COAPROVEL 300mg / 25mg tablets medication leaflet

CoAprovel 300 mg/25 mg film-coated tablets.

Each film-coated tablet contains 300 mg of irbesartan and 25 mg of hydrochlorothiazide.

Each film-coated tablet contains 53.3 mg of lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Pink, biconvex, oval-shaped, with a heart debossed on one side and the number 2788 engraved on theother side.

Treatment of essential hypertension.

This fixed dose combination is indicated in adult patients whose blood pressure is not adequatelycontrolled on irbesartan or hydrochlorothiazide alone (see section 5.1).

CoAprovel can be taken once daily, with or without food.

Dose titration with the individual components (i.e. irbesartan and hydrochlorothiazide) may berecommended.

When clinically appropriate direct change from monotherapy to the fixed combinations may beconsidered:

▪ CoAprovel 150 mg/12.5 mg may be administered in patients whose blood pressure is notadequately controlled with hydrochlorothiazide or irbesartan 150 mg alone.

▪ CoAprovel 300 mg/12.5 mg may be administered in patients insufficiently controlled byirbesartan 300 mg or by CoAprovel 150 mg/12.5 mg.

▪ CoAprovel 300 mg/25 mg may be administered in patients insufficiently controlled by

CoAprovel 300 mg/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 medicinal product(see sections pct. 4.3, pct. 4.4, 4.5 and 5.1).

Due to the hydrochlorothiazide component, CoAprovel is not recommended for patients with severerenal dysfunction (creatinine clearance < 30 ml/min). Loop diuretics are preferred to thiazides in thispopulation. No dosage adjustment is necessary in patients with renal impairment whose renalcreatinine clearance is ≥ 30 ml/min (see sections 4.3 and 4.4).

CoAprovel is not indicated in patients with severe hepatic impairment. Thiazides should be used withcaution in patients with impaired hepatic function. No dosage adjustment of CoAprovel is necessary inpatients with mild to moderate hepatic impairment (see section 4.3).

Older people

No dosage adjustment of CoAprovel is necessary in older people.

CoAprovel is not recommended for use in children and adolescents because the safety and efficacyhave not been established. No data are available.

For oral use.

▪ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or toother sulfonamide-derived substances (hydrochlorothiazide is a sulfonamide-derived substance)▪ Second and third trimesters of pregnancy (see sections 4.4 and 4.6)▪ Severe renal impairment (creatinine clearance < 30 ml/min)▪ Refractory hypokalaemia, hypercalcaemia▪ Severe hepatic impairment, biliary cirrhosis and cholestasis▪ The concomitant use of CoAprovel with aliskiren-containing products is contraindicated inpatients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR)<60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

Hypotension - Volume-depleted patients: CoAprovel has been rarely associated with symptomatichypotension in hypertensive patients without other risk factors for hypotension. Symptomatichypotension may be expected to occur in patients who are volume and/or sodium depleted by vigorousdiuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be correctedbefore initiating therapy with CoAprovel.

Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension andrenal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a singlefunctioning kidney are treated with angiotensin converting enzyme inhibitors or angiotensin-IIreceptor antagonists. While this is not documented with CoAprovel, a similar effect should beanticipated.

Renal impairment and kidney transplantation: when CoAprovel is used in patients with impaired renalfunction, 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 kidneytransplantation. CoAprovel should not be used in patients with severe renal impairment (creatinineclearance < 30 ml/min) (see section 4.3). Thiazide diuretic-associated azotaemia may occur in patientswith impaired renal function. No dosage adjustment is necessary in patients with renal impairmentwhose creatinine clearance is ≥ 30 ml/min. However, in patients with mild to moderate renalimpairment (creatinine clearance ≥ 30 ml/min but < 60 ml/min) this fixed dose combination should beadministered with caution.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that theconcomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk ofhypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dualblockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy isconsidered absolutely necessary, this should only occur under specialist supervision and subject tofrequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors andangiotensin II receptor blockers should not be used concomitantly in patients with diabeticnephropathy.

Hepatic impairment: thiazides should be used with caution in patients with impaired hepatic functionor progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitatehepatic 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 obstructivehypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond toantihypertensive medicinal products acting through inhibition of the renin-angiotensin system.

