Active ingredients: Irbesartan, Hydrochlorothiazide
CoAprovel 300 mg / 12.5 mg tablets
Coaprovel package inserts are available for pack sizes:- CoAprovel 300 mg / 12.5 mg tablets
- CoAprovel 300 mg / 25 mg film-coated tablets
Indications Why is Coaprovel used? What is it for?
CoAprovel is a "combination of two active substances: irbesartan and hydrochlorothiazide. Irbesartan belongs to a group of drugs known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body that binds to its receptors, located in the blood vessels, causing a narrowing of the latter. This leads to an increase in blood pressure. Irbesartan prevents the binding of angiotensin-II to these receptors, causing the blood vessels to relax and lower blood pressure. Hydrochlorothiazide belongs to a group of medicines (so-called thiazide diuretics) which cause increased urine production and consequently lower blood pressure.
The two active ingredients of CoAprovel act together causing a lowering of blood pressure values that is greater than that caused by the single drugs administered individually.
CoAprovel is used to treat high blood pressure when treatment with irbesartan or hydrochlorothiazide alone has not adequately controlled your blood pressure.
Contraindications When Coaprovel should not be used
Do not take CoAprovel
- if you are allergic to irbesartan or any of the other ingredients of this medicine (listed in section 6).
- if you are allergic to hydrochlorothiazide or to any of the medicines derived from sulphonamide
- if you are more than 3 months pregnant (it is also better to avoid CoAprovel in early pregnancy - see pregnancy section)
- if you have severe liver or kidney problems
- if you have difficulty urinating
- if your doctor determines that you have a persistently high level of calcium or a low level of potassium in your blood
- 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 Coaprovel
Talk to your doctor before taking CoAprovel and if you have any of the following:
- excessive vomiting or diarrhea
- if you have kidney problems or have had a kidney transplant
- if you suffer from heart problems
- if you suffer from liver problems
- if you have diabetes
- if you suffer from lupus erythematosus (also known as lupus or SLE)
- if you suffer from primary aldosteronism (a condition related to high production of the hormone aldosterone, which causes sodium retention and, subsequently, an increase in blood pressure)
- if you are taking any of the following medicines used to treat high blood pressure: - an "ACE inhibitor" (for example enalapril, lisinopril, ramipril), in particular 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 CoAprovel"
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). CoAprovel is not recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
Also, tell your doctor:
- if you are on a low-salt diet
- if you have symptoms such as excessive thirst, dry mouth, general weakness, sleepiness, muscle pain or cramps, nausea, vomiting, or an excessively fast heartbeat which may indicate an excessive effect of hydrochlorothiazide (contained in CoAprovel)
- if you have noticed an increase, faster than normal, in the sensitivity of your skin to the sun with symptoms of sunburn (such as redness, itching, swelling, rash)
- if you need to have surgery or take anesthetics if you experience changes in vision or pain in one or both eyes while you are taking CoAprovel. This could be a sign that glaucoma is occurring, raised eye pressure. You should stop CoAprovel and consult your doctor.
The hydrochlorothiazide contained in this medicine may give positive results in the anti-doping test.
Children and adolescents
CoAprovel should not be given to children and adolescents (under 18 years of age)
Interactions Which drugs or foods can modify the effect of Coaprovel
Other medicines and CoAprovel
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Diuretic drugs such as the hydrochlorothiazide contained in CoAprovel may have an effect on other medicines. Preparations containing lithium should not be taken together with CoAprovel unless under close medical supervision.
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 CoAprovel" and "Warnings and precautions")
You may need blood tests if you are using:
- potassium supplements
- salt substitutes that contain potassium
- potassium-sparing or other diuretics
- some laxatives
- drugs for the treatment of gout
- vitamin D supplements
- medicines to control your heartbeat
- medicines for diabetes (oral medicines or insulin)
- carbamazepine (a medicine to treat epilepsy).
It is also important to tell your doctor if you are taking other medications to lower blood pressure, steroids, medications to treat cancer, pain medications, arthritis medications, or cholestyramine and colestipol to lower blood cholesterol levels.
CoAprovel with food and drink
CoAprovel can be taken with or without food.
Because of the hydrochlorothiazide contained in CoAprovel, if you drink alcohol while taking this medicine, you may feel more dizzy while standing up, especially when you go from sitting to standing.
Warnings It is important to know that:
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 CoAprovel before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of CoAprovel. CoAprovel is not recommended during your pregnancy. pregnant and should not be taken if you are 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. CoAprovel is not recommended for women who are breastfeeding and your doctor may choose another treatment for you 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. CoAprovel is unlikely to affect the ability to drive or use machines. However, occasionally dizziness or tiredness may occur during treatment of high blood pressure. this happens to you, talk to your doctor before driving or using machines.
