ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Karvezide 150 mg/12.5 mg tablets.
2.
Each tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Excipient:
Each tablet contains 26.65 mg of lactose (as lactose monohydrate).
For a full list of excipients, see section 6.1.
3.
Tablet.
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2775 engraved on the
other side.
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).
Karvezide 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:
Karvezide 150 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
Karvezide 300 mg/12.5 mg may be administered in patients insufficiently controlled by
irbesartan 300 mg or by Karvezide 150 mg/12.5 mg.
Karvezide 300 mg/25 mg may be administered in patients insufficiently controlled by
Karvezide 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Karvezide may be administered with another antihypertensive medicinal product (see
section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Karvezide 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:
Karvezide is not indicated in patients with severe hepatic impairment. Thiazides
should be used with caution in patients with impaired hepatic function. No dosage adjustment of
Karvezide is necessary in patients with mild to moderate hepatic impairment (see section 4.3).
2
Elderly patients:
no dosage adjustment of Karvezide is necessary in elderly patients.
Paediatric patients:
Karvezide 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)
Severe renal impairment (creatinine clearance < 30 ml/min)
Refractory hypokalaemia, hypercalcaemia
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
Karvezide 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 Karvezide.
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 Karvezide, a similar effect should be
anticipated.
Renal impairment and kidney transplantation:
when Karvezide 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 Karvezide in patients with a recent kidney
transplantation. Karvezide 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 Karvezide 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 Karvezide is not recommended.
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 Karvezide, minimal or no effects were reported.
3
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
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 Karvezide 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 Karvezide (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 Karvezide 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 antihypertensive
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.
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 antihypertensive 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).
4
Lactose:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Other antihypertensive agents:
the antihypertensive effect of Karvezide 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 Karvezide. Therefore, the
combination of lithium and Karvezide 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 Karvezide 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
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:
5
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. Karvezide 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
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive 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.
6
Exposure to AIIRA 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 Karvezide 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 Karvezide during breast-feeding, Karvezide
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, Karvezide 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:
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to
300 mg/25 mg irbesartan/hydrochlorothiazide).
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*
Common:
increases in blood urea nitrogen (BUN),
creatinine and creatine kinase
Cardiac disorders:
Uncommon:
syncope, hypotension, tachycardia,
oedema
Common:
dizziness
Uncommon:
orthostatic dizziness
Nervous system disorders:
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
7
Investigations:
Uncommon:
decreases in serum potassium and
sodium
Renal and urinary disorders:
Common:
abnormal urination
Not known: impaired renal function including
isolated cases of renal failure in patients
at risk (see section 4.4)
Uncommon:
swelling extremity
Musculoskeletal and connective
tissue disorders:
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
Reproductive system and breast
disorders:
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 Karvezide. Tables 2 and 3 below detail the
adverse reactions reported with the individual components of Karvezide.
Table 2:
Adverse reactions reported with the use of
irbesartan
alone
General disorders and
administration site conditions:
Uncommon:
chest pain
Table 3:
Adverse reactions (regardless of relationship to medicinal product) reported with the
use of
hydrochlorothiazide
alone
Investigations:
Not known:
electrolyte imbalance (including
hypokalaemia and hyponatraemia, see
section 4.4), hyperuricaemia, glycosuria,
hyperglycaemia, increases in cholesterol
and triglycerides
Cardiac disorders:
Not known:
cardiac arrhythmias
Blood and lymphatic system
disorders:
Not known:
aplastic anaemia, bone marrow
depression, neutropenia/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
8
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 Karvezide. 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
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: C09DA04.
Karvezide 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,
9
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 mm Hg. 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 mm Hg.
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 mm Hg, 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 mm Hg
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
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
Karvezide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office
visits were 68% and 76% for Karvezide 150 mg/12.5 mg and Karvezide 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 mm Hg.
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 the Karvezide, 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 Karvezide, 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 Karvezide as initial therapy for severe hypertension (defined as SeDBP
≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week,
parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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.
10
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
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 Karvezide, the absolute oral bioavailability is 60-80%
and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of Karvezide. 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.
11
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
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/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.
