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CO APROVEL 300MG TAB

irbesartan/hydrochlorothiazide L

COMPOSITION
CoAprovel 150/12.5 mg Film coated tablets
Each film-coated tablet contains 150 mg irbesartan and 12.5 mg hyd rochtorothiazide.
CoAprovel 300/12.5 mg Film coated tablets
Each film-coated tablet contains 300 mg irbesartan and 12.5 mg hydrochlorothiazide.
PHARMACEUTICAL FORM 150mg/12.5mg   film coated tablet
Film-coated tablet.: Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2875 engraved on the other side.
300mg/12.5mg film coated tablet
Film-coated tablet.: Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2876 engraved on the other side.

CLINICAL PARTICULARS
Therapeutic indications
Treatment of essential hypertension.
This fixed dose combination is indicated in patients whose blood pressure is not
adequately controlled on irbesartan or hydrochlorothiazide alone.
Dosage and method of administration
CoAprovel can be used once daily, with or without food in patients whose blood
pressure is not adequately controlled  by irbesartan or hydrochlorothiazide
alone.
Dose   titration   with   the   individual   components   (i.e.    irbesartan    and
hydrochlorothiazide) can be recommended.
When  clinically appropriate  direct change  from  monotherapy to the fixed
combinations may be considered:  j
-  CoAprovel 150/12.5 mg may'be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
-   CoAprovel 300/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by CoAprovel 150/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily
are not recommended.
When     necessary,     CoAprovel     may    be    administered    with    another
antihypertensive drug [see "Interaction with other medicinal products and other
forms of interaction"].
Renal impairment: due to the hydrochlorothiazide component, CoAprovel 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 e  30 ml/min  (see  "Centra-indications and Special
warnings and special precautions for use").
Intravascular volume depletion: volume and/or sodium depletion should be
corrected prior to administration of CoAprovel.
Hepatic impairment: CoAprovel 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 CoAprovel is necessary in patients
with mild to moderate hepatic impairment (see "Contraindications").
Elderly patients: no dosage adjustment of CoAprovel is necessary in elderly
patients.
Children: safety and efficacy of CoAprovel have not been established in children
[< 18 years].
Contraindications
Second  and  third  trimester  of  pregnancy  (see  pregnancy and  lactation)
Lactation (see pregnancy and lactation).
Hypersensitivity to the active substances, to any of the excipients (see "List of
excipients"), or to other sulfonamide-derived substances (hydrochlorothiazide is
a sulfonamide-derived substance).

