1. Name Of The Medicinal Product
Aprovel 75 mg film-coated tablets.
Aprovel 150 mg film-coated tablets.
Aprovel 300 mg film-coated tablets
2. Qualitative And Quantitative Composition
Aprovel 75 mg
Each film-coated tablet contains 75 mg of irbesartan.
Excipient: 25.50 mg of lactose monohydrate per film-coated tablet.
Aprovel 150 mg
Each film-coated tablet contains 150 mg of irbesartan.
Excipient: 51.00 mg of lactose monohydrate per film-coated tablet.
Aprovel 300 mg
Each film-coated tablet contains 300 mg of irbesartan.
Excipient: 102.00 mg of lactose monohydrate per film-coated tablet.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Aprovel 75 mg
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2871 engraved on the other side.
Aprovel 150 mg
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2872 engraved on the other side.
Aprovel 300 mg
White to off-white biconvex, and oval-shaped with a heart debossed on one side and the number 2873 engraved on the other side.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of essential hypertension.
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see section 5.1).
4.2 Posology And Method Of Administration
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see section 5.1).
Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).
Hepatic impairment: no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.
Elderly patients: although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.
Paediatric patients: irbesartan is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).
4.3 Contraindications
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
4.4 Special Warnings And Precautions For Use
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may 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 the administration of Aprovel.
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 medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section 5.1).
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see section 4.5).
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5).
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 medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended.
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
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose:this medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric patients: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive effects of irbesartan; however Aprovel has been safely administered with other antihypertensive agents, such as beta
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see section 4.4).
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Non: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.
4.6 Pregnancy And Lactation
Pregnancy
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). |
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (see section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also sections 4.3 and 4.4).
Lactation:
Because no information is available regarding the use of CoAprovel during breast-feeding, CoAprovel is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.
4.8 Undesirable Effects
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo.
The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in> 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed below is defined using the following convention:
very common (
Investigations:
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (
Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events.
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed.
Cardiac disorders:
Uncommon: tachycardia
Nervous system disorders:
Common: dizziness, orthostatic dizziness*
Respiratory, thoracic and mediastinal disorders:
Uncommon: cough
Gastrointestinal disorders:
Common: nausea/vomiting
Uncommon: diarrhoea, dyspepsia/heartburn
Musculoskeletal and connective tissue disorders:
Common: musculoskeletal pain*
Vascular disorders:
Common: orthostatic hypotension*
Uncommon: flushing
General disorders and administration site conditions:
Common: fatigue
Uncommon: chest pain
Reproductive system and breast disorders:
Uncommon: sexual dysfunction
The following additional adverse reactions have been reported during post–marketing experience; they are derived from spontaneous reports and therefore, the frequency of these adverse reactions is not known:
Nervous system disorders:
Headache
Ear and labyrinth disorders:
Tinnitus
Gastrointestinal disorders:
Dysgeusia
Renal and urinary disorders:
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Skin and subcutaneous tissue disorders:
Leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders:
Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps
Metabolism and nutrition disorders:
Hyperkalaemia
Immune system disorders:
Hypersensitivity reactions such as angioedema, rash, urticaria
Hepato-biliary disorders:
Hepatitis, abnormal liver function
Paediatric patients: in a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following related adverse events occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.
4.9 Overdose
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdose with Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Angiotensin
ATC code: C09C A04.
Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin1) antagonist. It is expected to block all actions of angiotensin1 receptor, regardless of the source or route of synthesis of angiotensin1) receptors results in increases in plasma renin levels and angiotensin
Clinical efficacy:
Hypertension
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150
Peak reduction of blood pressure is achieved within 3
The blood pressure lowering effect of Aprovel is evident within 1
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.
There is no clinically important effect on serum uric acid or urinary uric acid secretion.
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2).
Hypertension and type 2 diabetes with renal disease
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30
5.2 Pharmacokinetic Properties
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 6014C irbesartan, 80In vitro studies indicate that irbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.
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 (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5
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.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.
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.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.
Studies have not been performed in patients with severe hepatic impairment.
5.3 Preclinical Safety Data
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hypromellose
Silicon dioxide
Magnesium stearate.
Film-coating:
Lactose monohydrate
Hypromellose
Titanium dioxide
Macrogol 3000
Carnauba wax.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 30°C.
6.5 Nature And Contents Of Container
Cartons of 28 film-coated tablets: 2 blister cards of 14 film-coated tablets in PVC/PVDC/Aluminium blisters.
6.6 Special Precautions For Disposal And Other Handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
SANOFI PHARMA BRISTOL
174 avenue de France
F
8. Marketing Authorisation Number(S)
EU/1/97/046/017
EU/1/97/046/022
EU/1/97/046/027
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 27 August 1997
Date of latest renewal: 27 August 2007
10. Date Of Revision Of The Text
31 March 2009
Legal Category: POM
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/
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