Therefore, the use of CoAprovel is not recommended.

Metabolic and endocrine effects: thiazide therapy may impair glucose tolerance. Latent diabetesmellitus may become manifest during thiazide therapy. Irbesartan may induce hypoglycaemia,particularly in diabetic patients. In patients treated with insulin or antidiabetics an appropriate bloodglucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may berequired when indicated (see section 4.5).

Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy;however at the 12.5 mg dose contained in CoAprovel, minimal or no effects were reported.

Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving thiazidetherapy.

Electrolyte imbalance: as for any patient receiving diuretic therapy, periodic determination of serumelectrolytes 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 aredryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps,muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nauseaor vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy withirbesartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patientswith cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receivinginadequate oral intake of electrolytes and in patients receiving concomitant therapy withcorticosteroids or ACTH. Conversely, due to the irbesartan component of CoAprovel hyperkalaemiamight 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-sparingdiuretics, potassium supplements or potassium-containing salts substitutes should be co-administeredcautiously with CoAprovel (see section 4.5).

There is no evidence that irbesartan would reduce or prevent diuretic-induced hyponatraemia. Chloridedeficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation ofserum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemiamay be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying outtests for parathyroid function.

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

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists,including CoAprovel (see section 4.8). These patients presented with abdominal pain, nausea,vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptorantagonists. If intestinal angioedema is diagnosed, CoAprovel should be discontinued and appropriatemonitoring should be initiated until complete resolution of symptoms has occurred.

Lithium: the combination of lithium and CoAprovel is not recommended (see section 4.5).

Anti-doping test: hydrochlorothiazide contained in this medicinal product could produce a positiveanalytic result in an anti-doping test.

General: in patients whose vascular tone and renal function depend predominantly on the activity ofthe renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure orunderlying renal disease, including renal artery stenosis), treatment with angiotensin convertingenzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associatedwith acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with anyantihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy orischemic cardiovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history ofallergy 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 thiazidediuretics.

Cases of photosensitivity reactions have been reported with thiazides diuretics (see section 4.8). Ifphotosensitivity 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 thesun 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 bechanged to alternative antihypertensive treatments which have an established safety profile for use inpregnancy. 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).

Choroidal effusion, Acute Myopia and Secondary Acute Angle-Closure Glaucoma: sulfonamide drugsor sulfonamide derivative drugs can cause an idiosyncratic reaction, resulting in choroidal effusionwith visual field defect, transient myopia and acute angle-closure glaucoma. Whilehydrochlorothiazide is a sulfonamide, only isolated cases of acute angle-closure glaucoma have beenreported so far with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity orocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closureglaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake asrapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocularpressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may includea history of sulfonamide or penicillin allergy (see section 4.8).

CoAprovel 300 mg/25 mg film-coated tablet contains lactose. Patients with rare hereditary problemsof galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not takethis medicine.

CoAprovel 300 mg/25 mg film-coated tablet contains sodium. This medicine contains less than1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamouscell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure hasbeen observed in two epidemiological studies based on the Danish National Cancer Registry.

Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check theirskin for any new lesions and promptly report any suspicious skin lesions. Possible preventivemeasures such as limited exposure to sunlight and UV rays and, in case of exposure, adequateprotection should be advised to the patients in order to minimize the risk of skin cancer. Suspiciousskin lesions should be promptly examined potentially including histological examinations of biopsies.

The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC(see also section 4.8).

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome(ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically developswithin minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea,fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, CoAprovel shouldbe withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered topatients who previously experienced ARDS following hydrochlorothiazide intake.

Other antihypertensive agents: the antihypertensive effect of CoAprovel may be increased with theconcomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with otherantihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Priortreatment with high dose diuretics may result in volume depletion and a risk of hypotension wheninitiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion iscorrected first (see section 4.4).

Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade ofthe renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors,angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse eventssuch as hypotension, hyperkalaemia and decreased renal function (including acute renal failure)compared to the use of a single RAAS-acting agent (see sections pct. 4.3, pct. 4.4 and 5.1).

