartan alone, in addition to the side effects listed
above, chest pain has also been reported.
Additional side effects associated with the use of hydrochlorothiazide alone are: loss of appetite;
stomach irritation; stomach cramps; constipation; jaundice seen as yellowing of the skin and/or whites
of the eyes; inflammation of the pancreas characterised by severe upper stomach pain, often with
nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, which can
result in frequent infections, fever; decrease in the number of platelets (a blood cell essential for the
clotting of the blood), decreased number of red blood cells (anaemia) characterised by tiredness,
headaches, being short of breath when exercising, dizziness and looking pale; kidney disease; lung
problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of the skin to the
sun; inflammation of blood vessels; a skin disease characterized by the peeling of the skin all over the
body; cutaneous lupus erythematosus, which is identified by a rash that may appear on the face, neck,
and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced blood pressure
after a change in body position; swelling of the salivary glands; high sugar levels in the blood; sugar in
the urine; increases in some kinds of blood fat; high uric acid levels in the blood, which may cause
gout.
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of
hydrochlorothiazide.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
62
Keep out of the reach and sight of children.
Do not use Irbesartan/Hydrochlorothiazide Teva after the expiry date that is stated on the outer carton
or foil. The expiry date refers to the last day of that month.
For Irbesartan/Hydrochlorothiazide Teva packaged in white opaque PVC-PVdC - aluminium blisters:
Do not store above 30°C.
For Irbesartan/Hydrochlorothiazide Teva packaged in aluminium – aluminium blisters: This medicinal
product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan/Hydrochlorothiazide Teva contains
-
The active ingredients are irbesartan and hydrochlorothiazide.
Each Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablet contains 150 mg
irbesartan and 12.5 mg hydrochlorothiazide.
-
The other ingredients are:
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline cellulose,
croscarmellose sodium, colloidal anhydrous silica and magnesium stearate.
Tablet coating for 150 mg/12.5 mg strength: hypromellose, titanium dioxide, polyethylene
glycol 6000 (macrogol), polyethylene glycol 400 (macrogol), iron oxide red, iron oxide yellow
and iron oxide black.
What Irbesartan/Hydrochlorothiazide Teva looks like and contents of the pack
Irbesartan/Hydrochlorothiazide Teva 150 mg/12.5 mg film-coated tablets are light pink to pink, film
coated capsule shaped tablets. One side of the tablet is debossed with the number "93" and the other
side of the tablet is debossed with the number "7238".
Irbesartan/Hydrochlorothiazide Teva is available in pack sizes of 7, 14, 15, 20, 28, 30, 56, 60, 90, 98
and 100 film-coated tablets and perforated unit dose blister 50x1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
63
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България
ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor
Biotech Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
64
Τηλ: +30 210 72 79 099
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
65
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablets
irbesartan / hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan/Hydrochlorothiazide Teva is and what it is used for
2. Before you take Irbesartan/Hydrochlorothiazide Teva
3. How to take Irbesartan/Hydrochlorothiazide Teva
4. Possible side effects
6.
How to store Irbesartan/Hydrochlorothiazide Teva
6.
Further information
1.
WHAT IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA IS AND WHAT IT IS
USED FOR
Irbesartan/Hydrochlorothiazide Teva is a combination of two active substances, irbesartan and
hydrochlorothiazide. Irbesartan belongs to a group of medicines known as angiotensin-II receptor
antagonists. Angiotensin-II is a substance produced in the body that binds to receptors in blood
vessels causing them to tighten. This results in an increase in blood pressure. Irbesartan prevents the
binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure
to lower. Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes
increased urine output and so causes a lowering of blood pressure.
The two active ingredients in Irbesartan/Hydrochlorothiazide Teva work together to lower blood
pressure further than if either was given alone.
Irbesartan/Hydrochlorothiazide Teva is used in the treatment of high blood pressure in adults
(essential hypertension), when treatment with irbesartan or hydrochlorothiazide alone did not provide
adequate control of your blood pressure.
2.
