Active ingredients: Perindopril (Perindopril arginine), Indapamide
TERAXANS 10mg / 2.5mg film-coated tablets
Why is Teraxans used? What is it for?
What is TERAXANS?
TERAXANS is a "combination of two active substances, perindopril and indapamide. It is an antihypertensive and is used in the treatment of high blood pressure (hypertension). TERAXANS is indicated in those patients who are already taking perindopril 10 mg and indapamide 2.5 mg separately. they can instead take a TERAXANS tablet that contains both active ingredients.
What is TERAXANS used for?
Perindopril belongs to a class of drugs called ACE inhibitors. These drugs work by dilating blood vessels, which makes it easier for the heart to pump blood through them. Indapamide is a diuretic. Diuretics increase the amount of urine produced by the kidneys. Indapamide, however, differs from other diuretics in that it causes only a slight increase in the amount of urine produced. Each active ingredient lowers blood pressure and together they work to control blood pressure.
Contraindications When Teraxans should not be used
Do not take TERAXANS
- if you are allergic (hypersensitive) to perindopril or any other ACE inhibitor, or to indapamide or any other sulphonamides, or to any of the other ingredients of TERAXANS,
- if you have had symptoms such as shortness of breath, swelling of the face or tongue, intense itching or severe skin rashes related to previous ACE inhibitor treatment or if you or a member of your family have experienced these symptoms in any other circumstances (disorder called angioedema),
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren,
- if you have severe liver disease or if you suffer from a disease called hepatic encephalopathy (a degenerative disease of the brain),
- if you have severe kidney disease or are undergoing dialysis,
- if you have a decrease or increase in plasma potassium,
- if you suspect that you have untreated decompensated heart failure (severe water retention, difficulty breathing),
- if you have been pregnant for more than three months. (TERAXANS is also best avoided in early pregnancy) (see "Pregnancy and Breastfeeding"),
- if you are breast-feeding.
Precautions for use What you need to know before taking Teraxans
Take special care with TERAXANS Before treatment with TERAXANS talk to your doctor if any of the following apply to you:
- if you have aortic stenosis (narrowing of the main artery originating from the heart) or hypertrophic cardiomyopathy (heart muscle disease) or renal artery stenosis (narrowing of the artery that supplies blood to the kidneys),
- if you have other heart problems,
- if you have liver problems,
- if you have a collagen disease (skin disease) such as systemic lupus erythematosus or scleroderma,
- if you suffer from atherosclerosis (hardening of the arteries),
- if you suffer from hyperparathyroidism (hyperactivity of the parathyroid glands),
- if you suffer from gout,
- if you have diabetes,
- if you are on a diet that restricts the use of salt or uses salt substitutes containing potassium,
- if you take lithium or potassium-sparing diuretics (spironolactone, triamterene) their use with TERAXANS should be avoided (see "Taking other medicines"),
- if you are taking any of the following medicines used to treat high blood pressure:
- an 'angiotensin II receptor antagonist' (AIIRA) (also known as sartans - eg valsartan, telmisartan, irbesartan), 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 TERAXANS".
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). TERAXANS is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at this stage (see "Pregnancy and breast-feeding").
If you are taking TERAXANS, please tell your doctor or medical staff:
- if you are due to undergo anesthesia and / or surgery,
- if you have recently had diarrhea or vomiting, or if you are dehydrated;
- if you are due to undergo dialysis or LDL apheresis (cleaning the blood of cholesterol by means of a machine),
- if you are undergoing desensitization treatment to reduce the effects of an allergy to bee or wasp stings, - if you are to undergo a medical examination that requires the injection of an iodinated contrast agent (a substance that makes visible on X-rays organs such as kidneys or stomach).
Sportsmen should be aware that TERAXANS contains an active substance (indapamide) which can induce a positive reaction to doping tests.
TERAXANS should not be given to children.
Interactions Which drugs or foods may change the effect of Teraxans
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You should not take TERAXANS with:
- lithium (used to treat depression),
- potassium-sparing diuretics (spironolactone, triamterene), potassium salts.