The following contraindications are associated with hydrochlorothiazide:
-  severe renal impairment [creatinine clearance < 30 ml/min),
-  refractory hypokalemia, hypercalcaemia,
-  severe hepatic impairment, biliary cirrhosis and cholestasis.
Special warnings and special precautions for use
Hypotension - Volume-depleted patients: CoAprovel 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 CoAprovel.
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 ll receptor antagonists. While this is not documented with CoAprovel, a similar effect should be anticipated.
Renal impairment and kidney transplantation: when CoAprovel 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 CoAprovel in patients with a recent kidney transplantation. CoAprovel should not be used in patients with severe renal impairment [creatinine clearance < 30 ml/min) (see'Contraindications"). 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 e 30 ml/min. However, in patients with mild to moderate renal impairment [creatinine clearance e 30 ml/min but < 60 mi/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 CoAprovel in patients with hepatic impairment. Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensh system. Therefore, the use of CoAprovel is not recommended. Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however at the 1 2.5 mg dose contained in CoAprovel, minimal or no effects were reported.
Hyperuricemia 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 [hypokalemia, hyponatremia, 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 hypokalemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia 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 CoAprovel hyperkalemia 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 CoAprovel (see Interaction with other medicinal products and other forms of interaction"). There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatremia. 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 CoAprovel is not recommended (see interaction with other medicinal product and other forms of interaction ).
Anti-doping test: hydrochlorothiazide contained in this medication 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. Although the possibility of similar effects cannot be exclude with angiotensin -II receptor antagonists, these effects are not documented with CoAprovel As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular
disease could result in a myocardiai 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.
In   the  first trimester  of  pregnancy,   CoAprovel   is   not recommended   (see
"Pregnancy and lactation").
Interaction with other medicinal products and other forms of interaction
Other antihypertensive agents: the antihypertensive effect of CoAprovel may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 30O 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 special warning and precautions for use).
Lithium: reversible increases in serum lithium concentrations and toxtcity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarefy reported with irbesartan so far. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with CoAprovel. Therefore, the combination of lithium and CoAprovel is not recommended (see special warning and precautions for use). 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 drugs associated with potassium oss and hypokalemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other drugs that blunt the reninangiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels [e.g. heparin sodium) may lead to increases in serum potassium. Medicinal products affected by serum potassium disturbances: periodic monitoring of serum potassium is recommended when CoAprovel is administered with drugs 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 drug 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 drugs may interact with thiazide diuretics: Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic drugs (oral agents and insulins): dosage adjustment of the antidiabetic drug may be required (see Special warning and precaution);
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalemia, may be
increased;
Digitalis glycosides: thiazide induced hypokalemia or hypomagnaesemia favour
the onset of digitalis-induced    cardiac arrhythmias (see Special warning and
precaution);
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): tl nondepolarizing skeletal muscle relaxants may be pate hydrochlorothiazide;
Antigout medication: dosage adjustments of antigout medicatir. necessary as hydrochlorothiazide may raise the level of serun Increase in dosage of probenecid or sulfinpyrazone may be nee administration of thiazide diuretics may increase the in hypersensitivity reactions to aliopurinol;
Calcium salts: thiazide diuretics may increase serum calcium k decreased excretion. If calcium supplements or calcium sparing Vitamin D therapy] must be prescribed, serum calcium levels monitored and calcium dosage adjusted accordingly;
Other interactions: the hyperglycaemic effect of beta-blockers a may be enhanced by thiazides. Anticholinergic agents (e.g. atropine may increase the unavailability of thiazide-type diuretics by gastrointestinal motility and stomach emptying rate. Thiazides n the risk of adverse effects caused by amantadine. Thiazides ma^ renal excretion of cytotoxic drugs (e.g. cyclophosphamtde, metho potentiate their myelosuppressive effects.
Pregnancy and lactation
Pregnancy: (see Contra indication and Special warning/ precautii Thiazides crass the placental barrier and appear in cord blood. The decrease placental perfusion, foetal electrolyte disturbances and p reactions that have occurred in the adults. Cases c thrombocytopenia, or foetal or neonatal jaundice have been re maternal thiazide therapy.
Since CoAprovel contains hydrochlorothiazide, it is not recomme the first trimester of pregnancy. A switch to a suitable alternate should be carried out in advance of a planned pregnancy. In the second and third trimesters, substances that act directly ( angiotensin-system can cause foetal or neonatal renal failure, hypoplasia and even foetal death, therefore, CoAprovel is contra the second and third trimesters of pregnancy. If pregnancy is CoAprovel should be discontinued as soon as possible, skull and n should be checked with echography if. inadvertently, the treatmer for a long period.
Lactation: because of the potential adverse effects on the nu CoAprovel is contra indicated during lactation (see Contra indicati known if irbesartan is excreted in human milk. It is excreted in lactating rats. Thiazides appear in human milk and may inhibit lacl
Effects on ability to drive and use machines
The effect of CoAprovel on ability to drive and use machines h studied, but based on its pharmacodynamic properties, CoAprovel affect this ability. When driving vehicles or operating machines, taken into account that occasionally dizziness or weariness may < treatment of hypertension.
Undesirable effects
The frequency of adverse reactions listed below is defined using ' convention: very common [> 1/10); common (> 1/100, < 1/10) (> 1/1,CO0, < 1/100); rare (> 1/10,000, < 1/1,000); v 1/10,000).
Irbesartan/hydrochlorothiazide combination: In placebo-controlled trials in patients with hypertension, the over of adverse events did not differ between the irbesartan/hydrocl and the placebo groups. Discontinuation due to any clinical o adverse event was less frequent for irbesartan/hydrochlorothJE patients than for placebo-treated patients. The incidence of adverse not related to gender, age, race, or dose with the recommended In placebo-controlled trials in which 898 hypertensive patients rece doses (range: 37.5 mg/6.25 mg to 300 mi irbesartan/hydrochlorothiazide, the fallowing adverse reactions we
Nervous system disorders:
Common             : dizziness
Uncommon        : orthostatic dizziness
Cardiac disorders:
Uncommon        : hypotension, oedema, syncope, tachycardia
Vascular disorders:
Uncommon       : flushing
Gastrointestinal disorders:
Common             : nausea/vomiting
Uncommon        : diarrhoea
Musculoskeletal. connective tissue and bone disorders:
Uncommon        : swelling extremity
Renal and urinary disorders:_

