Active ingredients: Irbesartan
Aprovel 75 mg tablets
Aprovel package inserts are available for pack sizes:- Aprovel 75 mg tablets
- Aprovel 150 mg tablets
- Aprovel 300 mg tablets
Indications Why is Aprovel used? What is it for?
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced by the body that binds to receptors in blood vessels causing them to constrict. This results in an increase in blood pressure. Aprovel prevents angiotensin-II from binding to these receptors, allowing blood vessels to dilate and blood pressure to drop. Aprovel slows the decay of kidney function in patients with high blood pressure and type 2 diabetes.
Aprovel is used in adult patients
- to treat high blood pressure levels (essential arterial hypertension)
- to protect the kidney in hypertensive patients with high blood pressure, type 2 diabetes and with evidence of renal dysfunction on laboratory tests.
Contraindications When Aprovel should not be used
Do not take Aprovel:
- if you are allergic to irbesartan or any of the other ingredients of this medicine
- if you are more than 3 months pregnant (it is also better to avoid Aprovel in early pregnancy - see pregnancy section)
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren
Precautions for use What you need to know before taking Aprovel
Talk to your doctor before taking Aprovel if you have any of the following conditions:
- excessive vomiting or diarrhea
- if you suffer from kidney problems
- if you suffer from heart problems
- if you are taking Aprovel for diabetic kidney disorders. In this case, your doctor may order regular blood tests, especially to measure serum potassium levels in case of poor kidney function.
- if you need to have surgery (surgery) or take anesthetics
- if you are taking any of the following medicines used to treat high blood pressure:
- an "ACE inhibitor" (eg enalapril, lisinopril, ramipril), particularly if you have diabetes-related kidney problems.
- aliskiren
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals.
See also information under the heading "Do not take Aprovel"
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Aprovel is not recommended in early pregnancy and must not be taken if more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
Children and adolescents
This medicine should not be used in children and adolescents as safety and efficacy have not yet been fully established.
Interactions Which drugs or foods can modify the effect of Aprovel
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Your doctor may need to change your dose and / or take other precautions:
If you are taking an ACE inhibitor or aliskiren (see also information under the headings: "Do not take Aprovel" and "Warnings and precautions")
You may need blood tests if you are using:
- potassium supplements
- potassium-containing table salt substitutes
- potassium-sparing medicines (such as some diuretics)
- medicines containing lithium If certain painkillers, called non-steroidal anti-inflammatory medicines, are taken, the effectiveness of irbesartan may be reduced.
Aprovel with food and drink
Aprovel can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You must tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant); your doctor will usually advise you to stop taking Aprovel before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not recommended for all " early pregnancy and must not be taken if more than 3 months pregnant as it may cause serious harm to your baby if taken after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding. Aprovel is not recommended for women who are breastfeeding and your doctor may choose another treatment if you wish to breastfeed, especially if the baby is newborn or was born prematurely.
Driving and using machines
No studies on the ability to drive and use machines have been performed.
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally, dizziness or fatigue may occur during treatment for high blood pressure. If this happens, talk to your doctor before driving or using machines.
Aprovel contains lactose.
If you have been told by your doctor that you have an "intolerance to some sugars (eg lactose), contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Aprovel: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist
Method of administration
Aprovel is for oral use. Swallow the tablets with sufficient fluid (eg a glass of water). You can take Aprovel with or without food. Try to take the medicine at the same time each day. Treatment should be continued for as long as your doctor considers it necessary. necessary.
- Patients with high blood pressure The usual dose is 150 mg once a day (two tablets a day). The dosage can be increased to 300 mg (four tablets a day) once a day depending on the reduction in blood pressure levels.
- Patients with high blood pressure and type 2 diabetes with kidney disease In patients with high blood pressure and type 2 diabetes, the indicated maintenance dose is 300 mg (four tablets a day) once a day for the treatment of kidney disease associated.
The doctor may decide to use lower doses, especially at the start of treatment, in particular patients such as those on hemodialysis, or in patients over 75 years of age.
The maximum antihypertensive effect should be achieved 4-6 weeks after the initiation of therapy.
Use in children and adolescents
Aprovel should not be given to children under 18 years of age. If a child swallows tablets, contact your doctor immediately.