BEFORE YOU TAKE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Do not take
Irbesartan/Hydrochlorothiazide Teva
-
If you are allergic (hypersensitive) to irbesartan and hydrochlorothiazide, or any of the other
ingredients of Irbesartan/Hydrochlorothiazide Teva or to medicines chemically related to
sulfonamide (ask your doctor or pharmacist for further clarification).
-
If you are more than 3 months pregnant (it is also better to avoid Irbesartan/Hydrochlorothiazide
Teva in early pregnancy – see pregnancy section).
-
If you have severe liver or kidney problems.
-
If you have difficulty in producing urine.
-
If you have a condition which is associated with persistently high calcium or low potassium
levels in your blood.
Irbesartan/Hydrochlorothiazide Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan/Hydrochlorothiazide Teva
66
-
If you have any further questions, ask your doctor or pharmacist.
Tell your doctor if any of the following apply to you:
-
If you suffer from kidney problems, including kidney transplantation.
-
If you suffer from heart problems.
-
If you suffer from liver problems.
-
If you suffer from diabetes.
-
If you suffer from lupus erythematosus (also known as lupus or SLE).
-
If your suffer from primary aldosteronism (a condition related to high production of the
hormone aldosterone, which causes sodium retention and, in turn, an increase in blood
pressure).
You must tell your doctor if you think you are (or might become) pregnant.
Irbesartan/Hydrochlorothiazide Teva is not recommended in early pregnancy, and must not be taken if
you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage
(see pregnancy section).
You should also tell your doctor:
-
If you are on a low-salt diet.
-
If you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle
pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an
excessive effect of hydrochlorothiazide (contained in Irbesartan/Hydrochlorothiazide Teva).
-
If you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such
as redness, itching, swelling, blistering) occurring more quickly than normal
-
If you are going to have an operation (surgery) or be given anaesthetics
Hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping test.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiaizde Teva may
have an effect on other medicines. Preparations containing lithium should not be taken with
Irbesartan/Hydrochlorothiaizde Teva without close supervision by your doctor.
You may need to have blood checks if you take:
-
Potassium supplements.
-
Salt substitutes containing potassium.
-
Potassium sparing medicines or other diuretics (water tablets).
-
Medicines for the treatment of gout.
-
Therapeutic vitamin D supplements.
-
Medicines to control heart rhythm.
-
Medicines for diabetes (oral agents or insulins).
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure,
steroids, medicines to treat cancer, pain killers, arthritis medicines or colestyramine and colestipol
resins for lowering blood cholesterol.
Taking
Irbesartan/Hydrochlorothiazide Teva with food and drink
Irbesartan/Hydrochlorothiazide Teva can be taken with or without food.
Due to the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiazide Teva, if you drink alcohol
while on treatment with this medicine, you may have an increased feeling of dizziness on standing up,
specially when getting up from a sitting position.
Pregnancy and breast-feeding
67
-
If you get excessive diarrhoea or vomiting.
-
Some laxatives.
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Irbesartan/Hydrochlorothiazide Teva before you become pregnant or as soon
as you know you are pregnant and will advise you to take another medicine instead of
Irbesartan/Hydrochlorothiazide Teva. Irbesartan/Hydrochlorothiazide Teva is not recommended in
early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding.
Irbesartan/Hydrochlorothiazide Teva is not recommended for mothers who are breast-feeding, and
your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is
newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Irbesartan/Hydrochlorothiazide Teva is unlikely to affect your ability to drive or use machines.
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If
you experience these, talk to your doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Always take Irbesartan/Hydrochlorothiazide Teva exactly as your doctor has told you. You should
check with your doctor or pharmacist if you are not sure.
Dosage
The usual dose of Irbesartan/Hydrochlorothiazide Teva is one or two tablets a day.
Irbesartan/Hydrochlorothiazide Teva will usually be prescribed by your doctor when your previous
treatment for high blood pressure did not provide appropriate blood pressure reduction. Your doctor
will instruct you how to switch from the previous treatment to Irbesartan/Hydrochlorothiazide Teva.
