1. Name Of The Medicinal Product
Aprovel 75 mg tablets.
Aprovel 150 mg tablets.
Aprovel 300 mg tablets.
2. Qualitative And Quantitative Composition
Each tablet contains 75 mg, 150 mg or 300 mg irbesartan.
For excipients, see 6.1.
3. Pharmaceutical Form
Tablet.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side. The other side is engraved with the number 2771 on the 75 mg tablet, 2772 on the 150 mg tablet and 2773 on the 300 mg tablet.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of essential hypertension.
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 4.5).
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.
Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Aprovel.
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.
Children: safety and efficacy of Aprovel have not been established in children.
4.3 Contraindications
Hypersensitivity to any component of the product (see 6.1).
Second and third trimester of pregnancy (see 4.6).
Lactation (see 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 drugs 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.
Hyperkalemia: as with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalemia may occur during the treatment with Aprovel, especially in the presence of renal impairment and/or heart failure. Adequate monitoring of serum potassium in patients at risk is recommended (see 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 drugs 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-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
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 drugs that affect the renin-angiotensin 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) may lead to increases in serum potassium (see 4.4).
Lithium:reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. While this is not documented with Aprovel, the possibility of a similar effect can not be excluded and careful monitoring of serum lithium levels is recommended during concomitant use.
Additional information on drug interactions: the pharmacokinetics of digoxin were not altered by coadministration of a 150 mg dose of irbesartan in healthy male volunteers. The pharmacokinetics of irbesartan are not affected by co-administration of hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. Inhibition of the glucuronyl transferase pathway is unlikely to result in clinically significant interactions. In vitro interactions were observed between irbesartan and warfarin, tolbutamide (CYP2C9 substrates) and nifedipine (CYP2C9 inhibitor). However, no significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin in healthy male volunteers. The pharmacokinetics of irbesartan are not affected by co-administration of nifedipine. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan were not evaluated. Based on in vitro data, no interaction would be expected to occur with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.
4.6 Pregnancy And Lactation
Pregnancy: see 4.3 Contra-indications.
As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death, therefore, irbesartan is contraindicated in the second and third trimesters of pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.
Lactation: Aprovel is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats (see 4.3).
4.7 Effects On Ability To Drive And Use Machines
The effect of irbesartan on ability to drive and use machines has not been studied, but 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 occasionally dizziness or weariness may occur during treatment of hypertension.
4.8 Undesirable Effects
Undesirable effects in patients receiving Aprovel are generally mild and transient.
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan and the placebo groups. Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients than for placebo-treated patients. The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment.
Clinical adverse events, regardless of whether attributed to therapy, occurring in 1% or more of hypertensive patients with Aprovel in placebo-controlled trials are presented in the following table:
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Adverse events occurred with similar frequency in placebo and irbesartan-treated patients, with the exception of headache, musculoskeletal trauma, and flushing. Headache occurred significantly more often in the placebo group. Musculoskeletal trauma of differing types and causes occurred with a significantly higher incidence in the irbesartan group; all reports of musculoskeletal trauma were considered unrelated to irbesartan by the investigators. Flushing occurred in 0.6% of irbesartan patients and in no placebo patients. The occurrence of flushing was not related to dose, was not accompanied by other clinical events, and the relationship with irbesartan therapy is unknown.
No clinically significant changes in laboratory test parameters occurred in controlled clinical trials. Although significant increases in plasma creatine kinase occurred more frequently in irbesartan-treated subjects (1.7% vs 0.7% in placebo-treated subjects), none of these increases were classified as serious, resulted in drug discontinuation, or were associated with identifiable clinical musculoskeletal events. No special monitoring of laboratory parameters is necessary for patients with essential hypertension receiving therapy with Aprovel, when the renal function is normal (see 4.4).
Post-marketing experience: as with other angiotensin
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 overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage 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 overdosage. Irbesartan is not removed by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Angiotensin
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
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 drugs 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.
5.2 Pharmacokinetic Properties
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of approximately 60
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53
Following oral or intravenous administration of 14C 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 1.5max values were also somewhat greater in elderly subjects (
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.
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 preclinical 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
Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and poloxamer 188.
6.2 Incompatibilities
None.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
Store in a dry place below 30°C.
6.5 Nature And Contents Of Container
Aprovel tablets are packaged in blister packs containing 28 tablets in PVC/PVDC/Aluminium strips.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
SANOFI PHARMA BRISTOL
174 avenue de France
F
8. Marketing Authorisation Number(S)
Aprovel 75 mg tablets: EU/1/97/046/001
Aprovel 150 mg tablets: EU/1/97/046/004
Aprovel 300 mg tablets: EU/1/97/046/007
9. Date Of First Authorisation/Renewal Of The Authorisation
27 August 1997
10. Date Of Revision Of The Text
23 April 2001
Legal category: POM
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