Treatment with TERAXANS can be affected by other medicines. Your doctor may need to change your dose and / or take other precautions. Be sure to tell your doctor if you are taking any of these medications, as special attention may be needed:
- other medicines to treat high blood pressure, including an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also information under "Do not take TERAXANS" and "Take special care with TERAXANS")
- procainamide (to treat irregular heartbeat),
- allopurinol (for the treatment of gout),
- terfenadine or astemizole (antihistamines for hay fever or allergies),
- corticosteroids used to treat various conditions including severe asthma and rheumatoid arthritis,
- immunosuppressants used to treat autoimmune diseases or following transplants to prevent rejection (e.g. cyclosporine),
- cancer treatment drugs,
- injectable erythromycin (an antibiotic),
- halofantrine (used to treat certain types of malaria),
- pentamidine (used to treat pneumonia),
- vincamine (used to treat symptomatic cognitive disorders in the elderly including memory loss),
- bepridil (used to treat angina pectoris),
- sultopride (for the treatment of psychosis),
- medicines used to treat heart rhythm disorders (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol),
- digoxin or other digitalis (to treat heart problems),
- baclofen (to treat muscle stiffness in conditions such as multiple sclerosis),
- medicines to treat diabetes such as insulin or metformin,
- calcium including calcium supplements,
- stimulant laxatives (e.g. senna),
- non-steroidal anti-inflammatory drugs (e.g. ibuprofen) or high-dose salicylates (e.g. aspirin),
- injectable amphotericin B (to treat severe fungal infections),
- medicines for the treatment of mental disorders such as depression, anxiety, schizophrenia (e.g. tricyclic antidepressants, neuroleptics), - tetracosactide (for the treatment of Crohn's disease).
Taking TERAXANS with food and drink
It is preferable to take TERAXANS before a meal.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant.) Your doctor will normally advise you to stop taking TERAXANS before planning to become pregnant or as soon as you start to know that you are pregnant and will advise you to take another medicine instead of TERAXANS. TERAXANS is not recommended in early pregnancy, and should not be taken if you are more than three months pregnant as it may cause serious harm to the baby if taken after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or if you need to start breastfeeding. TERAXANS is contraindicated for mothers who are breastfeeding, and your doctor may choose another treatment if you wish to breastfeed, especially if your baby is just born or was born prematurely. Notify your doctor immediately.
Driving and using machines
TERAXANS does not affect alertness but different reactions such as dizziness or tiredness related to the reduction in blood pressure may occur in some patients. If you get these symptoms, your ability to drive or use machines may be reduced.
Important information about some of the ingredients of TERAXANS
TERAXANS contains lactose (a type of sugar).If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this drug.
Dose, Method and Time of Administration How to use Teraxans: Posology
Always take TERAXANS exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. The usual dose is one tablet per day. Take the tablet preferably in the morning and before a meal. The tablet should be swallowed with a glass of water.
If you forget to take TERAXANS
It is important to take the medicine every day as regular treatment is more effective. However, if you forget to take a dose of TERAXANS, just take your next dose at the usual time. Do not take a double dose to make up for a forgotten previous dose.
If you stop taking TERAXANS
As the treatment of hypertension is usually for life, you should speak to your doctor before stopping taking this medicine. If you have any further questions on the use of TERAXANS, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Teraxans
If you have taken too many tablets, consult your doctor immediately or go to the nearest emergency department immediately. The most likely effect of an overdose is a drop in blood pressure. If you experience a marked drop in blood pressure (symptoms such as dizziness or fainting), lying down with your legs elevated may help.
Side Effects What are the side effects of Teraxans
Like all medicines, TERAXANS can cause side effects, although not everybody gets them.
If any of the following occur, stop taking the medicine immediately and contact your doctor immediately:
- swelling of the face, lips, mouth, tongue or throat, difficulty in breathing,
- severe dizziness or fainting,
- irregular or unusually fast heartbeat.