Method of administration
Irbesartan/Hydrochlorothiazide Teva is for oral use. Swallow the tablets with a sufficient amount of
fluid (e.g. one glass of water). You can take Irbesartan/Hydrochlorothiazide Teva with or without
food. Try to take your daily dose at about the same time each day. It is important that you continue to
take Irbesartan/Hydrochlorothiazide Teva until your doctor tells you otherwise.
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment.
If you take more Irbesartan/Hydrochlorothiazide Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take
Irbesartan/Hydrochlorothiazide Teva
Irbesartan/Hydrochlorothiazide Teva should not be given to children under 18 years of age. If a child
swallows some tablets, contact your doctor immediately.
If you forget to take Irbesartan/Hydrochlorothiazide Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
68
Like all medicines, Irbesartan/Hydrochlorothiazide Teva can cause side effects, although not
everybody gets them. Some of these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan/Hydrochlorothiazide Teva and contact
your doctor immediately.
The frequency of the side effects listed below is defined using the following convention:
Common: affects 1 to 10 users in 100
Uncommon: affects 1 to 10 users in 1,000
Not known: frequency cannot be estimated from the available data.
Side effects reported in clinical studies for patients treated with the combination of irbesartan and
hydrochlorothiazide were:
•
Common: nausea/vomiting, abnormal urination, fatigue and dizziness (including when getting
up from a lying or sitting position) and blood tests may show raised levels of an enzyme that
measures the muscle and heart function (creatine kinase) or raised levels of substances that
measure kidney function (blood urea nitrogen, creatinine).
•
Uncommon: diarrhoea, low blood pressure, fainting, heart rate increased, flushing, swelling and
sexual dysfunction (problems with sexual performance). Blood tests may show lowered levels
of potassium and sodium in your blood.
Some undesirable effects have been reported since the marketing of the combination of irbesartan and
hydrochlorothiazide but the frequency for them to occur is not known. These undesirable effects are:
headache, ringing in the ears, cough, taste disturbance, indigestion, pain in joints and muscles, liver
function abnormal and impaired kidney function, increased level of potassium in your blood and
allergic reactions such as rash, hives, swelling of the face, lips, mouth, tongue or throat.
As for any combination of two active substances, side effects associated with each individual
component cannot be excluded. In patients taking irbesartan alone, in addition to the side effects listed
above, chest pain has also been reported.
Additional side effects associated with the use of hydrochlorothiazide alone are: loss of appetite;
stomach irritation; stomach cramps; constipation; jaundice seen as yellowing of the skin and/or whites
of the eyes; inflammation of the pancreas characterised by severe upper stomach pain, often with
nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, which can
result in frequent infections, fever; decrease in the number of platelets (a blood cell essential for the
clotting of the blood), decreased number of red blood cells (anaemia) characterised by tiredness,
headaches, being short of breath when exercising, dizziness and looking pale; kidney disease; lung
problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of the skin to the
sun; inflammation of blood vessels; a skin disease characterized by the peeling of the skin all over the
body; cutaneous lupus erythematosus, which is identified by a rash that may appear on the face, neck,
and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced blood pressure
after a change in body position; swelling of the salivary glands; high sugar levels in the blood; sugar in
the urine; increases in some kinds of blood fat; high uric acid levels in the blood, which may cause
gout.
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of
hydrochlorothiazide.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
69
Keep out of the reach and sight of children.
Do not use Irbesartan/Hydrochlorothiazide Teva after the expiry date that is stated on the outer carton
or foil. The expiry date refers to the last day of that month.
For Irbesartan/Hydrochlorothiazide Teva packaged in white opaque PVC-PVdC - aluminium blisters:
Do not store above 30°C.
For Irbesartan/Hydrochlorothiazide Teva packaged in aluminium – aluminium blisters: This medicinal
product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan/Hydrochlorothiazide Teva contains
-
The active ingredients are irbesartan and hydrochlorothiazide.
Each Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablet contains 300 mg
irbesartan and 12.5 mg hydrochlorothiazide.
-
The other ingredients are:
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline cellulose,
croscarmellose sodium, colloidal anhydrous silica and magnesium stearate.