Common            : abnormal urination
Reproductive system and breast disorders:
Uncommon      : libido changes, sexual dysfunction
General disorders and administration site conditions:
Common            : fatigue
Investigation:   patients   treated   with   irbesartan/hydrochlorothiazide   had
changed in laboratory test parameters which were rarely clinically significant.
Common            : increases in BUN, creatinine and creatine kinase
Uncommon       : decreases in serum potassium and sodium.
In addition, since introduction of irbesartan/hydrochlorothiazide in the market the following adverse reactions have also been reported:
Immune system disorders:
Rare                  : as with other angiotensin-ll receptor antagonists, rare cases
of hypersensitivity reactions such as angiodema, rash, urticaria have     been
reported.
Metabolism and nutrition disorders:
Very rare          : hyperkalemia
Nervous system disorders:
Very rare           : headache
Ear and labyrinth disorders:
Very rare           : tinnitus
Respiratory, thoracic and mediastinal disorders:
Very rare           : cough
Gastrointestinal disorders:
Very rare          :   dysgeusia , dyspepsia
Hepato-biliary disorders:
Very rare           :   abnormal liver function, hepatitis
Musculoskeletal. connective tissue and bone disorders:
Very rare          : arthralgia, myalgia
Renal and urinary disorders:
Very rare: impaired renal function including isolated cases of renal failure in
patients at risk [see Special warning and precautions).
Additional information on individual components: in addition to the adverse
reactions listed above for the combination product, other undesirable effects
previously reported with one of the individual components may be potential
undesirable effect with CoAprovel.
Irbesartan:
General disorders and administration site conditions: Uncommon: chest pain
Hydrochlorothiazide:
Adverse events (regardless of relationship to drug] reported with the use of hydrochlorothiazide alone include:
Blood and lymphatic system:
Aplastic anemia,  bone marrow depression,  haemolytic anemia,  leucopenia,
neutropenia/agranulocytosis, thrombacytopenia.
Psychiatric disorders:
Depression, sleep disturbances
Nervous system disorders:
Light-headedness, paraesthesia, restlessness, vertigo
Eye disorders:
Transient blurred vision, xanthopsia
Cardiac disorders:
Cardiac arrhythmias
Vascular disorders:
Postural hypotension
Respiratory, thoracic and mediastinal disorders:
Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders:
Pancreatitis,   anorexia,   constipation,   diarrhoea,   gastric   irritation,   loss   of
appetite, sialadenitis
Heoatobiliarv disorders:
Jaundice [intrahepatic chofestatic jaundice)
Sign and subcutaneous tissue disorders:
Anaphylactic   reactions,   toxic   epidermal   necrolysis,    cutaneous   lupus
erythematosus-like   reactions,   necrotizing   angitis   [vasculitis,      cutaneous
vasculitis),  photosensitivity reactions,  rash,  reactivation of cutaneous  lupus
erythematosus, urticaria.
Musculoskeletal. connective tissue and bone disorders:
Muscle spasm, weakness
Renal and urinary disorders:
Interstitial nephritis, renal dysfunction

General disorders and administration site conditions:
Fever
Investigations:
Electrolyte imbalance [including hypokalemia and hyponatremia,  see special
warning   and   special   precaution   for   use),   glycosuria,   hyperglycemia,
hyperuricemia, increases in cholesterol and triglycerides.

Overdose
No  specific  information  is  available  on the treatment of overdosage  with CoAprovel. 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 overdosage.  Serum
electrolytes  and  creatinine  should  be  monitored  frequently.   If  hypotension
occurs, the patient should be placed in a supine position, with salt and volume
replacements given quickly.
The most likely manifestations of irbesartan overdosage are expected to be
hypotension and tachycardia; bradycardia might also occur.
Overdosage with hydrochlorothiazide is associated with electrolyte depletion
[hypokalemia,  hypochloremia,  hyponatremia) and dehydration  resulting from
excessive diuresis. The most common signs and symptoms of overdosage are
nausea and somnolence. Hypokalemia may result in muscle spasms and/or
accentuate   cardiac  arrhythmias  associated  with  the   concomitant  use  of
digitalis glycosides or certain anti-arrhythmic drugs.
Irbesartan   is   not   removed   by   haemodialysis.   The   degree   to   which
hydrochlorothiazide is removed by haemodialysis has not been established.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmaco-therapeutic group: angiotensin II antagonists, combinations: ATC code C09D A04.
CoAprovel 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 [ATi subtype) antagonist. It is expected to block all actions otengiotensin II mediated by the AT-] receptor, regardless of the source
or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II [AT-]] receptors results in increases in plasma renin levels and angiotensin 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 "Special warnings and Special precautions for use" and "Interaction with other medicinal products and other forms of interactions"}. 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 renirt-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 - IE 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 3CO 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/disstolic reductions of up to 13.6/11.5 mm Hg. Once daly 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-moderata hypertension. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, the combination 1 50 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.S/10.0 mm Hg. When measured by ambulatory blood pressure monitoring, the trough to peak effects of CoAprovel 150/12.5 mg were 100%. The trough to peak effects measured by cuff curing office visits were 68% and 76% for CoAprovel 150/12.5 mg and CoAprovel 300/12.5 mg, respectively.
These 24 hour effects were observed without excessive blood presure 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 CoAprovel, 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 CoAprovel, regardless of age or gender.
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.

Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either drug.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Fallowing oral administration of CoAprovel, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of CoAprovel. 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 Cma)( 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 5-1 5 hours.
Following oral or intravenous: admin'Stration of 14C irbesartan, BO 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 IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast milk.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours. Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.

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 montns.
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 drugs 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 IMnduced inhib release, with stimulation of the renin-producing cells] and oo angiotensin converting enzyme inhibitors. These findings appes relevance to the use of therapeutic doses of irbesartan/hydroch humans.
No teratogenic effects were seen in rats given irbt hydrochlorothiazide in combination at doses that produced mal The effects of the irbesartan/hydrochlorothiazide combination oi not been evaluated in animal studies, as there is no evidence of; on fertility in animals or humans with either irbesartan or hydro when administered alone. However, another angiotensin II antag fertility parameters in animal studies when given alone. These also observed with lower doses of this other angiotensin II ant given in combination with hydrochlorothiazide. There was no evidence of mutagenicity or clastogenic irbesartan/hydrochlorothiazide combination. The carcinogenic irbesartan and hydrochlorothiazide in combination has not beei animal studies.
Irbesartan: there was no evidence of abnormal systemic or toxicity at clinically relevant doses.
In preclinical safety studies, high doses of irbesartan (> 250 mg/ and > 100 mg/kg/day in macaques) caused a reduction of i parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (> 500 mg/kg/day) degenerative changes (such as interstitial nephritis, tubular distention, basophilic tubu plasma concentrations of urea and creatinine] were induced by the rat and the macaque and are considered secondary to th effects of the drug which led to decreased renal perfusion. irbesartan induced hyperplasia/hypertrophy of the juxtaglomerulc at a 90 mg/kg/day, in macaques at > 10 mg/kg/day). All of t were considered to be caused by the pharmacological action of ir therapeutic doses of irbesartan in humans, the hyperplasia/hype renal juxtaglomerular cells does not appear to have any relevant There was no evidence of mutagenicity, clastogenicity or carcino Animal studies with irbesartan showed transient toxic effects (in pelvic cavitation, hydroureter or subcutaneous oedema) in rat tc were resolved after birth. In rabbits, abortion or early resorptior doses causing significant maternal toxicity, including mortality, r-effects were observed in the rat or rabbit.
Hydrochlorothiazide:   although   equivocal  evidence   for   a carcinogenic effect was found in some experimental models, human experience with hydrochlorothiazide has failed to show • between its use and an increase in neoplasms.

PHARMACEUTICAL PARTICULARS :
LIST OF EXCIPIENTS
Tablet core: lactose monohydrate, microcrystalline cellulose, c sodium, hypromellose, silicon dioxide, magnesium stearate. Film-coating:   lactose   monohydrate,   hypromellose,  titanium  di macrogol, red and yellow ferric oxides (E172), carnauba wax.
Incompatibilities: Not applicable.
Special precautions for storage Do not store above 30°C. Store in the original package.
Shelf life: 3 years
Nature and contents of container
CoAprovel film coated tablets are packaged in cartons containing
14  film coated tablets in PVC/PVDC/aluminium blisters.
Instructions for use and handling, and disposal No special requirements.

HARUS DENGAN RESEP DOKTER

COAPROVEL 150/12.5 mg Reg. No. DKI 0277401117A1 COAPROVEL 300/12.5 mg Reg. No. DKI 0377401117B1

Manufactured by:
Sanofi Winthrop Industrie
1, rue de la Vierge - Ambares et Lagrave
33565 Carbon Blanc Cedex- France

Imported by:
PT Sanofi~Synthelabo Combiphar
Jakarta, Indonesia
sanoFi~synftielabo
SmPC0423Q1/RPU06D6                          i

Harga Tersebut diatas Tidak Mengikat, Sewaktu-Waktu Dapat Berubah Tanpa Pemberitahuan Terlebih Dahulu.