Overdose What to do if you have taken too much Aprovel
If you take more Aprovel than you should
If you accidentally take too many tablets, contact your doctor immediately.
If you forget to take Aprovel
If you accidentally forget to take a dose, continue with your therapy as normal. Do not take a double dose to make up for a forgotten dose.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Aprovel
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some of these effects can be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (redness, hives) as well as localized swelling of the face, lips and / or tongue have been reported in patients taking irbesartan. If you get any of these symptoms or if you have difficulty breathing, stop taking Aprovel and contact your doctor immediately.
The frequency of side effects listed below is defined using the following convention:
Very common: may affect more than 1 in 10 people
Common: may affect up to 1 in 10 people
Uncommon: may affect up to 1 in 100 people
Undesirable effects reported in clinical trials for patients treated with Aprovel were:
- Very common (may affect more than 1 in 10 people): If you have high blood pressure and type 2 diabetes with kidney disease, blood tests may show elevated potassium levels.
- Common (may affect up to 1 in 10 people): dizziness, feeling sick / vomiting, fatigue, and blood tests may show increased levels of an enzyme that measures muscle and heart function (creatine kinase). In patients with high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from a lying or sitting position, low blood pressure when getting up from a lying or sitting position, pain in joints or muscles have also been reported. decrease in the levels of a protein in the red blood cells (hemoglobin).
- Uncommon (may affect up to 1 in 100 people): increased heart rate, flushing, cough, diarrhea, indigestion / heartburn, sexual dysfunction (problems relating to sexual performance), chest pain.
Some undesirable effects have been reported since marketing of Aprovel. Side effects with an unknown frequency are: spinning sensation, headache, taste disturbance, ringing in the ears, muscle cramps, pain in the joints and muscles, abnormal liver function, increased blood potassium levels, disturbances of kidney function and inflammation of small blood vessels mainly affecting the skin (a condition known as leukocytoclastic vasculitis). Uncommon cases of jaundice (yellowing of the skin and / or whites of the eyes) have also been reported.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.
Do not store above 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Aprovel contains
- The active substance is irbesartan. Each Aprovel 75 mg tablet contains 75 mg of irbesartan.
- The other ingredients are: microcrystalline cellulose, cross-linked carmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch and poloxamer 188.
What Aprovel looks like and contents of the pack
Aprovel 75 mg tablets are white to off-white, biconvex, oval shaped with a heart debossed on one side and the number 2771 debossed on the other side.
Aprovel 75 mg tablets are available in packs of 14, 28, 56 or 98 tablets in blisters. Single-dose blisters of 56 x 1 tablet are also available for hospital use.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
APROVEL 75 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 75 mg of irbesartan.
Excipient: 15.37 mg of lactose monohydrate per tablet.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
White to off-white, biconvex, oval in shape with a heart engraved on one side and the number 2771 embossed on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Aprovel is indicated in adults for the treatment of essential arterial hypertension.
It is also indicated for the treatment of renal disease in adult hypertensive patients with type 2 diabetes mellitus as part of an antihypertensive drug treatment (see section 5.1).
04.2 Posology and method of administration
Dosage
The usual recommended starting and maintenance dose is 150 mg once daily, regardless of concomitant food intake. Aprovel at a dose of 150 mg once daily generally provides better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg should be considered, particularly in hemodialysis patients and patients. elderly patients over the age of 75.
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other antihypertensive agents can be co-administered. In particular, the addition of a diuretic such as hydrochlorothiazide has shown an additive effect with Aprovel (see section 4.5).
In hypertensive patients with type 2 diabetes, therapy should be initiated with irbesartan 150 mg once daily and increased to 300 mg once daily as the recommended maintenance dose for the treatment of renal disease. The demonstration of kidney benefit of Aprovel in hypertensive patients with type 2 diabetes is based on studies in which irbesartan was used as an adjunct to other antihypertensive medicinal products, as needed, to achieve target blood pressure (see section 5.1).
Special populations
Kidney failure: in subjects with reduced renal function no dosage variation is necessary. A lower starting dose (75 mg) should be considered in patients undergoing hemodialysis (see section 4.4).