Tablet coating for 300 mg/12.5 mg strength: hypromellose, titanium dioxide, polyethylene
glycol 6000 (macrogol), polyethylene glycol 400 (macrogol), iron oxide red, iron oxide yellow
and iron oxide black.
What Irbesartan/Hydrochlorothiazide Teva looks like and contents of the pack
Irbesartan/Hydrochlorothiazide Teva 300 mg/12.5 mg film-coated tablets are light pink to pink, film
coated capsule shaped tablets. One side of the tablet is debossed with the number "93" and the other
side of the tablet is debossed with the number "7239".
Irbesartan/Hydrochlorothiazide Teva is available in pack sizes of 7, 14, 15, 20, 28, 30, 56, 60, 90, 98
and 100 film-coated tablets and perforated unit dose blister 50x1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
70
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България
ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor
Biotech Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
71
Τηλ: +30 210 72 79 099
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
72
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg film-coated tablets
irbesartan / hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan/Hydrochlorothiazide Teva is and what it is used for
2. Before you take Irbesartan/Hydrochlorothiazide Teva
3. How to take Irbesartan/Hydrochlorothiazide Teva
4. Possible side effects
7.
How to store Irbesartan/Hydrochlorothiazide Teva
6.
Further information
1.
WHAT IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA IS AND WHAT IT IS
USED FOR
Irbesartan/Hydrochlorothiazide Teva is a combination of two active substances, irbesartan and
hydrochlorothiazide. Irbesartan belongs to a group of medicines known as angiotensin-II receptor
antagonists. Angiotensin-II is a substance produced in the body that binds to receptors in blood
vessels causing them to tighten. This results in an increase in blood pressure. Irbesartan prevents the
binding of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure
to lower. Hydrochlorothiazide is one of a group of medicines (called thiazide diuretics) that causes
increased urine output and so causes a lowering of blood pressure.
The two active ingredients in Irbesartan/Hydrochlorothiazide Teva work together to lower blood
pressure further than if either was given alone.
Irbesartan/Hydrochlorothiazide Teva is used in the treatment of high blood pressure in adults
(essential hypertension), when treatment with irbesartan or hydrochlorothiazide alone did not provide
adequate control of your blood pressure.
2.
BEFORE YOU TAKE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Do not take
Irbesartan/Hydrochlorothiazide Teva
-
If you are allergic (hypersensitive) to irbesartan and hydrochlorothiazide, or any of the other
ingredients of Irbesartan/Hydrochlorothiazide Teva or to medicines chemically related to
sulfonamide (ask your doctor or pharmacist for further clarification).
-
If you are more than 3 months pregnant (it is also better to avoid Irbesartan/Hydrochlorothiazide
Teva in early pregnancy – see pregnancy section).
-
If you have severe liver or kidney problems.
-
If you have difficulty in producing urine.
-
If you have a condition which is associated with persistently high calcium or low potassium
levels in your blood.
Irbesartan/Hydrochlorothiazide Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan/Hydrochlorothiazide Teva
73
-
If you have any further questions, ask your doctor or pharmacist.
Tell your doctor if any of the following apply to you:
-
If you suffer from kidney problems, including kidney transplantation.
-
If you suffer from heart problems.
-
If you suffer from liver problems.
-
If you suffer from diabetes.
-
If you suffer from lupus erythematosus (also known as lupus or SLE).
-
If your suffer from primary aldosteronism (a condition related to high production of the
hormone aldosterone, which causes sodium retention and, in turn, an increase in blood
pressure).
You must tell your doctor if you think you are (or might become) pregnant.
Irbesartan/Hydrochlorothiazide Teva is not recommended in early pregnancy, and must not be taken if
you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage
(see pregnancy section).
You should also tell your doctor:
-
If you are on a low-salt diet.
-
If you have signs such as abnormal thirst, dry mouth, general weakness, drowsiness, muscle
pain or cramps, nausea, vomiting, or an abnormally fast heart beat which may indicate an
excessive effect of hydrochlorothiazide (contained in Irbesartan/Hydrochlorothiazide Teva).
-
If you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such
as redness, itching, swelling, blistering) occurring more quickly than normal
-
If you are going to have an operation (surgery) or be given anaesthetics
Hydrochlorothiazide contained in this medicine could produce a positive result in an anti-doping test.