CO APROVEL 300 MG


irbesartan/hydrochlorothiazide
L
COMPOSITION
CoAprovel 150/12.5 mg Film coated tablets
Each film-coated tablet contains 150 mg irbesartan and 12.5 mg hyd rochtorothiazide.
CoAprovel 300/12.5 mg Film coated tablets
Each film-coated tablet contains 300 mg irbesartan and 12.5 mg hydrochlorothiazide.
PHARMACEUTICAL FORM 150mg/12.5mg   film coated tablet
Film-coated tablet.: Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2875 engraved on the other side.
300mg/12.5mg film coated tablet
Film-coated tablet.: Peach, biconvex, oval-shaped, with a heart debossed on one side and the number 2876 engraved on the other side.


CLINICAL PARTICULARS
Therapeutic indications
Treatment of essential hypertension.
This fixed dose combination is indicated in patients whose blood pressure is not
adequately controlled on irbesartan or hydrochlorothiazide alone.
Dosage and method of administration
CoAprovel can be used once daily, with or without food in patients whose blood
pressure is not adequately controlled  by irbesartan or hydrochlorothiazide
alone.
Dose   titration   with   the   individual   components   (i.e.    irbesartan    and
hydrochlorothiazide) can be recommended.
When  clinically appropriate  direct change  from  monotherapy to the fixed
combinations may be considered:  j
-  CoAprovel 150/12.5 mg may'be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone;
-   CoAprovel 300/12.5 mg may be administered in patients insufficiently controlled by irbesartan 300 mg or by CoAprovel 150/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily
are not recommended.
When     necessary,     CoAprovel     may    be    administered    with    another
antihypertensive drug [see "Interaction with other medicinal products and other
forms of interaction"].
Renal impairment: due to the hydrochlorothiazide component, CoAprovel 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 e  30 ml/min  (see  "Centra-indications and Special
warnings and special precautions for use").
Intravascular volume depletion: volume and/or sodium depletion should be
corrected prior to administration of CoAprovel.
Hepatic impairment: CoAprovel 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 CoAprovel is necessary in patients
with mild to moderate hepatic impairment (see "Contraindications").
Elderly patients: no dosage adjustment of CoAprovel is necessary in elderly
patients.
Children: safety and efficacy of CoAprovel have not been established in children
[< 18 years].
Contraindications
Second  and  third  trimester  of  pregnancy  (see  pregnancy and  lactation)
Lactation (see pregnancy and lactation).
Hypersensitivity to the active substances, to any of the excipients (see "List of
excipients"), or to other sulfonamide-derived substances (hydrochlorothiazide is
a sulfonamide-derived substance).