12
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
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Colloidal hydrated silica
Pregelatinised maize starch
Red and yellow ferric oxides (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Cartons of 14 tablets; 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 28 tablets; 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 tablets; 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 98 tablets; 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 x 1 tablets; 7 blister cards of 8 x 1 tablets each in PVC/PVDC/Aluminium perforated
unit dose blisters.
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.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH - United Kingdom
13
8.
EU/1/98/085/001-003
EU/1/98/085/007
EU/1/98/085/009
9.
Date of first authorisation: 16 October 1998
Date of latest renewal: 1 October 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
14
1.
Karvezide 300 mg/12.5 mg tablets.
2.
Each tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Excipient:
Each tablet contains 65.8 mg of lactose (as lactose monohydrate).
For a full list of excipients, see section 6.1.
3.
Tablet.
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2776 engraved on the
other side.
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).
Karvezide 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:
Karvezide 150 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
Karvezide 300 mg/12.5 mg may be administered in patients insufficiently controlled by
irbesartan 300 mg or by Karvezide 150 mg/12.5 mg.
Karvezide 300 mg/25 mg may be administered in patients insufficiently controlled by
Karvezide 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Karvezide may be administered with another antihypertensive medicinal product (see
section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Karvezide 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:
Karvezide is not indicated in patients with severe hepatic impairment. Thiazides
should be used with caution in patients with impaired hepatic function. No dosage adjustment of
Karvezide is necessary in patients with mild to moderate hepatic impairment (see section 4.3).
15
Elderly patients:
no dosage adjustment of Karvezide is necessary in elderly patients.
Paediatric patients:
Karvezide 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)
Severe renal impairment (creatinine clearance < 30 ml/min)
Refractory hypokalaemia, hypercalcaemia
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
Karvezide 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 Karvezide.
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 Karvezide, a similar effect should be
anticipated.
Renal impairment and kidney transplantation:
when Karvezide 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 Karvezide in patients with a recent kidney
transplantation. Karvezide 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 Karvezide 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 Karvezide is not recommended.
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 Karvezide, minimal or no effects were reported.
16
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
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 Karvezide 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 Karvezide (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 Karvezide 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 antihypertensive
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.
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 antihypertensive 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).
17
Lactose:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Other antihypertensive agents:
the antihypertensive effect of Karvezide 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 Karvezide. Therefore, the
combination of lithium and Karvezide 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 Karvezide 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
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:
18
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. Karvezide 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
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive 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.
19
Exposure to AIIRA 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 Karvezide 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 Karvezide during breast-feeding, Karvezide
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, Karvezide 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:
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to
300 mg/25 mg irbesartan/hydrochlorothiazide).
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*
Common:
increases in blood urea nitrogen (BUN),
creatinine and creatine kinase
Cardiac disorders:
Uncommon:
syncope, hypotension, tachycardia,
oedema
Common:
dizziness
Uncommon:
orthostatic dizziness
Nervous system disorders:
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
20
Investigations:
Uncommon:
decreases in serum potassium and
sodium
Renal and urinary disorders:
Common:
abnormal urination
Not known: impaired renal function including
isolated cases of renal failure in patients
at risk (see section 4.4)
Uncommon:
swelling extremity
Musculoskeletal and connective
tissue disorders:
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
Reproductive system and breast
disorders:
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 Karvezide. Tables 2 and 3 below detail the
adverse reactions reported with the individual components of Karvezide.
Table 2:
Adverse reactions reported with the use of
irbesartan
alone
General disorders and
administration site conditions:
Uncommon:
chest pain
Table 3:
Adverse reactions (regardless of relationship to medicinal product) reported with the
use of
hydrochlorothiazide
alone
Investigations:
Not known:
electrolyte imbalance (including
hypokalaemia and hyponatraemia, see
section 4.4), hyperuricaemia, glycosuria,
hyperglycaemia, increases in cholesterol
and triglycerides
Cardiac disorders:
Not known:
cardiac arrhythmias
Blood and lymphatic system
disorders:
Not known:
aplastic anaemia, bone marrow
depression, neutropenia/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
21
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 Karvezide. 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
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: C09DA04.