CoAprovel contains lactose. If you have been told by your doctor that you have an "intolerance to some sugars (for example: lactose), contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Coaprovel: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Dosage
The recommended dose of CoAprovel is one tablet per day. CoAprovel will be prescribed to you by your doctor if your previous therapy has not reduced your blood pressure enough. Your doctor will advise you on how to switch from the previous treatment to CoAprovel.
Method of administration
CoAprovel is for oral use. Swallow the tablets with a sufficient amount of liquid (for example a glass of water). You can take CoAprovel with or without food. You should try to take the medicine at the same time every day. It is important to continue therapy unless your doctor tells you otherwise. .
The maximum blood pressure lowering effect should be achieved 6-8 weeks after starting treatment.
Overdose What to do if you have taken too much Coaprovel
If you take more CoAprovel than you should
If you accidentally take too many tablets contact your doctor immediately.
Children should not take CoAprovel
CoAprovel should not be given to children under 18 years of age. If a child swallows tablets, contact your doctor immediately.
If you forget to take CoAprovel
If you forget to take a dose of the medicine, 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 Coaprovel
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.
Rare cases of allergic skin reactions (rash, urticaria) as well as localized swelling of the face, lips and / or tongue have been reported in patients receiving irbesartan. If you have any of the above symptoms or if you have difficulty breathing, stop taking CoAprovel and contact your doctor immediately.
The frequency of side effects listed below is defined using the following convention:
Common: may affect up to 1 in 10 patients
Uncommon: may affect up to 1 in 100 patients
Undesirable effects reported in clinical trials in patients treated with CoAprovel were:
Common side effects (may affect up to 1 in 10 patients)
- nausea / vomiting
- urinary disorders
- fatigue
- dizziness (including when going from a sitting or supine position to standing)
- blood tests may show increased levels of an enzyme that measures muscle and heart function (creatine kinase) or increased levels of substances that measure kidney function (BUN, creatinine).
Tell your doctor if any of these side effects cause you problems.
Uncommon side effects (may affect up to 1 in 100 people)
- diarrhea
- hypotension
- weakness
- rapid heartbeat
- hot flashes
- swelling
- sexual dysfunction (problems with sexual activity)
- blood tests may show lowering of potassium and sodium levels in the blood.
Tell your doctor if any of these side effects cause you problems.
Undesirable effects reported after CoAprovel was placed on the market
Some undesirable effects have been reported since marketing of CoAprovel. Side effects with a frequency not known are: headache, tinnitus, cough, taste disturbances, indigestion, joint and muscle pain, abnormal liver function and renal dysfunction, high blood potassium levels and allergic reactions (rash, hives, localized swelling of the face, lips, mouth, tongue or throat). Uncommon cases of jaundice (yellowing of the skin and / or whites of the eyes) have also been reported.
As with any combination of two active substances, the undesirable effects associated with each of the components cannot be excluded.
Side effects associated with irbesartan alone
In addition to the side effects listed above, chest pain has also been reported.
Undesirable effects associated with hydrochlorothiazide alone
Loss of appetite; stomach irritation; stomach cramps; constipation; jaundice (yellowing of the skin and / or whites of the eyes); inflammation of the pancreas characterized by severe pain in the upper stomach, often with nausea and vomiting; discomfort sleep; depression; blurred vision; lack of white blood cells, which can lead to frequent infections, fever; decrease in the number of platelets (essential component for blood clotting), decrease in the number of red blood cells (anemia) characterized by tiredness, headache , shortness of breath during exercise, dizziness and pale appearance; kidney disorders; lung problems including pneumonia or increased fluid in the lungs; increased sensitivity of the skin to the sun; inflammation of blood vessels; a skin disorder characterized by peeling of the skin all over the body; lupus erythematosus, identified by a rash that can appear on the face, neck and scalp; allergic reactions; muscle weakness and spasm; altered heartbeat; lowering of blood pressure as a result of a change in body position; swelling of the salivary glands; high blood sugar levels; sugar in the urine; increases in some types of fat in the blood; high levels of uric acid in the blood which can cause gout.
The undesirable effects associated with hydrochlorothiazide are known to increase with higher doses of hydrochlorothiazide.
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 that month.
Do not store above 30 ° C.
Store in the original package to keep it away from moisture.
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.