The following contraindications are associated with hydrochlorothiazide:
-  severe renal impairment [creatinine clearance < 30 ml/min),
-  refractory hypokalemia, hypercalcaemia,
-  severe hepatic impairment, biliary cirrhosis and cholestasis.
Special warnings and special precautions for use
Hypotension - Volume-depleted patients: CoAprovel 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 CoAprovel.
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 ll receptor antagonists. While this is not documented with CoAprovel, a similar effect should be anticipated.
Renal impairment and kidney transplantation: when CoAprovel 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 CoAprovel in patients with a recent kidney transplantation. CoAprovel should not be used in patients with severe renal impairment [creatinine clearance < 30 ml/min) (see'Contraindications"). 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 e 30 ml/min. However, in patients with mild to moderate renal impairment [creatinine clearance e 30 ml/min but < 60 mi/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 CoAprovel in patients with hepatic impairment. Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Primary aldosteronism: patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensh system. Therefore, the use of CoAprovel is not recommended. Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however at the 1 2.5 mg dose contained in CoAprovel, minimal or no effects were reported.
Hyperuricemia 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 [hypokalemia, hyponatremia, 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 hypokalemia may develop with the use of thiazide diuretics, concurrent therapy with irbesartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia 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 CoAprovel hyperkalemia 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 CoAprovel (see Interaction with other medicinal products and other forms of interaction"). There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatremia. 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 CoAprovel is not recommended (see interaction with other medicinal product and other forms of interaction ).
Anti-doping test: hydrochlorothiazide contained in this medication 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. Although the possibility of similar effects cannot be exclude with angiotensin -II receptor antagonists, these effects are not documented with CoAprovel As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic cardiovascular
disease could result in a myocardiai 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.
In   the  first trimester  of  pregnancy,   CoAprovel   is   not recommended   (see
"Pregnancy and lactation").
Interaction with other medicinal products and other forms of interaction
Other antihypertensive agents: the antihypertensive effect of CoAprovel may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 30O 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 special warning and precautions for use).
Lithium: reversible increases in serum lithium concentrations and toxtcity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarefy reported with irbesartan so far. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with CoAprovel. Therefore, the combination of lithium and CoAprovel is not recommended (see special warning and precautions for use). 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 drugs associated with potassium oss and hypokalemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other drugs that blunt the reninangiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels [e.g. heparin sodium) may lead to increases in serum potassium. Medicinal products affected by serum potassium disturbances: periodic monitoring of serum potassium is recommended when CoAprovel is administered with drugs 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 drug 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 drugs may interact with thiazide diuretics: Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic drugs (oral agents and insulins): dosage adjustment of the antidiabetic drug may be required (see Special warning and precaution);
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalemia, may be
increased;
Digitalis glycosides: thiazide induced hypokalemia or hypomagnaesemia favour
the onset of digitalis-induced    cardiac arrhythmias (see Special warning and
precaution);
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): tl nondepolarizing skeletal muscle relaxants may be pate hydrochlorothiazide;
Antigout medication: dosage adjustments of antigout medicatir. necessary as hydrochlorothiazide may raise the level of serun Increase in dosage of probenecid or sulfinpyrazone may be nee administration of thiazide diuretics may increase the in hypersensitivity reactions to aliopurinol;
Calcium salts: thiazide diuretics may increase serum calcium k decreased excretion. If calcium supplements or calcium sparing Vitamin D therapy] must be prescribed, serum calcium levels monitored and calcium dosage adjusted accordingly;
Other interactions: the hyperglycaemic effect of beta-blockers a may be enhanced by thiazides. Anticholinergic agents (e.g. atropine may increase the unavailability of thiazide-type diuretics by gastrointestinal motility and stomach emptying rate. Thiazides n the risk of adverse effects caused by amantadine. Thiazides ma^ renal excretion of cytotoxic drugs (e.g. cyclophosphamtde, metho potentiate their myelosuppressive effects.
Pregnancy and lactation
Pregnancy: (see Contra indication and Special warning/ precautii Thiazides crass the placental barrier and appear in cord blood. The decrease placental perfusion, foetal electrolyte disturbances and p reactions that have occurred in the adults. Cases c thrombocytopenia, or foetal or neonatal jaundice have been re maternal thiazide therapy.
Since CoAprovel contains hydrochlorothiazide, it is not recomme the first trimester of pregnancy. A switch to a suitable alternate should be carried out in advance of a planned pregnancy. In the second and third trimesters, substances that act directly ( angiotensin-system can cause foetal or neonatal renal failure, hypoplasia and even foetal death, therefore, CoAprovel is contra the second and third trimesters of pregnancy. If pregnancy is CoAprovel should be discontinued as soon as possible, skull and n should be checked with echography if. inadvertently, the treatmer for a long period.
Lactation: because of the potential adverse effects on the nu CoAprovel is contra indicated during lactation (see Contra indicati known if irbesartan is excreted in human milk. It is excreted in lactating rats. Thiazides appear in human milk and may inhibit lacl
Effects on ability to drive and use machines
The effect of CoAprovel on ability to drive and use machines h studied, but based on its pharmacodynamic properties, CoAprovel affect this ability. When driving vehicles or operating machines, taken into account that occasionally dizziness or weariness may < treatment of hypertension.
Undesirable effects
The frequency of adverse reactions listed below is defined using ' convention: very common [> 1/10); common (> 1/100, < 1/10) (> 1/1,CO0, < 1/100); rare (> 1/10,000, < 1/1,000); v 1/10,000).
Irbesartan/hydrochlorothiazide combination: In placebo-controlled trials in patients with hypertension, the over of adverse events did not differ between the irbesartan/hydrocl and the placebo groups. Discontinuation due to any clinical o adverse event was less frequent for irbesartan/hydrochlorothJE patients than for placebo-treated patients. The incidence of adverse not related to gender, age, race, or dose with the recommended In placebo-controlled trials in which 898 hypertensive patients rece doses (range: 37.5 mg/6.25 mg to 300 mi irbesartan/hydrochlorothiazide, the fallowing adverse reactions we
Nervous system disorders:
Common             : dizziness
Uncommon        : orthostatic dizziness
Cardiac disorders:
Uncommon        : hypotension, oedema, syncope, tachycardia
Vascular disorders:
Uncommon       : flushing
Gastrointestinal disorders:
Common             : nausea/vomiting
Uncommon        : diarrhoea
Musculoskeletal. connective tissue and bone disorders:
Uncommon        : swelling extremity
Renal and urinary disorders:_