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effectshave been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium isreduced by thiazides so the risk of lithium toxicity could be increased with CoAprovel. Therefore, thecombination of lithium and CoAprovel is not recommended (see section 4.4). If the combinationproves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide isattenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazideon serum potassium would be expected to be potentiated by other medicinal products associated withpotassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of othermedicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparingdiuretics, potassium supplements, salt substitutes containing potassium or other medicinal productsthat may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serumpotassium. Adequate monitoring of serum potassium in patients at risk is recommended (seesection 4.4).

Medicinal products affected by serum potassium disturbances: periodic monitoring of serumpotassium is recommended when CoAprovel is administered with medicinal products affected byserum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administeredsimultaneously 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 effectmay occur.

As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to anincreased risk of worsening of renal function, including possible acute renal failure, and an increase inserum potassium, especially in patients with poor pre-existing renal function. The combination shouldbe administered with caution, especially in the elderly. Patients should be adequately hydrated andconsideration should be given to monitoring renal function after initiation of concomitant therapy, andperiodically thereafter.

Repaglinide: irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported thatirbesartan increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevantpharmacokinetic interaction was reported, when the two drugs were co-administered. Therefore, doseadjustment of antidiabetic treatment such as repaglinide may be required (see section 4.4).

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartanis not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesserextent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions wereobserved when irbesartan was coadministered with warfarin, a medicinal product metabolised by

CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartanhave not been evaluated. The pharmacokinetic of digoxin was not altered by co-administration ofirbesartan.

Additional information on hydrochlorothiazide interactions: when administered concurrently, thefollowing medicinal products may interact with thiazide diuretics:

Alcohol: potentiation of orthostatic hypotension may occur;

Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabeticmedicinal product may be required (see section 4.4);

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence ofanionic exchange resins. CoAprovel should be taken at least one hour before or four hours after thesemedications;

Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;

Digitalis glycosides: thiazide induced hypokalaemia or hypomagnesaemia favour the onset ofdigitalis-induced cardiac arrhythmias (see section 4.4);

Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drugmay 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 notsufficiently to preclude their use;

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletalmuscle relaxants may be potentiated by hydrochlorothiazide;

Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary ashydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid orsulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidenceof hypersensitivity reactions to allopurinol;

Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. Ifcalcium supplements or calcium sparing medicinal products (e.g. vitamin D therapy) must beprescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;

Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated withthe risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. Ifpossible, another class of diuretics should be used;

Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced bythiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides mayincrease the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion ofcytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate theirmyelosuppressive effects.

Angiotensin II Receptor Antagonists (AIIRAs)

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). Theuse of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot 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 alternativeantihypertensive treatments which have an established safety profile for use in pregnancy. Whenpregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce humanfoetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonataltoxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound checkof renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (seesections 4.3 and 4.4).

There is limited experience with hydrochlorothiazide during pregnancy, especially during the firsttrimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on thepharmacological mechanism of action of hydrochlorothiazide its use during the second and thirdtrimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects likeicterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension orpreeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without abeneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in raresituations where no other treatment could be used.

Since CoAprovel contains hydrochlorothiazide, it is not recommended during the first trimester ofpregnancy. A switch to a suitable alternative treatment should be carried out in advance of a plannedpregnancy.

Angiotensin II Receptor Antagonists (AIIRAs)

Because no information is available regarding the use of CoAprovel during breast-feeding, CoAprovelis not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

It is unknown whether irbesartan or its metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or itsmetabolites in milk (for details see 5.3).

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causingintense diuresis can inhibit the milk production. The use of CoAprovel during breast feeding is notrecommended. If CoAprovel is used during breast feeding, doses should be kept as low as possible.

Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducingthe first signs of parental toxicity (see section 5.3).

Based on its pharmacodynamic properties, CoAprovel is unlikely to affect the ability to drive and usemachines. When driving vehicles or operating machines, it should be taken into account thatoccasionally dizziness or weariness may occur during treatment of hypertension.

Irbesartan/hydrochlorothiazide combination

Among 898 hypertensive patients who received various doses of irbesartan/hydrochlorothiazide(range: 37.5 mg/6.25 mg to 300 mg/25 mg) in placebo-controlled trials, 29.5% of the patientsexperienced adverse reactions. The most commonly reported ADRs were dizziness (5.6%), fatigue(4.9%), nausea/vomiting (1.8%), and abnormal urination (1.4%). In addition, increases in blood ureanitrogen (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) were also commonly observed inthe trials.