Composition and pharmaceutical form
What CoAprovel contains
- The active substances are irbesartan and hydrochlorothiazide. Each CoAprovel 300 mg / 12.5 mg tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
- The other ingredients are: microcrystalline cellulose, cross-linked carmellose sodium, lactose monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, red and yellow iron oxides (E172).
What CoAprovel looks like and contents of the pack
CoAprovel 300 mg / 12.5 mg tablets are peach-colored, biconvex, oval, with a heart debossed on one side and the number 2776 on the other side.
CoAprovel 300 mg / 12.5 mg tablets are supplied in blister packs containing 14, 28, 56, or 98 tablets. Packs containing perforated unit dose blisters of 56 x 1 tablet for hospital use are also available.
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
COAPROVEL 300 MG / 12.5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 300 mg of irbesartan and 12.5 mg of hydrochlorothiazide.
Excipient:
Each tablet contains 65.8 mg of lactose (as lactose monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Peach colored, biconvex, oval in shape, with a heart embossed on one side and the number 2776 on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of essential arterial hypertension.
Fixed dose combination therapy is indicated in adult patients whose blood pressure is not adequately controlled by irbesartan or hydrochlorothiazide alone (see section 5.1).
04.2 Posology and method of administration
Dosage
CoAprovel can be taken once daily, regardless of food intake.
Progressive dose adjustment with the individual components (e.g. irbesartan and hydrochlorothiazide) may be recommended.
If clinically appropriate, a direct switch from monotherapy to fixed combination may be considered:
• CoAprovel 150 mg / 12.5 mg may be administered in patients whose blood pressure is not adequately controlled by hydrochlorothiazide or irbesartan 150 mg alone;
• CoAprovel 300 mg / 12.5 mg may be administered in patients inadequately controlled by irbesartan 300 mg or CoAprovel 150 mg / 12.5 mg;
• CoAprovel 300 mg / 25 mg can be administered in patients inadequately controlled by CoAprovel 300 mg / 12.5 mg.
Doses greater than 300 mg of irbesartan / 25 mg of hydrochlorothiazide once daily are not recommended.
When needed CoAprovel can be administered with other antihypertensive medicinal products (see section 4.5).
Special populations
Kidney failure: Due to the presence of hydrochlorothiazide CoAprovel is not recommended in patients with severe renal insufficiency (creatinine clearance loop diuretics are preferable to thiazides. No dosage adjustments are required in those patients with renal dysfunction whose creatinine clearance is ≥ 30 ml / min (see sections 4.3 and 4.4).
Hepatic insufficiency: CoAprovel is not indicated in subjects with severe hepatic insufficiency. Thiazides should be used with caution in patients with hepatic dysfunction. No dosage adjustment of CoAprovel is required in patients with mild or moderate hepatic dysfunction (see section 4.3).
Elderly patients: No dosage adjustment of CoAprovel is required in elderly patients.
Pediatric population: CoAprovel is not recommended for use in children and adolescents as safety and efficacy have not been established. No data are available.
Method of administration
For oral use.
04.3 Contraindications
• Hypersensitivity to the active substances, to any of the excipients (see section 6.1) or to other substances derived from sulfonamide (hydrochlorothiazide is a derivative of sulfonamide)
• Second and third trimester of pregnancy (see sections 4.4 and 4.6)
• Severe renal insufficiency (creatinine clearance
• Refractory hypokalemia, hypercalcemia
• Severe liver failure, biliary cirrhosis and cholestasis
04.4 Special warnings and appropriate precautions for use
Hypotension - Hypovolaemic patients: in hypertensive patients with no other risk factors for hypotension CoAprovel has been rarely associated with symptomatic hypotension. This may occur in hypovolaemic patients or patients with hyponatremia due to intense diuretic therapy, low sodium diet, diarrhea or vomiting. In such cases, underlying condition must be corrected before starting CoAprovel therapy.
Renal artery stenosis - Renovascular hypertension: there is an increased risk of severe hypotension and renal failure in patients with bilateral renal artery stenosis, or renal artery stenosis with functioning mono-kidney, and treated with angiotensin converting enzyme inhibitors or antagonists of angiotensin-II receptors. Although this is not documented with CoAprovel therapy, a similar effect is to be expected.