Hepatic insufficiency: in subjects with mild or moderate hepatic insufficiency, no dosage adjustment is necessary. There are no clinical data in patients with severe hepatic insufficiency.
Elderly patients: Although consideration should be given to initiating therapy with 75 mg in the elderly over 75 years of age, dose adjustment is generally not necessary.
Pediatric population: The safety and efficacy of Aprovel in children aged 0 to 18 years have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Method of administration
For oral use.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
04.4 Special warnings and appropriate precautions for use
Volume reduction: in volume and / or sodium-depleted patients due to intense diuretic treatment, low sodium diet, diarrhea or vomiting, episodes of symptomatic hypotension may occur, especially after administration of the first dose. In such cases, the underlying condition must be corrected before initiating therapy with Aprovel.
Renovascular hypertensionThere is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis, or renal artery stenosis with only one functioning kidney, treated with medicinal products that act in the renin-angiotensin-aldosterone system.
Although this is not documented in Aprovel therapy, a similar effect will also be expected with angiotensin-II receptor antagonists.
Renal failure and renal transplantPeriodic monitoring of serum potassium and creatinine levels is recommended when Aprovel is used in patients with renal insufficiency. There are no clinical data regarding the administration of Aprovel to patients with recent kidney transplantation.
Hypertensive patients with type 2 diabetes and kidney disease: In an analysis performed in the study with patients with advanced renal disease, the effects of irbesartan on renal and cardiovascular events were not uniform across all subgroups. In particular, they were less favorable in women and non-white subjects (see section 5.1).
Hyperkalaemia: As with other medicinal products that interfere with the renin-angiotensin-aldosterone system, hyperkalaemia may occur during treatment with Aprovel, especially in the presence of renal dysfunction, overt proteinuria due to diabetic kidney disease and / or heart failure. Close monitoring of serum potassium is recommended in patients at risk (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 attention is required in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism: Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products which act through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended.
General: in patients whose vascular tone and renal function predominantly depend on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure or with underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists affecting this system has been associated with acute hypotension, BUN, oliguria, or rarely acute renal failure. excessive drop in blood pressure in patients with ischemic heart disease or ischemic cardiovascular disease can lead to myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and other angiotensin antagonists are apparently less effective in lowering blood pressure in black patients than in non-black patients, possibly due to a higher prevalence. of low-renin conditions in the black hypertensive population (see section 5.1).
Pregnancy: therapy with angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. An alternative antihypertensive treatment with a proven safety profile for use in pregnancy should be used for patients planning pregnancy. unless continued therapy with an AIIRA is considered essential.
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 medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose / galactose malabsorption should not take this medicine.
Pediatric population: irbesartan has been studied in the pediatric population between 6 and 16 years of age but current data, pending the availability of new ones, are not sufficient to support its extension of use also in children (see sections 4.8, 5.1 and 5.2).
04.5 Interactions 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 in combination with other antihypertensive medicinal products, such as beta-blockers, long-acting calcium channel blockers and thiazide diuretics. Previous treatment with high dose diuretics may lead to a condition of hypovolaemia and risk of hypotension upon initiation of therapy with Aprovel (see section 4.4).
Potassium supplements and potassium-sparing diuretics: Based on the experience on the use of other drugs active on the renin-angiotensin system, the concomitant use of potassium-sparing diuretics, potassium supplements, table salt substitutes containing potassium or other drugs that may increase potassium (eg heparin) can lead to an increase in serum potassium levels and is therefore not recommended (see section 4.4).
LithiumReversible increases in serum lithium concentrations and toxicity have been observed during concomitant administration of lithium and angiotensin converting enzyme inhibitors. Similar effects have so far been very rarely documented with irbesartan. Therefore this combination is not recommended (see section 4.4). If there is a real need for the combination, careful monitoring of serum lithium levels is recommended.
Non-steroidal anti-inflammatory drugs: When angiotensin II antagonists are co-administered with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and non-selective non-steroidal anti-inflammatory drugs), attenuation of the antihypertensive effect may occur . As with ACE inhibitors, the simultaneous use of angiotensin II antagonists and non-steroidal anti-inflammatory drugs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and to an increase in serum potassium particularly in patients with pre-existing modest renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and renal function monitoring should be considered after initiation of combination therapy and periodically thereafter.