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Diuretic agents such as the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiaizde Teva may
have an effect on other medicines. Preparations containing lithium should not be taken with
Irbesartan/Hydrochlorothiaizde Teva without close supervision by your doctor.
You may need to have blood checks if you take:
-
Potassium supplements.
-
Salt substitutes containing potassium.
-
Potassium sparing medicines or other diuretics (water tablets).
-
Medicines for the treatment of gout.
-
Therapeutic vitamin D supplements.
-
Medicines to control heart rhythm.
-
Medicines for diabetes (oral agents or insulins).
It is also important to tell your doctor if you are taking other medicines to reduce your blood pressure,
steroids, medicines to treat cancer, pain killers, arthritis medicines or colestyramine and colestipol
resins for lowering blood cholesterol.
Taking
Irbesartan/Hydrochlorothiazide Teva with food and drink
Irbesartan/Hydrochlorothiazide Teva can be taken with or without food.
Due to the hydrochlorothiazide contained in Irbesartan/Hydrochlorothiazide Teva, if you drink alcohol
while on treatment with this medicine, you may have an increased feeling of dizziness on standing up,
specially when getting up from a sitting position.
Pregnancy and breast-feeding
74
-
If you get excessive diarrhoea or vomiting.
-
Some laxatives.
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Irbesartan/Hydrochlorothiazide Teva before you become pregnant or as soon
as you know you are pregnant and will advise you to take another medicine instead of
Irbesartan/Hydrochlorothiazide Teva. Irbesartan/Hydrochlorothiazide Teva is not recommended in
early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious
harm to your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding.
Irbesartan/Hydrochlorothiazide Teva is not recommended for mothers who are breast-feeding, and
your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is
newborn, or was born prematurely.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Irbesartan/Hydrochlorothiazide Teva is unlikely to affect your ability to drive or use machines.
However, occasionally dizziness or weariness may occur during treatment of high blood pressure. If
you experience these, talk to your doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
Always take Irbesartan/Hydrochlorothiazide Teva exactly as your doctor has told you. You should
check with your doctor or pharmacist if you are not sure.
Dosage
The usual dose of Irbesartan/Hydrochlorothiazide Teva is one or two tablets a day.
Irbesartan/Hydrochlorothiazide Teva will usually be prescribed by your doctor when your previous
treatment for high blood pressure did not provide appropriate blood pressure reduction. Your doctor
will instruct you how to switch from the previous treatment to Irbesartan/Hydrochlorothiazide Teva.
Method of administration
Irbesartan/Hydrochlorothiazide Teva is for oral use. Swallow the tablets with a sufficient amount of
fluid (e.g. one glass of water). You can take Irbesartan/Hydrochlorothiazide Teva with or without
food. Try to take your daily dose at about the same time each day. It is important that you continue to
take Irbesartan/Hydrochlorothiazide Teva until your doctor tells you otherwise.
The maximal blood pressure lowering effect should be reached 6-8 weeks after beginning treatment.
If you take more Irbesartan/Hydrochlorothiazide Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take
Irbesartan/Hydrochlorothiazide Teva
Irbesartan/Hydrochlorothiazide Teva should not be given to children under 18 years of age. If a child
swallows some tablets, contact your doctor immediately.
If you forget to take Irbesartan/Hydrochlorothiazide Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
75
Like all medicines, Irbesartan/Hydrochlorothiazide Teva can cause side effects, although not
everybody gets them. Some of these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan/Hydrochlorothiazide Teva and contact
your doctor immediately.
The frequency of the side effects listed below is defined using the following convention:
Common: affects 1 to 10 users in 100
Uncommon: affects 1 to 10 users in 1,000
Not known: frequency cannot be estimated from the available data.
Side effects reported in clinical studies for patients treated with the combination of irbesartan and
hydrochlorothiazide were:
•
Common: nausea/vomiting, abnormal urination, fatigue and dizziness (including when getting
up from a lying or sitting position) and blood tests may show raised levels of an enzyme that
measures the muscle and heart function (creatine kinase) or raised levels of substances that
measure kidney function (blood urea nitrogen, creatinine).