Renal failure and renal transplantPeriodic monitoring of potassium, creatinine and uric acid serum levels is recommended when CoAprovel is used in patients with renal dysfunction. There are no clinical data regarding the administration of CoAprovel to patients with recent kidney transplantation. CoAprovel should not be used in patients with severe renal insufficiency (creatinine clearance azotaemia induced by thiazides. No dosage adjustments are required in patients with renal dysfunction whose creatinine clearance is ≥ 30 ml / min. However in patients with mild renal insufficiency. -moderate (creatinine clearance ≥ 30 ml / min, but
Hepatic insufficiency: Special attention is required when thiazides are administered to patients with hepatic insufficiency or progressive liver disease, as slight alterations in the water and electrolyte balance may result in hepatic coma. There is no clinical experience with CoAprovel in patients with hepatic insufficiency.
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 CoAprovel is not recommended.
Metabolic and endocrine effects: The use of thiazides may interfere with glucose tolerance. In diabetic patients it may be necessary to adjust the doses of insulin or oral hypoglycemic drugs. Latent diabetes mellitus may become manifest during therapy with thiazides.
Increases in cholesterol and triglyceride levels have been associated with the use of thiazide diuretics; however, at the 12.5 mg dose in CoAprovel, no or minimal effects were reported.
Hyperuricaemia or gout crisis may occur in some patients taking thiazides.
Electrolyte imbalance: As for all patients on diuretic therapy, periodic monitoring of serum electrolytes at appropriate intervals is recommended.
Thiazides, including hydrochlorothiazide, can induce a water-electrolyte imbalance (hypokalemia, hyponatremia and hypochloraemic alkalosis). Alarm symptoms for a water-electrolyte imbalance are: dry mouth, thirst, weakness, lethargy, drowsiness, agitation , muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may occur in patients receiving thiazide diuretics, this may be reduced by concomitant therapy with irbesartan. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients undergoing intense diuresis, in patients receiving insufficient oral intake of electrolytes and in patients receiving concomitant corticosteroid or ACTH therapy. Conversely, due to the presence of irbesartan in CoAprovel, hyperkalaemia may occur, especially in the presence of renal dysfunction and / or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium is recommended in patients at risk. Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes should be administered with caution concomitantly with CoAprovel (see section 4.5).
There is no evidence that irbesartan reduces or prevents diuretic-induced hyponatremia. The hypochloraemia that may occur is usually mild and requires no treatment.
Thiazides can reduce urinary elimination of calcium and can cause an intermittent and mild increase in serum calcium levels in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may reveal unmanifest hyperparathyroidism. Therapy with thiazides should be stopped before performing parathyroid function tests.
Thiazides have been shown to increase urinary excretion of magnesium, causing hypomagnesaemia.
Lithium: the combination of lithium and CoAprovel is not recommended (see section 4.5).
Doping test: The hydrochlorothiazide contained in this medicine may give positive results in the anti-doping test.
General warnings: in patients whose vascular tone and renal function are predominantly dependent on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure or with kidney disease, including renal artery stenosis), treatment with Angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists, affecting this system, have been associated with acute hypotension, BUN, oliguria, or rarely acute renal failure. As with any antihypertensive, an excessive decrease blood pressure in patients with ischemic heart disease or ischemic cardiovascular disease, can lead to myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a previous history of allergies or bronchial asthma; however, in the former, such reactions are more likely.
Onset and / or worsening of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
Cases of photosensitivity reactions have been reported with the use of thiazide diuretics (see section 4.8). If a photosensitization reaction occurs during treatment, it is recommended that therapy be discontinued. If resuming treatment is deemed necessary, it is recommended that treatment be resumed. protect areas exposed to sunlight or artificial UVA rays.
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 to become pregnant. 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.
04.5 Interactions with other medicinal products and other forms of interaction
Other antihypertensives: The antihypertensive effect of CoAprovel may increase with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan / 25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents, including calcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics may result in hypovolaemia and, if not corrected earlier, may lead to a risk of hypotension upon initiation of irbesartan therapy with or without thiazide diuretics (see section 4.4).
Lithium: A reversible increase in serum concentrations and toxicity of lithium has been found when it is administered concomitantly with angiotensin converting enzyme inhibitors. Similar effects have been reported very rarely with irbesartan so far. Furthermore, renal clearance of lithium is reduced by thiazides with increased risk of lithium toxicity with CoAprovel. Therefore, the combination of lithium and CoAprovel is not recommended (see section 4.4). If there is a real need for the combination, careful monitoring of serum lithium levels is recommended.
Medicines that affect potassium levels: Potassium depletion caused by hydrochlorothiazide is attenuated by the potassium-sparing effect induced by irbesartan. However, this effect of hydrochlorothiazide on serum potassium would be potentiated by other medicinal products that induce potassium loss and hypokalaemia (other potassium-sparing, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on experience with other medicinal products that reduce the activity of the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products capable of Increased serum potassium levels (eg sodium heparin) may cause increases in serum potassium Adequate monitoring of serum potassium is recommended in patients at risk (see section 4.4).