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlledtrials.

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 effectsare presented in order of decreasing seriousness.

Table 1: Adverse Reactions in Placebo-Controlled Trials and Spontaneous Reports

Investigations: 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

Nervous system disorders: Common: dizziness

Uncommon: orthostatic dizziness

Not known: headache

Ear and labyrinth disorders: Not known: tinnitus

Respiratory, thoracic and Not known: coughmediastinal disorders:

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 casesof renal failure in patients at risk (seesection 4.4)

Musculoskeletal and connective Uncommon: swelling extremitytissue disorders: Not known: arthralgia, myalgia

Metabolism and nutrition Not known: hyperkalaemiadisorders:

Vascular disorders: Uncommon: flushing

General disorders and Common: fatigueadministration site conditions:

Immune system disorders: Not known: cases of hypersensitivity reactions such asangioedema, rash, urticaria

Hepatobiliary disorders: Uncommon: jaundice

Not known: hepatitis, abnormal liver function

Reproductive system and breast Uncommon: sexual dysfunction, libido changesdisorders:

Additional information on individual components: in addition to the adverse reactions listed above forthe combination product, other adverse reactions previously reported with one of the individualcomponents may be potential adverse reactions with CoAprovel. Tables 2 and 3 below detail theadverse reactions reported with the individual components of CoAprovel.

Table 2: Adverse reactions reported with the use of irbesartan alone

Blood and lymphatic system Not known: anaemia, thrombocytopeniadisorders:

General disorders and Uncommon: chest painadministration site conditions:

Immune system disorders: Not known: Anaphylactic reaction including anaphylacticshock

Metabolism and nutrition Not known: hypoglycaemiadisorders:

Gastrointestinal disorders: Rare: intestinal angioedema

Table 3: Adverse reactions reported with the use of hydrochlorothiazide alone

Investigations: Not known: electrolyte imbalance (including hypokalaemiaand hyponatraemia, see section 4.4),hyperuricaemia, glycosuria, hyperglycaemia,increases in cholesterol and triglycerides

Cardiac disorders: Not known: cardiac arrhythmias

Blood and lymphatic system Not known: aplastic anaemia, bone marrow depression,disorders: neutropenia/agranulocytosis, haemolyticanaemia, leucopenia, thrombocytopenia

Nervous system disorders: Not known: vertigo, paraesthesia, light-headedness,restlessness

Eye disorders: Not known: transient blurred vision, xanthopsia, acutemyopia and secondary acute angle-closureglaucoma, choroidal effusion

Respiratory, thoracic and Very rare: acute respiratory distress syndrome (ARDS)mediastinal disorders: (see section 4.4)

Not known: respiratory distress (including pneumonitis andpulmonary 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 Not known: anaphylactic reactions, toxic epidermaldisorders: necrolysis, necrotizing angiitis (vasculitis,cutaneous vasculitis), cutaneous lupuserythematosus-like reactions, reactivation ofcutaneous lupus erythematosus, photosensitivityreactions, rash, urticaria

Musculoskeletal and connective Not known: weakness, muscle spasmtissue disorders:

Vascular disorders: Not known: postural hypotension

General disorders and Not known: feveradministration site conditions:

Hepatobiliary disorders: Not known: jaundice (intrahepatic cholestatic jaundice)

Psychiatric disorders: Not known: depression, sleep disturbances

Neoplasms benign, malignant Not known: non-melanoma skin cancer (basal celland unspecified (incl cysts and carcinoma and squamous cell carcinoma)polyps)

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dosedependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

The dose dependent adverse events of hydrochlorothiazide (particularly electrolyte disturbances) mayincrease when titrating the hydrochlorothiazide.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with CoAprovel. The patient shouldbe closely monitored, and the treatment should be symptomatic and supportive. Management dependson the time since ingestion and the severity of the symptoms. Suggested measures include induction ofemesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serumelectrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient shouldbe 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.

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The mostcommon signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result inmuscle spasms and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalisglycosides or certain anti-arrhythmic medicinal products.

Irbesartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed byhaemodialysis has not been established.

Pharmacotherapeutic group: angiotensin-II antagonists, combinations

ATC code: C09DA04.

CoAprovel is a combination of an angiotensin-II receptor antagonist, irbesartan, and a thiazidediuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensiveeffect, reducing blood pressure to a greater degree than either component alone.

Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It isexpected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the sourceor route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptorsresults in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasmaaldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone atthe 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 alsodegrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for itsactivity.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazidediuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption,directly increasing excretion of sodium and chloride in approximately equivalent amounts. Thediuretic 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-aldosteronesystem, co-administration of irbesartan tends to reverse the potassium loss associated with thesediuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs atabout 4 hours, while the action persists for approximately 6-12 hours.

The combination of hydrochlorothiazide and irbesartan produces dose-related additive reductions inblood pressure across their therapeutic dose ranges. The addition of 12.5 mg hydrochlorothiazide to300 mg irbesartan once daily in patients not adequately controlled on 300 mg irbesartan alone resultedin further placebo-corrected diastolic blood pressure reductions at trough (24 hours post-dosing) of6.1 mm Hg. The combination of 300 mg irbesartan and 12.5 mg hydrochlorothiazide resulted in anoverall 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 the300 mg/12.5 mg combination may respond when uptitrated to 300 mg/25 mg. In these patients, anincremental blood pressure lowering effect was observed for both systolic blood pressure (SBP) anddiastolic 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/diastolicmean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) of 12.9/6.9 mm Hgin patients with mild-to-moderate hypertension. Peak effects occurred at 3-6 hours. When assessed byambulatory blood pressure monitoring, the combination 150 mg irbesartan and 12.5 mghydrochlorothiazide once daily produced consistent reduction in blood pressure over the 24 hoursperiod with mean 24-hour placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mm Hg. Whenmeasured by ambulatory blood pressure monitoring, the trough to peak effects of

CoAprovel 150 mg/12.5 mg were 100%. The trough to peak effects measured by cuff during officevisits were 68% and 76% for CoAprovel 150 mg/12.5 mg and CoAprovel 300 mg/12.5 mg,respectively. These 24-hour effects were observed without excessive blood pressure lowering at peakand 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 irbesartangave 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 apparentafter 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 maintainedfor over one year. Although not specifically studied with the CoAprovel, rebound hypertension has notbeen seen with either irbesartan or hydrochlorothiazide.

The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality hasnot been studied. Epidemiological studies have shown that long term treatment withhydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

There is no difference in response to CoAprovel, regardless of age or gender. As is the case with othermedicinal products that affect the renin-angiotensin system, black hypertensive patients have notablyless response to irbesartan monotherapy. When irbesartan is administered concomitantly with a lowdose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patientsapproaches that of non-black patients.

Efficacy and safety of CoAprovel as initial therapy for severe hypertension (defined as SeDBP≥ 110 mmHg) was evaluated in a multicentre, randomized, double-blind, active-controlled, 8-week,parallel-arm study. A total of 697 patients were randomized in a 2:1 ratio to eitherirbesartan/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 toirbesartan/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% werehyperlipidaemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% ofthe participants.

The primary objective of this study was to compare the proportion of patients whose SeDBP wascontrolled (SeDBP < 90 mmHg) at Week 5 of treatment. Forty-seven percent (47.2%) of patients onthe 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 treatmentgroup and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg forirbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).

The types and incidences of adverse events reported for patients treated with the combination weresimilar 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 patientswith hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in thecombination and monotherapy groups, respectively.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs

Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with anangiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history ofcardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence ofend-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus anddiabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension ascompared to monotherapy was observed. Given their similar pharmacodynamic properties, theseresults are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly inpatients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitoror an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidneydisease, cardiovascular disease, or both. The study was terminated early because of an increased riskof adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in thealiskiren group than in the placebo group and adverse events and serious adverse events of interest(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskirengroup than in the placebo group.

Based on available data from epidemiological studies, cumulative dose-dependent association between

HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of

BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively.

High HCTZ use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationshipwas observed for both BCC and SCC. Another study showed a possible association between lip cancer(SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls,using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with anadjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

Concomitant administration of hydrochlorothiazide and irbesartan has no effect on thepharmacokinetics of either medicinal product.