Learn more about irbesartan interactions: In clinical studies, the pharmacokinetics of irbesartan were not affected by hydrochlorothiazide. Irbesartan is primarily metabolised by CYP2C9 and to a lesser extent via glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed following concomitant administration of irbesartan with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers, such as rifampicin, on the pharmacokinetics of irbesartan have not been evaluated.
The pharmacokinetics of digoxin were not altered by concomitant administration of irbesartan.
04.6 Pregnancy and lactation
Pregnancy:
The use of angiotensin II receptor antagonists (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 on 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. Although no controlled epidemiological data on risk with angiotensin II receptor antagonists (AIIRAs) are available, a similar risk may also exist for this class of medicinal products. For patients planning pregnancy, alternative antihypertensive treatment should be used. with a proven safety profile for use in pregnancy unless continued therapy with an AIIRA is considered essential.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to AIIRAs during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women (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.
Neonates whose mothers have taken AIIRAs should be closely monitored for hypotension (see sections 4.3 and 4.4).
Feeding time
As no data are available regarding the use of Aprovel during breastfeeding, Aprovel is not recommended and alternative treatments with a proven safety profile for use during breastfeeding are preferred, especially when breastfeeding newborns and preterms.
04.7 Effects on ability to drive and use machines
No studies have been conducted on the effects of irbesartan on the ability to drive and use machines. Based on its pharmacodynamic properties, irbesartan is unlikely to affect these abilities. When driving or using machines, it should be noted that dizziness or tiredness may occur during treatment.
04.8 Undesirable effects
In placebo-controlled clinical trials in hypertensive patients, the total incidence of adverse events in irbesartan-treated subjects (56.2%) was comparable to that seen in placebo-treated subjects (56.5%). therapy due to clinical or laboratory undesirable effects were less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not dose-dependent ( recommended dose range), gender, age, race or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and hypotension were reported in 0.5% (i.e. uncommon) of the patients themselves, but superior to placebo.
The following table presents the pharmacological adverse reactions reported in placebo-controlled clinical trials in which 1,965 hypertensive patients received irbesartan. Items marked with an asterisk (*) refer to adverse reactions that were further reported in> 2% of diabetic hypertensive patients with chronic renal failure and overt proteinuria and mostly for placebo.
The frequency of adverse reactions reported below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to
Adverse reactions further reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports and therefore, their frequency "is not known" (cannot be estimated from the available data)
Disorders of the immune system :
Not known: hypersensitivity reactions such as angioedema, rash, urticaria
Metabolism and nutrition disorders :
Not known: hyperkalaemia
Nervous system disorders :
Common: dizziness, orthostatic vertigo (*)
Not known: vertigo, headache
Ear and labyrinth disorders :
Not known: tinnitus
Cardiac pathologies :
Uncommon: tachycardia
Vascular pathologies :
Common: orthostatic hypotension (*)
Uncommon: redness
Respiratory, thoracic and mediastinal disorders :
Uncommon: cough
Gastrointestinal disorders :
Common: nausea / vomiting
Uncommon: diarrhea, pain / burning
Not known: dysgeusia
Hepatobiliary disorders :
Not known: hepatitis, hepatic dysfunction
Skin and subcutaneous tissue disorders :
Not known: leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders :
Common: musculoskeletal pain
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps
Renal and urinary disorders :
Not known: impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Diseases of the reproductive system and breast :
Uncommon: sexual dysfunction
General disorders and administration site conditions :
Common: fatigue
Uncommon: chest pain
Diagnostic tests :
Very common: Hyperkalaemia (*) occurred more often in diabetic patients treated with irbesartan than in those treated with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5 mEq / L) occurred in 29.4% of patients in the irbesartan 300 mg group and 22% of patients in the placebo group. In diabetic hypertensive patients with chronic renal failure and overt proteinuria, hyperkalaemia (≥ 5.5 mEq / L) occurred in 46.3% of patients in the irbesartan group and 26.3% of patients in the placebo group.