Medicinal products affected by alterations in potassium: when CoAprovel is administered in combination with other potentially dangerous drugs in case of alterations in serum potassium (eg digitalis glycosides, antiarrhythmics), periodic monitoring of potassium is recommended.
Non-steroidal anti-inflammatory drugs: When angiotensin-II antagonists are administered concomitantly 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 effect may occur antihypertensive.
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.
Learn more about hydrochlorothiazide interactions: When administered concomitantly, the following drugs may interact with thiazide diuretics:
Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic medicines (oral antidiabetic drugs and insulin): dosage adjustment of the antidiabetic may be required (see section 4.4);
Colestyramine and colestipol: The absorption of hydrochlorothiazide is impaired in the presence of the anion exchange resins. CoAprovel should be taken at least 1 hour before or 4 hours after these medicines;
Corticosteroids, ACTH: electrolyte depletion, especially potassium, may be increased;
Digitalis glycosides: thiazide-induced hypokalaemia and hypomagnesaemia favor the onset of digitalis cardiac arrhythmias (see section 4.4);
Non-steroidal anti-inflammatory drugs: in some patients the administration of a non-steroidal anti-inflammatory drug may reduce the diuretic, sodium uretic and antihypertensive effects of thiazide diuretics;
Pressor amines (e.g. norepinephrine): the effect of the pressor amines can be diminished, but not so much as to preclude their use;
Nondepolarizing musculoskeletal muscle relaxants (e.g. tubocurarine): the effect of non-depolarising musculoskeletal relaxants can be enhanced by hydrochlorothiazide;
Anti-gout medicines: Dosage adjustment of antigout medicinal products may be required as hydrochlorothiazide may increase serum uric acid levels. An increase in probenecid or sulfinpyrazone dosage may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity to allopurinol;
Calcium salts: Thiazide diuretics may increase serum calcium levels due to reduced excretion. If it is necessary to administer calcium supplements or calcium-sparing drugs (eg vitamin D therapy), the calcium level should be controlled and the calcium dosage adjusted accordingly;
Carbamazepine: Concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatremia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used.
Other interactions: thiazides may increase the hyperglycemic effect of beta-blockers and diazoxide. Anticholinergic drugs (eg atropine, beperiden) may increase the bioavailability of thiazide-type diuretics through a decrease in gastrointestinal motility and gastric emptying rate. Thiazides may increase the risk of amantidine side effects. Thiazides may reduce the renal excretion of cytotoxic drugs (eg cyclophosphamide, methotrexate) and enhance their myelosuppressive effect.
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).
Thiazides cross the placental barrier and are found in the umbilical cord, causing a decrease in placental perfusion, alterations in the electrolytes of the fetus and other possible reactions observed in adults. Maternal use of thiazides has been documented to cause neonatal thrombocytopenia or fetal or neonatal jaundice. As CoAprovel contains hydrochlorothiazide, it is not recommended for use during the first trimester of pregnancy. Switching to an appropriate alternative treatment should be considered before planning a pregnancy.
Feeding time:
As no data are available regarding the use of CoAprovel during breastfeeding, CoAprovel 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 on the ability to drive and use machines have been performed. CoAprovel is unlikely to affect these abilities due to its pharmacodynamic properties. When driving vehicles or using machines, it should be noted that occasionally dizziness or fatigue may occur during the treatment of hypertension.
04.8 Undesirable effects
Irbesartan / hydrochlorothiazide combination
29.5% of the 898 hypertensive patients who received various doses of irbesartan / hydrochlorothiazide (range: 37.5 mg / 6.25 mg up to 300 mg / 25 mg), during the placebo-controlled studies, had reactions adverse. The most commonly reported adverse reactions were dizziness (5.6%), fatigue (4.9%), nausea / vomiting (1.8%) and abnormal urination (1.4%). In addition, azotemia (BUN) (2.3%), creatine kinase (1.7%) and creatinine (1.1%) elevation were commonly observed during clinical trials.
Table 1 reports adverse reactions from spontaneous and observed adverse reactions in placebo-controlled clinical trials.
The frequency of adverse reactions described below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to
Additional information on the individual components: In addition to the adverse reactions described above for the combination, other adverse reactions previously reported with one of the components may be potential adverse reactions with CoAprovel. In Tables 2 and 3 below, the adverse reactions reported with the individual components of CoAprovel are listed.