Karvezide 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,
22
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 mm Hg. 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 mm Hg.
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 mm Hg, 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 mm Hg
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
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
Karvezide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office
visits were 68% and 76% for Karvezide 150 mg/12.5 mg and Karvezide 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 mm Hg.
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 the Karvezide, 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 Karvezide, 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 Karvezide as initial therapy for severe hypertension (defined as SeDBP
≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week,
parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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.
23
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
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 Karvezide, the absolute oral bioavailability is 60-80%
and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of Karvezide. 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.
24
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
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/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.
25
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
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Colloidal hydrated silica
Pregelatinised maize starch
Red and yellow ferric oxides (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Cartons of 14 tablets; 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 28 tablets; 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 tablets; 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 98 tablets; 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 x 1 tablets; 7 blister cards of 8 x 1 tablets each in PVC/PVDC/Aluminium perforated
unit dose blisters.
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.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH - United Kingdom
26
8.
EU/1/98/085/004-006
EU/1/98/085/008
EU/1/98/085/010
9.
Date of first authorisation: 16 October 1998
Date of latest renewal: 1 October 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
27
1.
Karvezide 150 mg/12.5 mg film-coated tablets.
2.
Each film-coated tablet contains 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Excipient:
Each film-coated tablet contains 38.5 mg of lactose (as lactose monohydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2875 engraved on the
other side.
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).
Karvezide 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:
Karvezide 150 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
Karvezide 300 mg/12.5 mg may be administered in patients insufficiently controlled by
irbesartan 300 mg or by Karvezide 150 mg/12.5 mg.
Karvezide 300 mg/25 mg may be administered in patients insufficiently controlled by
Karvezide 300 mg/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not recommended.
When necessary, Karvezide may be administered with another antihypertensive medicinal product (see
section 4.5).
Renal impairment:
due to the hydrochlorothiazide component, Karvezide 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:
Karvezide is not indicated in patients with severe hepatic impairment. Thiazides
should be used with caution in patients with impaired hepatic function. No dosage adjustment of
Karvezide is necessary in patients with mild to moderate hepatic impairment (see section 4.3).
28
Elderly patients:
no dosage adjustment of Karvezide is necessary in elderly patients.
Paediatric patients:
Karvezide 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)
Severe renal impairment (creatinine clearance < 30 ml/min)
Refractory hypokalaemia, hypercalcaemia
Severe hepatic impairment, biliary cirrhosis and cholestasis
Hypotension - Volume-depleted patients:
Karvezide 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 Karvezide.
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 Karvezide, a similar effect should be
anticipated.
Renal impairment and kidney transplantation:
when Karvezide 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 Karvezide in patients with a recent kidney
transplantation. Karvezide 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 Karvezide 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 Karvezide is not recommended.
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 Karvezide, minimal or no effects were reported.
29
Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
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 Karvezide 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 Karvezide (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 Karvezide 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 antihypertensive
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.
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 antihypertensive 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).
30
Lactose:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Other antihypertensive agents:
the antihypertensive effect of Karvezide 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 Karvezide. Therefore, the
combination of lithium and Karvezide 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 Karvezide 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
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:
31
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. Karvezide 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
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive 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.
32
Exposure to AIIRA 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 Karvezide 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 Karvezide during breast-feeding, Karvezide
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, Karvezide 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:
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled
trials in which 898 hypertensive patients received various doses (range: 37.5 mg/6.25 mg to
300 mg/25 mg irbesartan/hydrochlorothiazide).
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*
Common:
increases in blood urea nitrogen (BUN),
creatinine and creatine kinase
Uncommon:
decreases in serum potassium and sodium
Cardiac disorders:
Uncommon:
syncope, hypotension, tachycardia, oedema
Common:
dizziness
Uncommon:
orthostatic dizziness
Nervous system disorders:
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
Renal and urinary disorders:
Common:
abnormal urination
Not known:
impaired renal function including isolated cases
33
Investigations:
Musculoskeletal and connective
tissue disorders:
of renal failure in patients at risk (see
section 4.4)
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
Reproductive system and breast
disorders:
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 Karvezide. Tables 2 and 3 below detail the
adverse reactions reported with the individual components of Karvezide.