Irbesartan and hydrochlorothiazide are orally active agents and do not require biotransformation fortheir activity. Following oral administration of CoAprovel, the absolute oral bioavailability is 60-80%and 50-80% for irbesartan and hydrochlorothiazide, respectively. Food does not affect thebioavailability of CoAprovel. Peak plasma concentration occurs at 1.5-2 hours after oraladministration for irbesartan and 1-2.5 hours for hydrochlorothiazide.

Plasma protein binding of irbesartan is approximately 96%, with negligible binding to cellular bloodcomponents. 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; themechanism 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 plasmaconcentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limitedaccumulation 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 dosageadjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhatgreater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminalhalf-life was not significantly altered. No dosage adjustment is necessary in older people. The meanplasma half-life of hydrochlorothiazide reportedly ranges from 5-15 hours.

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasmaradioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver viaglucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by thecytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral orintravenous 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 unchangedirbesartan. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidneys. At least61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses theplacental but not the blood-brain barrier, and is excreted in breast milk.

In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parametersof irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. In patients withcreatinine clearance < 20 ml/min, the elimination half-life of hydrochlorothiazide was reported toincrease to 21 hours.

In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are notsignificantly altered. Studies have not been performed in patients with severe hepatic impairment.

Irbesartan/hydrochlorothiazide

The potential toxicity of the irbesartan/hydrochlorothiazide combination after oral administration wasevaluated in rats and macaques in studies lasting up to 6 months. There were no toxicological findingsobserved of relevance to human therapeutic use.

The following changes, observed in rats and macaques receiving the irbesartan/hydrochlorothiazidecombination at 10/10 and 90/90 mg/kg/day, were also seen with one of the two medicinal productsalone and/or were secondary to decreases in blood pressure (no significant toxicologic interactionswere observed):

▪ kidney changes, characterized by slight increases in serum urea and creatinine, andhyperplasia/hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of theinteraction 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 a6 months toxicity study at irbesartan 90 mg/kg/day, hydrochlorothiazide 90 mg/kg/day, andirbesartan/hydrochlorothiazide 10/10 mg/kg/day. These lesions were not observed in macaques;▪ decreases in serum potassium due to hydrochlorothiazide and partly prevented whenhydrochlorothiazide 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-producingcells) and occur also with angiotensin converting enzyme inhibitors. These findings appear to have norelevance to the use of therapeutic doses of irbesartan/hydrochlorothiazide in humans.

No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination atdoses that produced maternal toxicity. The effects of the irbesartan/hydrochlorothiazide combinationon fertility have not been evaluated in animal studies, as there is no evidence of adverse effect onfertility in animals or humans with either irbesartan or hydrochlorothiazide when administered alone.

However, another angiotensin-II antagonist affected fertility parameters in animal studies when givenalone. These findings were also observed with lower doses of this other angiotensin-II antagonist whengiven in combination with hydrochlorothiazide.

There was no evidence of mutagenicity or clastogenicity with the irbesartan/hydrochlorothiazidecombination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has notbeen evaluated in animal studies.

Irbesartan

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. Innon-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day inmacaques) 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 interstitialnephritis, tubular distention, basophilic tubules, increased plasma concentrations of urea andcreatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to thehypotensive 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, inmacaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by thepharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, thehyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.

There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even atoral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), includingmortality at the highest dose. No significant effects on the number of corpora lutea, implants, or livefoetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring.

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses.

Irbesartan is excreted in the milk of lactating rats.

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, includingmortality. No teratogenic effects were observed in the rat or rabbit.

Equivocal evidence of a genotoxic or carcinogenic effect was observed in some experimental models.

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Pregelatinised starch

Silicon dioxide

Magnesium stearate

Red and yellow ferric oxides

Lactose monohydrate

Hypromellose

Titanium dioxide

Macrogol 3350

Red and black ferric oxides

Carnauba wax

Not applicable.

3 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 x 1 film-coated tablets in PVC/PVDC/Aluminium perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/98/086/023-028

EU/1/98/086/031

EU/1/98/086/034

Date of first authorisation: 15 October 1998

Date of latest renewal: 01 October 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/