Dose dependent adverse events of hydrochlorothiazide (especially electrolyte disorders) may increase with gradual increase in its dosage.
04.9 Overdose
No specific information is available for the treatment of CoAprovel overdose. The patient should be closely monitored, treatment should be symptomatic and supportive and will depend on the time since ingestion and the severity of symptoms. Suggested measures include induction of vomiting and / or gastric lavage. activated charcoal Serum electrolytes and creatinine should be checked frequently If hypotension occurs the patient should be placed supine and promptly replenished with salts and fluids.
The main manifestations of irbesartan overdose are hypotension and tachycardia; Bradycardia may also occur.
Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatremia) and dehydration following excessive diuresis. The main signs and symptoms of overdose are nausea and sleepiness. Hypokalaemia may cause muscle spasms and / or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic drugs.
Irbesartan is not dialysable. The amount of hydrochlorothiazide removed by hemodialysis is not known.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin-II antagonists, combinations
ATC code: C09DA04.
CoAprovel is a combination of an angiotensin-II receptor antagonist irbesartan and a thiazide diuretic, hydrochlorothiazide. The combination of these active ingredients determines an additive antihypertensive effect, reducing blood pressure to a greater extent than the individual components.
Irbesartan is a potent and selective angiotensin-II receptor antagonist (AT1 subtype), active for oral administration. The drug is believed to block all AT1-mediated effects of angiotensin-II, regardless of the origin or route of angiotensin-II synthesis. Selective antagonism for angiotensin-II (AT1 ) causes an increase in plasma renin and angiotensin-II levels and a decrease in plasma aldosterone concentration. In patients not at risk of electrolyte imbalance (see sections 4.4 and 4.5), potassium is not substantially changed by irbesartan alone at the recommended dosages. Irbesartan does not inhibit ACE (kininase-II), an enzyme that generates angiotensin-II and degrades bradykinin to produce inactive metabolites. Irbesartan does not require metabolic activation to exert its pharmacological activity.
Hydrochlorothiazide is a thiazide diuretic. The mechanism by which thiazide diuretics exert their antihypertensive effects is not fully understood. Thiazides act on the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chloride in substantially equivalent quantities. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, and increases aldosterone secretion, resulting in increased loss of urinary potassium and bicarbonate and decreased serum potassium. Presumably by blocking the renin-angiotensin-aldosterone system, concomitant administration of irbesartan tends to correct the potassium loss associated with these diuretics. With hydrochlorothiazide, diuresis begins within 2 hours, the peak occurs at approximately the fourth hour, and the effect lasts approximately 6-12 hours.
Within the therapeutic range, the combination of hydrochlorothiazide and irbesartan results in a dose-dependent additive reduction in blood pressure. The addition of 12.5 mg hydrochlorothiazide to irbesartan 300 mg once daily in patients inadequately controlled on irbesartan 300 mg monotherapy resulted in a further 6.1 mmHg reduction in diastolic blood pressure compared to placebo (24 hours later). administration). The combination of irbesartan 300 mg and hydrochlorothiazide 12.5 mg results in an overall reduction in systolic / diastolic blood pressure, compared to placebo, up to 13.6 / 11.5 mmHg.
Limited clinical data (7 of 22 patients) suggest that patients not controlled with the 300 mg / 12.5 mg combination may respond when treated with the 300 mg / 25 mg combination. A superior hypotensive effect on both systolic blood pressure (PAS) and diastolic blood pressure (PAD) was observed in these patients (13.3 and 8.3 mmHg, respectively).
In patients with mild to moderate hypertension once daily administration of 150 mg irbesartan and 12.5 mg hydrochlorothiazide produced a mean reduction of 12.9 / 6.9 mmHg in systolic / diastolic blood pressure compared to placebo (24 hours post dose). ). The antihypertensive peak is reached after 3-6 hours. Continuous 24-hour monitoring of blood pressure shows that the combination of 150 mg of irbesartan and 12.5 mg of hydrochlorothiazide once daily produces a similar reduction in blood pressure over 24 hours, with an average reduction in systolic / diastolic compared to placebo, over 24 hours of 15.8 / 10.0 mmHg. Measured with continuous monitoring over 24 hours, the trough / peak effect of CoAprovel 150 mg / 12.5 mg was 100%. Measured by cuff during an outpatient visit, the trough / peak effect was 68% and 76% for CoAprovel 150 mg / 12.5 mg and CoAprovel 300 mg / 12.5 mg, respectively. These effects were observed during 24 hours. hours without excessive lowering of blood pressure to peak and are consistent with the safe and effective lowering obtained with once-daily dosing. In patients insufficiently controlled on 25 mg hydrochlorothiazide alone, the addition of irbesartan produced a further mean reduction in values. systolic / diastolic, compared to placebo, of 11.1 / 7.2 mmHg.