•
Uncommon: diarrhoea, low blood pressure, fainting, heart rate increased, flushing, swelling and
sexual dysfunction (problems with sexual performance). Blood tests may show lowered levels
of potassium and sodium in your blood.
Some undesirable effects have been reported since the marketing of the combination of irbesartan and
hydrochlorothiazide but the frequency for them to occur is not known. These undesirable effects are:
headache, ringing in the ears, cough, taste disturbance, indigestion, pain in joints and muscles, liver
function abnormal and impaired kidney function, increased level of potassium in your blood and
allergic reactions such as rash, hives, swelling of the face, lips, mouth, tongue or throat.
As for any combination of two active substances, side effects associated with each individual
component cannot be excluded. In patients taking irbesartan alone, in addition to the side effects listed
above, chest pain has also been reported.
Additional side effects associated with the use of hydrochlorothiazide alone are: loss of appetite;
stomach irritation; stomach cramps; constipation; jaundice seen as yellowing of the skin and/or whites
of the eyes; inflammation of the pancreas characterised by severe upper stomach pain, often with
nausea and vomiting; sleep disorders; depression; blurred vision; lack of white blood cells, which can
result in frequent infections, fever; decrease in the number of platelets (a blood cell essential for the
clotting of the blood), decreased number of red blood cells (anaemia) characterised by tiredness,
headaches, being short of breath when exercising, dizziness and looking pale; kidney disease; lung
problems including pneumonia or build-up of fluid in the lungs; increased sensitivity of the skin to the
sun; inflammation of blood vessels; a skin disease characterized by the peeling of the skin all over the
body; cutaneous lupus erythematosus, which is identified by a rash that may appear on the face, neck,
and scalp; allergic reactions; weakness and muscle spasm; altered heart rate; reduced blood pressure
after a change in body position; swelling of the salivary glands; high sugar levels in the blood; sugar in
the urine; increases in some kinds of blood fat; high uric acid levels in the blood, which may cause
gout.
It is known that side effects associated with hydrochlorothiazide may increase with higher doses of
hydrochlorothiazide.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN/HYDROCHLOROTHIAZIDE TEVA
76
Keep out of the reach and sight of children.
Do not use Irbesartan/Hydrochlorothiazide Teva after the expiry date that is stated on the outer carton
or foil. The expiry date refers to the last day of that month.
For Irbesartan/Hydrochlorothiazide Teva packaged in white opaque PVC-PVdC - aluminium blisters:
Do not store above 30°C.
For Irbesartan/Hydrochlorothiazide Teva packaged in aluminium – aluminium blisters: This medicinal
product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan/Hydrochlorothiazide Teva contains
-
The active ingredients are irbesartan and hydrochlorothiazide.
Each Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg film-coated tablet contains 300 mg
irbesartan and 25 mg hydrochlorothiazide.
-
The other ingredients are:
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline cellulose,
croscarmellose sodium, colloidal anhydrous silica and magnesium stearate.
Tablet coating for 300 mg/25 mg strength: hypromellose, titanium dioxide, polyethylene glycol
6000 (macrogol), polyethylene glycol 400 (macrogol), iron oxide red, Indigotine (Indigo
carmine aluminium lake FD&C blue #2) and iron oxide black.
What Irbesartan/Hydrochlorothiazide Teva looks like and contents of the pack
Irbesartan/Hydrochlorothiazide Teva 300 mg/25 mg film-coated tablets are pink to dark pink, film
coated capsule shaped tablet. One side of the tablet debossed with the number "93". The other side of
the tablet debossed with the number "7469".
Irbesartan/Hydrochlorothiazide Teva is available in pack sizes of 7, 14, 15, 20, 28, 30, 56, 60, 90, 98
and 100 film-coated tablets and perforated unit dose blister 50x1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
77
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България
ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor
Biotech Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
78
Τηλ: +30 210 72 79 099
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this product is available on the European Medicines Agency (EMA) web site:
http://www.ema.europa.eu/
79
Source: European Medicines Agency
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