Common: Significant increases in plasma creatine kinase (1.7%) were observed in subjects treated with irbesartan. None of these increases were associated with identifiable musculoskeletal clinical events. A decrease in hemoglobin * values, which is not clinically significant, was observed in 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan.
Pediatric population:
In a randomized clinical study of 318 hypertensive children and adolescents, between 6 and 16 years of age, the following adverse reactions occurred during the three-week double-blind phase: headache (7.9%), hypotension (2 , 2%), dizziness (1.9%), cough (0.9%). In the open-label 26-week period of this clinical study, the most frequent laboratory abnormalities reported were: increases in creatinine (6.5%) and elevated CK values in 2% of treated children.
04.9 Overdose
Studies conducted in adult subjects treated with doses up to 900 mg / day for 8 weeks have shown no signs of toxicity. The most likely manifestations of overdose are believed to be hypotension and tachycardia; bradycardia may also be associated with overdose. No specific information is available for the treatment of Aprovel overdose. The patient should be closely monitored and treatment should be symptomatic and Supportive measures Suggested measures include induction of emesis and / or gastric lavage Activated charcoal can be used in the treatment of overdose Irbesartan is not removed by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin-II antagonists, unassociated.
ATC code: C09C A04.
Mechanism of action: Irbesartan is a potent and selective angiotensin-II receptor (type AT1) antagonist, active for oral administration. It is believed to block all AT1-mediated effects of angiotensin-II, regardless of whether "origin of angiotensin-II synthesis."
Selective antagonism for angiotensin-II (AT1) receptors causes an increase in plasma renin and angiotensin-II levels and a decrease in plasma aldosterone concentration. Potassemia is not substantially modified by irbesartan alone. recommended dosages. Irbesartan does not inhibit ACE (kininase-II), an enzyme that generates angiotensin-II and catabolizes bradykinin to produce inactive metabolites. Irbesartan does not require metabolic activation to perform its pharmacological activity.
Clinical efficacy:
Hypertension
Irbesartan reduces blood pressure values with minimal changes in heart rate. The reduction in blood pressure is dose-dependent for once daily dosing with a trend towards a plateau at doses above 300 mg. Doses of 150-300 mg once a day were found to be able to reduce the blood pressure values measured in the supine or sitting position for the entire period considered (up to 24 hours from the last intake of the drug), with higher average decreases of 8-13 / 5-8 mmHg (respectively systolic and diastolic values) compared to those detected with placebo.
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At the recommended dosages, at 24 hours the reduction in blood pressure is still approximately 60-70%. of the corresponding maximum peak of systolic and diastolic reduction.A dose of 150 mg once daily produced a trough and mean 24 hour antihypertensive response quite similar to administration of the same amount of drug in 2 divided doses.
The antihypertensive effect of Aprovel is evident within 1-2 weeks of treatment, with a maximum effect obtainable within 4-6 weeks of initiation of therapy. The antihypertensive effect is constant during long-term therapy. After abrupt withdrawal of the drug, blood pressure gradually returns to baseline. No "rebound" effect on blood pressure was observed.
The blood pressure lowering effects of irbesartan and thiazide diuretics add up. In patients insufficiently controlled on irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to once daily irbesartan produces a further reduction in blood pressure up to a maximum of 7-10 / 3-6 mmHg compared to placebo (systolic and diastolic values, respectively).
The effectiveness of Aprovel is not influenced by age or gender. As with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have a significantly lower response to irbesartan monotherapy. When irbesartan is given in combination with a low dose of hydrochlorothiazide (e.g. 12.5 mg / day), the antihypertensive response of black patients reflects that of white patients.
There is no clinically relevant effect on serum uric acid levels or urinary uric acid secretion.
Pediatric population
Blood pressure reduction with established titrated doses of irbesartan of 0.5 mg / kg (low), 1.5 mg / kg (medium) and 4.5 mg / kg (high) was evaluated over a period of three weeks on 318 children and adolescents, between 6 and 16 years of age, hypertensive or at risk (diabetic, family history of hypertension).