The antihypertensive effect of irbesartan in combination with hydrochlorothiazide occurs after the first dose and is evident within 1-2 weeks, with a maximum effect occurring within 6-8 weeks. In long-term studies, the effect of irbesartan and hydrochlorothiazide was constant for more than one year. Although not specifically studied with CoAprovel, rebound hypertension was not observed with either irbesartan or hydrochlorothiazide.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality has not been studied. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effectiveness of CoAprovel is not influenced by age or gender. As with other medicinal products that affect the renin-angiotensin system, black hypertensive patients respond significantly less to irbesartan alone. When irbesartan is co-administered with low-dose hydrochlorothiazide (e.g. 12.5 mg / day), the antihypertensive response in black patients approximates that in non-black patients.
The efficacy and safety of CoAprovel as initial therapy for severe hypertension (defined as SeDBP ≥ 110 mmHg) was evaluated in an 8-week, multi-center, randomized, double-blind, active-controlled, parallel-arm study. A total of 697 patients were randomized in a 2: 1 ratio to receive either irbesartan / hydrochlorothiazide 150 mg / 12.5 mg or irbesartan 150 mg which was systematically titrated (before response to the minimal dose was found) and after one week of irbesartan / hydrochlorothiazide 300 mg / 25 mg or irbesartan 300 mg, respectively.
The study recruited 58% male patients. The mean age of the patients was 52.5 years, 13% were ≥ 65 years of age, and only 2% were ≥ 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were dyslipidemic and the most frequent cardiovascular pathology was stable angina pectoris present in 3.5% of the subjects studied.
The primary objective of this study was to compare the percentage of patients in whom SeDBP achieved control (SeDBP
The quality and incidence of adverse effects recorded for patients treated with combination therapy was similar to the adverse event profile for patients on monotherapy. During 8 weeks of treatment, no cases of syncope were reported in either treated group. There were 0.6% and 0% cases of hypotension and 2.8% and 3.1% cases of dizziness as adverse events reported in the combination and monotherapy patient groups, respectively.
05.2 Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and irbesartan has no influence on the pharmacokinetics of either.
Irbesartan and hydrochlorothiazide are orally active as such and do not require biotransformation to be active. After oral administration of CoAprovel the absolute oral bioavailability is 60-80% for irbesartan and 50-80% for hydrochlorothiazide. Food does not affect the bioavailability of CoAprovel. The maximum plasma concentration is reached 1.5-2 hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Protein binding is approximately 96% with a negligible amount of binding to blood cells. The volume of distribution of irbesartan is 53-93 liters. The protein binding for hydrochlorothiazide is 68%, with an apparent volume of distribution of 0.83-1.14 l / kg.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10-600 mg. A less than proportional increase in oral absorption was observed at doses above 600 mg; the mechanism by which this is determined is unknown. Total body and renal clearance are 157-176 and 3.0-3.5 ml / min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours.Steady-state plasma concentrations are achieved within 3 days of initiation of once-daily dosing. A reduced accumulation of irbesartan (plasma after repeated once-daily dosing. In one study, slightly 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 slightly higher in elderly patients (≥ 65 years) than in young subjects ( However, the final half-life was not significantly altered. No dosage adjustments are required in elderly patients. The mean plasma half-life of hydrochlorothiazide varies between 5-15 hours.
Following oral or intravenous administration of 14C-labeled irbesartan, 80-85% of the detected plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via oxidation and glucuronide conjugation. The major circulating metabolite (approximately 6%) is irbesartan glucuronide. Studies in vitro indicate that irbesartan is mainly oxidized via the cytochrome P450 enzyme CYP2C9; the CYP3A4 isoenzyme has a negligible effect. 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 may be recovered in the urine, while the remainder is detectable in the faeces. Less than 2% of the dose taken is excreted in the urine as unchanged irbesartan. Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placenta, but is unable to cross the blood-brain barrier, and is excreted in breast milk.
Kidney failure: in subjects with renal insufficiency or in hemodialysis patients, the pharmacokinetic parameters of irbesartan are not significantly modified. Irbesartan is not removed during the hemodialysis process. It is reported that in patients with creatinine clearance
Hepatic insufficiency: In subjects with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly modified. Studies in patients with severe hepatic impairment have not been conducted.