Common            : abnormal urination
Reproductive system and breast disorders:
Uncommon      : libido changes, sexual dysfunction
General disorders and administration site conditions:
Common            : fatigue
Investigation:   patients   treated   with   irbesartan/hydrochlorothiazide   had
changed in laboratory test parameters which were rarely clinically significant.
Common            : increases in BUN, creatinine and creatine kinase
Uncommon       : decreases in serum potassium and sodium.
In addition, since introduction of irbesartan/hydrochlorothiazide in the market the following adverse reactions have also been reported:
Immune system disorders:
Rare                  : as with other angiotensin-ll receptor antagonists, rare cases
of hypersensitivity reactions such as angiodema, rash, urticaria have     been
reported.
Metabolism and nutrition disorders:
Very rare          : hyperkalemia
Nervous system disorders:
Very rare           : headache
Ear and labyrinth disorders:
Very rare           : tinnitus
Respiratory, thoracic and mediastinal disorders:
Very rare           : cough
Gastrointestinal disorders:
Very rare          :   dysgeusia , dyspepsia
Hepato-biliary disorders:
Very rare           :   abnormal liver function, hepatitis
Musculoskeletal. connective tissue and bone disorders:
Very rare          : arthralgia, myalgia
Renal and urinary disorders:
Very rare: impaired renal function including isolated cases of renal failure in
patients at risk [see Special warning and precautions).
Additional information on individual components: in addition to the adverse
reactions listed above for the combination product, other undesirable effects
previously reported with one of the individual components may be potential
undesirable effect with CoAprovel.
Irbesartan:
General disorders and administration site conditions: Uncommon: chest pain
Hydrochlorothiazide:
Adverse events (regardless of relationship to drug] reported with the use of hydrochlorothiazide alone include:
Blood and lymphatic system:
Aplastic anemia,  bone marrow depression,  haemolytic anemia,  leucopenia,
neutropenia/agranulocytosis, thrombacytopenia.
Psychiatric disorders:
Depression, sleep disturbances
Nervous system disorders:
Light-headedness, paraesthesia, restlessness, vertigo
Eye disorders:
Transient blurred vision, xanthopsia
Cardiac disorders:
Cardiac arrhythmias
Vascular disorders:
Postural hypotension
Respiratory, thoracic and mediastinal disorders:
Respiratory distress (including pneumonitis and pulmonary oedema)
Gastrointestinal disorders:
Pancreatitis,   anorexia,   constipation,   diarrhoea,   gastric   irritation,   loss   of
appetite, sialadenitis
Heoatobiliarv disorders:
Jaundice [intrahepatic chofestatic jaundice)
Sign and subcutaneous tissue disorders:
Anaphylactic   reactions,   toxic   epidermal   necrolysis,    cutaneous   lupus
erythematosus-like   reactions,   necrotizing   angitis   [vasculitis,      cutaneous
vasculitis),  photosensitivity reactions,  rash,  reactivation of cutaneous  lupus
erythematosus, urticaria.
Musculoskeletal. connective tissue and bone disorders:
Muscle spasm, weakness
Renal and urinary disorders:
Interstitial nephritis, renal dysfunction


General disorders and administration site conditions:
Fever
Investigations:
Electrolyte imbalance [including hypokalemia and hyponatremia,  see special
warning   and   special   precaution   for   use),   glycosuria,   hyperglycemia,
hyperuricemia, increases in cholesterol and triglycerides.


Overdose
No  specific  information  is  available  on the treatment of overdosage  with CoAprovel. 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 overdosage.  Serum
electrolytes  and  creatinine  should  be  monitored  frequently.   If  hypotension
occurs, the patient should be placed in a supine position, with salt and volume
replacements given quickly.
The most likely manifestations of irbesartan overdosage are expected to be
hypotension and tachycardia; bradycardia might also occur.
Overdosage with hydrochlorothiazide is associated with electrolyte depletion
[hypokalemia,  hypochloremia,  hyponatremia) and dehydration  resulting from
excessive diuresis. The most common signs and symptoms of overdosage are
nausea and somnolence. Hypokalemia may result in muscle spasms and/or
accentuate   cardiac  arrhythmias  associated  with  the   concomitant  use  of
digitalis glycosides or certain anti-arrhythmic drugs.
Irbesartan   is   not   removed   by   haemodialysis.   The   degree   to   which
hydrochlorothiazide is removed by haemodialysis has not been established.


PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmaco-therapeutic group: angiotensin II antagonists, combinations: ATC code C09D A04.
CoAprovel 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 [ATi subtype) antagonist. It is expected to block all actions otengiotensin II mediated by the AT-] receptor, regardless of the source
or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II [AT-]] receptors results in increases in plasma renin levels and angiotensin 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 "Special warnings and Special precautions for use" and "Interaction with other medicinal products and other forms of interactions"}. 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 renirt-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 - IE 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 3CO 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/disstolic reductions of up to 13.6/11.5 mm Hg. Once daly 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-moderata hypertension. Peak effects occurred at 3-6 hours. When assessed by ambulatory blood pressure monitoring, the combination 1 50 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.S/10.0 mm Hg. When measured by ambulatory blood pressure monitoring, the trough to peak effects of CoAprovel 150/12.5 mg were 100%. The trough to peak effects measured by cuff curing office visits were 68% and 76% for CoAprovel 150/12.5 mg and CoAprovel 300/12.5 mg, respectively.
These 24 hour effects were observed without excessive blood presure 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 CoAprovel, 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 CoAprovel, regardless of age or gender.
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.


Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the pharmacokinetics of either drug.
Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation for their activity. Fallowing oral administration of CoAprovel, the absolute oral bioavailability is 60-80% and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect the bioavailability of CoAprovel. 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 Cma)( 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 5-1 5 hours.
Following oral or intravenous: admin'Stration of 14C irbesartan, BO 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 IV administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier, and is excreted in breast milk.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients with creatinine clearance < 20 ml/min, the elimination half-life of hydrochlorothiazide was reported to increase to 21 hours. Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.


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 montns.
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 drugs 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 IMnduced inhib release, with stimulation of the renin-producing cells] and oo angiotensin converting enzyme inhibitors. These findings appes relevance to the use of therapeutic doses of irbesartan/hydroch humans.
No teratogenic effects were seen in rats given irbt hydrochlorothiazide in combination at doses that produced mal The effects of the irbesartan/hydrochlorothiazide combination oi not been evaluated in animal studies, as there is no evidence of; on fertility in animals or humans with either irbesartan or hydro when administered alone. However, another angiotensin II antag fertility parameters in animal studies when given alone. These also observed with lower doses of this other angiotensin II ant given in combination with hydrochlorothiazide. There was no evidence of mutagenicity or clastogenic irbesartan/hydrochlorothiazide combination. The carcinogenic irbesartan and hydrochlorothiazide in combination has not beei animal studies.
Irbesartan: there was no evidence of abnormal systemic or toxicity at clinically relevant doses.
In preclinical safety studies, high doses of irbesartan (> 250 mg/ and > 100 mg/kg/day in macaques) caused a reduction of i parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (> 500 mg/kg/day) degenerative changes (such as interstitial nephritis, tubular distention, basophilic tubu plasma concentrations of urea and creatinine] were induced by the rat and the macaque and are considered secondary to th effects of the drug which led to decreased renal perfusion. irbesartan induced hyperplasia/hypertrophy of the juxtaglomerulc at a 90 mg/kg/day, in macaques at > 10 mg/kg/day). All of t were considered to be caused by the pharmacological action of ir therapeutic doses of irbesartan in humans, the hyperplasia/hype renal juxtaglomerular cells does not appear to have any relevant There was no evidence of mutagenicity, clastogenicity or carcino Animal studies with irbesartan showed transient toxic effects (in pelvic cavitation, hydroureter or subcutaneous oedema) in rat tc were resolved after birth. In rabbits, abortion or early resorptior doses causing significant maternal toxicity, including mortality, r-effects were observed in the rat or rabbit.
Hydrochlorothiazide:   although   equivocal  evidence   for   a carcinogenic effect was found in some experimental models, human experience with hydrochlorothiazide has failed to show • between its use and an increase in neoplasms.


PHARMACEUTICAL PARTICULARS :
LIST OF EXCIPIENTS

Tablet core: lactose monohydrate, microcrystalline cellulose, c sodium, hypromellose, silicon dioxide, magnesium stearate. Film-coating:   lactose   monohydrate,   hypromellose,  titanium  di macrogol, red and yellow ferric oxides (E172), carnauba wax.
Incompatibilities: Not applicable.
Special precautions for storage Do not store above 30°C. Store in the original package.
Shelf life: 3 years
Nature and contents of container
CoAprovel film coated tablets are packaged in cartons containing
14  film coated tablets in PVC/PVDC/aluminium blisters.
Instructions for use and handling, and disposal No special requirements.


  HARUS DENGAN RESEP DOKTER


COAPROVEL 150/12.5 mg Reg. No. DKI 0277401117A1 COAPROVEL 300/12.5 mg Reg. No. DKI 0377401117B1
Manufactured by:
Sanofi Winthrop Industrie
1, rue de la Vierge - Ambares et Lagrave
33565 Carbon Blanc Cedex- France
Imported by:
PT Sanofi~Synthelabo Combiphar

Jakarta, Indonesia
sanoFi~synftielabo
SmPC0423Q1/RPU06D6                          i