At the end of the three weeks, the mean reduction from baseline in the primary efficacy variable was for sitting downstream systolic blood pressure (SeSBP) of 11.7 mmHg (low dose), 9.3 mmHg (medium dose) , 13.2 mgHg (high dose). No significant differences were observed between these dosages. The adjusted mean change in seated downstream diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). In the subsequent 2-week period, during which patients were randomized to either active substance or placebo, patients treated with placebo had increases of 2.4 mmHg in SeSBP and 2.0 mmHg in SeDBP compared to changes of + 0.1 and - 0.3 mmHg in those treated with all doses of irbesartan (see section 4.2).
Hypertension and type 2 diabetes with kidney disease
The "Irbesartan Diabetic Nephropathy Trial (IDNT)" shows that irbesartan decreases the progression of renal disease in patients with chronic renal failure and overt proteinuria. The IDNT was a controlled, double-blind, morbidity and mortality study comparing Aprovel, amlodipine and placebo. The long-term effects (mean 2.6 years) of Aprovel on renal disease progression and all cause mortality in 1715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg / day and serum creatinine between 1 and 3 mg / dL. Patients were gradually upgraded from 75 mg to a maintenance dose of 300 mg of Aprovel, 2.5 mg to 10 mg of amlodipine, or placebo, as tolerated. Generally, patients in all groups received between 2 and 4 antihypertensive medicinal products (e.g. diuretics, beta blockers, alpha blockers) to achieve a target blood pressure ≤ 135/85 mmHg or a 10 mmHg reduction in systolic BP if blood pressure was> 160 mmHg. 60% of patients in the placebo group achieved this blood pressure goal where the number was 76% and 78%, respectively in the irbesar group tan and amlodipine in that.
Irbesartan significantly reduced the relative risk of occurrence of the combined primary endpoint including doubling of serum creatinine, end-stage renal disease (ESRD) or all cause mortality. Approximately 33% of patients in the irbesartan group achieved the primary composite renal endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23 % relative risk reduction compared to amlodipine (p = 0.006)]. When each component of the primary endpoint was analyzed individually, there was no effect on all-cause mortality, while there was a positive trend in ESRD reduction and a significant reduction in doubling of serum creatinine.
Subgroups were analyzed based on gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate to verify efficacy. In women and black patients, they accounted for 32, respectively. % and 26% of the total study population, no renal benefit was evident, although confidence intervals did not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, no difference was observed. among the three groups in the total population, although in the irbesartan group, compared to the placebo group, an "increased incidence of non-fatal MI was noted in females and a decrease in its incidence in men. In women in the irbesartan group, compared to amlodipine. , an increased incidence of non-fatal MI and stroke was observed, while hospitalization due to heart failure was reduced in the population total.
However, no explanation was identified for these findings in women.
The "Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with Type 2 Diabetes Mellitus (IRMA 2)" study shows that irbesartan 300 mg decreases progression to overt proteinuria in patients with microalbuminuria. IRMA 2 was a morbidity study placebo-controlled, double-blind, in 590 patients with type 2 diabetes, microalbuminuria, (30-300 mg / day) and normal renal function (serum creatinine ≤ 1.5 mg / dl in men and 300 mg / day and a increase in UAER of at least 30% from baseline]. The default blood pressure target was ≤ 135/85 mmHg. Additional antihypertensive drugs (excluding ACE inhibitors, angiotensin-II receptor antagonists and calcium dihydropyridine antagonists) were added as needed to allow the desired blood pressure to be achieved. While similar blood pressure was achieved in all groups, few subjects in the irbesartan 300 mg group (5.2%) compared placebo (14.9%) or irbesartan 150 mg group (9.7%) achieved the overt proteinuria endpoint, demonstrating a 70% relative risk reduction compared to placebo (p = 0.0004) for higher doses. During the first three months of treatment, no parallel improvement in glomerular filtration rate (GFR) was observed. The slowing of progression to clinical proteinuria was evident as early as three months and continued over a two-year period.