05.3 Preclinical safety data
Irbesartan / hydrochlorothiazide: The potential toxicity of the irbesartan / hydrochlorothiazide combination after oral administration was evaluated in rats and macaques in studies up to 6 months. There were no toxicological observations of relevance for human therapeutic use.
The following changes observed in rats and macaques treated with the irbesartan / hydrochlorothiazide combination at 10/10 and 90/90 mg / kg / day were also observed with either drug alone and / or were secondary to blood pressure decreases arterial (no significant toxicological interactions were observed):
• renal changes, characterized by mild increases in uric acid and creatinine, and by hyperplasia / hypertrophy of the juxtaglomerular apparatus, which are a direct consequence of the interaction of irbesartan with the renin-angiotensin system;
• slight decreases in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit);
• Gastric discoloration, ulcers and focal necrosis of the gastric mucosa were observed in a few rats in a 6-month toxicity study with irbesartan administered at a dose of 90 mg / kg / day, hydrochlorothiazide 90 mg / kg / day and irbesartan / hydrochlorothiazide 10 / 10 mg / kg / day. These lesions were not observed in macaques;
• decreases in blood potassium due to hydrochlorothiazide and partially prevented when this was given together with irbesartan.
Most of the above effects appear to be due to the pharmacological activity of irbesartan (blockade of angiotensin-II-induced inhibition of renin release, with stimulation of renin-producing cells) and also occur with enzyme inhibitors. conversion of angiotensin. These observations appear to have no relevance to the therapeutic dosages of irbesartan / hydrochlorothiazide used in humans.
No teratogenic effects were observed in rats treated with the combination of irbesartan and hydrochlorothiazide at doses that produce maternal toxicity. The effects of the combination ibersartan / hydrochlorothiazide on fertility have not yet been evaluated in animal studies, as they have not been reported. Evidence of effects on fertility in animals or humans with both irbesartan and hydrochlorothiazide when given alone. However, another angiotensin-II antagonist affected fertility parameters when given alone, in studies about animals. These findings have also been seen with low doses of this angiotensin-II antagonist when given together with hydrochlorothiazide.
There is no evidence of mutagenicity or clastogenicity with the irbesartan / hydrochlorothiazide combination. The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been evaluated in animal studies.
Irbesartan: No signs of systemic or target organ toxicity are found at clinical doses. In non-clinical safety studies, high doses of irbesartan (≥ 250 mg / kg / day in rats and ≥ 100 mg / kg / day in macaques ) caused a reduction in some erythrocyte parameters (erythrocytes, hemoglobin, hematocrit). At very high doses (≥ 500 mg / kg / day), degenerative changes in the kidneys (such as interstitial nephritis, tubular dilation, basophilic tubules, increased plasma concentrations of urea and creatinine). These effects are considered secondary to the hypotensive effect of the drug, which leads to decreased renal perfusion. Furthermore, irbesartan induced hyperplasia / hypertrophy of juxtaglomerular cells (≥ 90 mg / kg / day in rats and ≥ 10 mg / kg / day in macaques). All these changes are considered to be induced by the pharmacological action of irbesartan. . Hyperplasia / hypertrophy of kidney juxtaglomerular cells does not appear to be of relevance to therapeutic doses of irbesartan used in humans.
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 dosages capable of causing maternal toxicity, including death. No teratogenic effects were observed in either the rat or the rabbit.
Hydrochlorothiazide: Although uncertain evidence of genotoxicity and carcinogenicity has been observed in some experimental models, the extensive experience of use in humans with hydrochlorothiazide has not shown a correlation between its use and an increase in neoplasms.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Microcrystalline cellulose
Cross-linked sodium carmellose
Lactose monohydrate
Magnesium stearate
Colloidal silica hydrates
Pregelatinised maize starch
Red and yellow iron oxides (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store at temperatures above 30 ° C.
Store in the original package to keep it away from moisture.
06.5 Nature of the immediate packaging and contents of the package
Cartons containing 14 tablets; 1 PVC / PVDC / aluminum blister of 14 tablets.
Cartons containing 28 tablets; 2 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons containing 56 tablets; 4 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons containing 98 tablets; 7 PVC / PVDC / aluminum blisters of 14 tablets.
Cartons containing 56 x 1 tablet; 7 PVC / PVDC / aluminum perforated unit dose blisters of 8 x 1 tablet each.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
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 / 1/98/086 / 004-006
034191041
034191054
034191066
EU / 1/98/086/008
EU / 1/98/086/010
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 15 October 1998
Date of last renewal: 1 October 2008
10.0 DATE OF REVISION OF THE TEXT
September 2011