Table 2:
Adverse reactions reported with the use of
irbesartan
alone
General disorders and
administration site conditions:
Uncommon:
chest pain
Table 3:
Adverse reactions (regardless of relationship to medicinal product) reported with the use of
hydrochlorothiazide
alone
Investigations:
Not known:
electrolyte imbalance (including hypokalaemia
and hyponatraemia, see section 4.4),
hyperuricaemia, glycosuria, hyperglycaemia,
increases in cholesterol and triglycerides
Cardiac disorders:
Not known:
cardiac arrhythmias
Blood and lymphatic system
disorders:
Not known:
aplastic anaemia, bone marrow depression,
neutropenia/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
34
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 Karvezide. 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
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: C09DA04.
Karvezide 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.
35
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 mm Hg. 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 mm Hg.
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 mm Hg, 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 mm Hg
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
period with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. When
measured by ambulatory blood pressure monitoring, the trough to peak effects of
Karvezide 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during office
visits were 68% and 76% for Karvezide 150 mg/12.5 mg and Karvezide 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 mm Hg.
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 the Karvezide, 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 Karvezide, 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 Karvezide as initial therapy for severe hypertension (defined as SeDBP
≥ 110 mmHg) was evaluated in a multicenter, randomized, double-blind, active-controlled, 8-week,
parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to either
irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically 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
36
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
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 Karvezide, the absolute oral bioavailability is 60-80%
and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the
bioavailability of Karvezide. 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.
37
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
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/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.
38
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:
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hypromellose
Silicon dioxide
Magnesium stearate
Film-coating:
Lactose monohydrate
Hypromellose
Titanium dioxide
Macrogol 3000
Red and yellow ferric oxides
Carnauba wax
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Cartons of 14 film-coated tablets; 1 blister card of 14 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 28 film-coated tablets; 2 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 30 film-coated tablets; 2 blister cards of 15 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 56 film-coated tablets; 4 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 84 film-coated tablets; 6 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 90 film-coated tablets; 6 blister cards of 15 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 98 film-coated tablets; 7 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium
blisters.
Cartons of 56 x 1 film-coated tablets; 7 blister cards of 8 x 1 film-coated tablets each in
PVC/PVDC/Aluminium perforated unit dose blisters.
39
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.
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH - United Kingdom
8.
EU/1/98/085/011-015
EU/1/98/085/021
EU/1/98/085/029
EU/1/98/085/032
9.
Date of first authorisation: 16 October 1998
Date of latest renewal: 1 October 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
40
1.
FURTHER INFORMATION
What Karvezide contains
The active substances are irbesartan and hydrochlorothiazide. Each film-coated tablet of
Karvezide 300 mg/25 mg contains 300 mg irbesartan and 25 mg hydrochlorothiazide.
The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose
sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3350,
red, yellow and black ferric oxides, pregelatinized starch, carnauba wax.
What Karvezide looks like and contents of the pack
Karvezide 300 mg/25 mg film-coated tablets are pink, biconvex, oval-shaped, with a heart debossed
on one side and the number 2788 engraved on the other side.
Karvezide 300 mg/25 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or
98 film-coated tablets. Unit dose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are
also available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
BRISTOL-MYERS SQUIBB PHARMA EEIG
Uxbridge Business Park
Sanderson Road
Uxbridge UB8 1DH - United Kingdom
Manufacturer
SANOFI WINTHROP INDUSTRIE
1, rue de la Vierge
Ambarès & Lagrave
F-33565 Carbon Blanc Cedex - France
SANOFI SYNTHELABO LIMITED
Edgefield Avenue - Fawdon
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom
CHINOIN PRIVATE CO. LTD.
Lévai u.5.
2112 Veresegyház - Hungary
121
SANOFI WINTHROP INDUSTRIE
30-36 Avenue Gustave Eiffel
37100 Tours - France
122
For any information about this medicine, please contact the local representative of the Marketing
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This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
124
Source: European Medicines Agency
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