Regression to normoalbuminuria (
05.2 Pharmacokinetic properties
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of about 60-80%. Concomitant food intake does not significantly affect the bioavailability of irbesartan. Protein binding is approximately 96%, with a negligible amount of binding to blood cells. The volume of distribution is 53-93 liters. Following oral or intravenous administration of 14C-labeled irbesartan, 80-85% of the detected radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver by oxidation and glucuronoconjugation. The most represented circulating metabolite (approximately 6%). is irbesartan glucuronide. Education in vitro indicate that irbesartan is primarily oxidized via the cytochrome P450-isoenzyme CYP2C9. The CYP3A4 isoenzyme has a 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 was observed at doses above 600 mg (twice the maximum recommended dose); the mechanism for this is unknown. Peak plasma concentrations are reached 1.5-2 hours after oral administration. Total body and renal clearances are 157-176 and 3-3.5 ml / min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are reached within 3 days of initiation of once-daily dosing. Reduced accumulation of irbesartan (plasma after repeated once-daily dosing. In one study somewhat higher plasma concentrations were observed in hypertensive patients. , there was no difference in the half-life or accumulation of irbesartan. No dosage adjustments are required in patients. Irbesartan AUC and Cmax values were also somewhat higher in elderly patients (≥ 65 years) than to young subjects (18-40 years). However, the terminal half-life was not significantly modified. No dosage adjustments are necessary in elderly patients.
Irbesartan and its metabolites are eliminated by both biliary and renal routes. After oral or intravenous administration of 14C-irbesartan, approximately 20% of the radioactivity is recovered in the urine and the remainder is detectable in the faeces. Less than 2% of the dose taken is excreted in the urine as unchanged irbesartan.
Pediatric population
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children following single and multiple administration of 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 evaluated for comparison with adult pharmacokinetics (twelve children were over 12 years old, nine were between 6 and 12 years of age). The results showed that Cmax, AUC and clearance levels were comparable to those seen in adult patients administered irbesartan 150 mg per day. A limited accumulation of irbesartan in the blood (18%) was observed. after a daily dose repeated once.
Kidney failure: in subjects with renal insufficiency or hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly modified. Irbesartan is not removed during the hemodialysis process.
Hepatic insufficiency: In subjects with mild to moderate hepatic cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly modified.
No studies have been conducted in patients with severe hepatic impairment.
05.3 Preclinical safety data
There is no evidence of abnormal target organ or systemic toxicity at clinically appropriate doses.
In preclinical safety studies, high doses of irbesartan (≥ 250 mg / kg / day in rats and ≥ 100 mg / kg / day in macaques) caused a reduction in red blood cell parameters (erythrocytes, hemoglobin, hematocrit). At very high doses (≥ 500 mg / kg / day) degenerative changes in the kidney (such as interstitial nephritis, tubular distention, basophilic tubules, increased plasma urea and creatinine concentrations) were induced by irbesartan in the rat and macaque and are considered secondary to the hypotensive effect of the drug which leads to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia / hypertrophy of juxtaglomerular cells (in rats ≥ 90 mg / kg / day, in macaques ≥ 10 mg / kg / day). All these changes were considered to be caused by the pharmacological action of irbesartan. At therapeutic doses of irbesartan in humans, renal juxtaglomerular cell hyperplasia / hypertrophy does not appear to be of relevance.
No mutagenicity, clastogenicity or carcinogenicity effects were detected.
Animal studies with irbesartan show transient toxic effects (dilatation of the renal pelvis, hydroureter and subcutaneous edema) in rat fetuses, which regress after birth. Abortion or early embryo resorption was reported in rabbits at doses associated with significant maternal toxicity, including death. No teratogenic effects were observed in either rat or rabbit.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Microcrystalline cellulose,
cross-linked carmellose sodium,
lactose monohydrate,
magnesium stearate,
colloidal hydrated silica,
pregelatinised corn starch,
poloxamer 188.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Cartons of 14 tablets: 1 PVC / PVDC / aluminum blister of 14 tablets.
Cartons of 28 tablets: 2 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons of 56 tablets: 4 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons of 98 tablets: 7 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons of 56 x 1 tablet: 7 perforated unit dose blisters in PVC / PVDC / aluminum of 8 x 1 tablet.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
The unused product and the waste derived from this medicinal product must be disposed of in compliance
to the local legislation in force.
07.0 MARKETING AUTHORIZATION HOLDER
SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC
174 avenue de France
F-75013 Paris - France
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/97/046 / 001-003
033264019
033264021
033264033
EU / 1/97/046/010
EU / 1/97/046/013
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 27 August 1997
Date of last renewal: 27 August 2007