In decreasing order of frequency, side effects may include:
- Common (less than 1 case in 10, but more than 1 case in 100): headache, dizziness, vertigo, tingling, disturbed vision, tinnitus (sensation of ringing in the ears), dizziness due to a drop in blood pressure, cough, shortness of breath, gastrointestinal disturbances (nausea, vomiting, abdominal pain, taste disturbance, dry mouth, dyspepsia or difficulty in digestion, diarrhea, constipation), allergic reaction (such as rash, itching), muscle cramps, tired feeling,
- Uncommon (less than 1 in 100 but more than 1 in 1000 cases): mood changes, sleep disturbances, bronchospasm (chest tightness, wheezing and breathlessness), angioedema (symptoms such as breathlessness and swelling of the face or tongue), hives, purpura (red spots on the skin), kidney problems, impotence, sweating,
- Very rare (less than 1 case in 10,000): confusion, cardiovascular disorders (irregular heartbeat, angina, heart attack), eosinophilic pneumonia (a rare type of pneumonia), rhinitis (stuffy or secreting nose), severe skin manifestations such as " erythema multiforme. If you suffer from systemic lupus erymatosus (a collagen disease) this can get worse. There have also been reports of photosensitivity reactions (change in the appearance of the skin) after exposure to the sun or artificial UVA rays. Blood, kidney, liver or pancreatic disorders and changes in laboratory parameters (blood tests) may occur. Your doctor may order laboratory tests to check your condition. In the case of liver failure (liver disease) it is possible for hepatic encephalopathy (a degenerative disease of the brain) to appear.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep TERAXANS out of the reach and sight of children.
Do not use TERAXANS after the expiry date which is stated on the carton and container. The expiry date refers to the last day of the month.
Keep the container tightly closed to protect the product from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What TERAXANS contains
- The active ingredients are perindopril arginine and indapamide. One film-coated tablet contains 10 mg of perindopril arginine (equivalent to 6.79 mg of perindopril) and 2.5 mg of indapamide.
- The other ingredients contained in the tablet core are: lactose monohydrate, magnesium stearate (E470B), maltodextrin, anhydrous colloidal silica (E551), sodium starch glycolate (type A), and in the film coating: glycerol (E422), hypromellose (E464) , macrogol 6000, magnesium stearate (E470B), titanium dioxide (E171).
What TERAXANS looks like and contents of the pack
TERAXANS tablets are white, round shaped film-coated tablets. One film-coated tablet contains 10 mg of perindopril arginine and 2.5 mg of indapamide.
The tablets are available in containers of 14, 20, 28, 30, 50, 56, 60, 90, 100 or 500 tablets.
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 -
TERAXANS TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One film-coated tablet contains 6.79 mg of perindopril equivalent to 10 mg of perindopril arginine and 2.5 mg of indapamide.
Excipient: lactose monohydrate
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet.
White, round film-coated tablet.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
TERAXANS is indicated as replacement therapy for the treatment of essential arterial hypertension in patients already controlled on perindopril and indapamide given concurrently at the same dose.
04.2 Posology and method of administration -
Oral use.
One tablet of TERAXANS per day as a single dose, preferably to be taken in the morning and before a meal.
Elderly (see section 4.4)
In elderly patients, plasma creatinine must be adjusted for age, weight and gender. Elderly patients can be treated if renal function is normal and after assessment of blood pressure response.
Patients with renal insufficiency (see section 4.4)
In case of severe and moderate renal insufficiency (creatinine clearance less than 60 ml / min), treatment is contraindicated.
Current medical practice must include frequent monitoring of creatinine and potassium.
Patients with hepatic insufficiency (see sections 4.3,4.4 and 5.2)
Treatment is contraindicated in cases of severe hepatic insufficiency.
There is no need to adjust the dose in patients with moderate hepatic impairment.
Children and adolescents
TERAXANS should not be administered to children and adolescents as the efficacy and tolerability of perindopril, alone or in combination, have not been established.
04.3 Contraindications -
Related to perindopril
• Hypersensitivity to perindopril or any other ACE inhibitor
• History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy
• Hereditary / idiopathic angioedema
• Second and third trimester of pregnancy (see sections 4.4 and 4.6)
• Concomitant use of TERAXANS with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR
Related to indapamide
• Hypersensitivity to indapamide or any other sulfonamides
• Hepatic encephalopathy
• Severe hepatic insufficiency
• Hypokalaemia
• This medicinal product is generally not recommended in combination with non-antiarrhythmic drugs that cause torsades de pointes (see section 4.5).
• Breastfeeding (see section 4.6).
Related to TERAXANS
• Hypersensitivity to any of the excipients
• Severe and moderate renal insufficiency (creatinine clearance less than 60 ml / min).
Due to lack of sufficient therapeutic experience, TERAXANS should not be used in:
• patients on dialysis
• patients with untreated decompensated heart failure.
04.4 Special warnings and appropriate precautions for use -
Special warnings
Common to perindopril and indapamide
Lithium
The combination of lithium with the perindopril-indapamide combination is generally not recommended (see section 4.5).
Related to perindopril
Neutropenia / agranulocytosis
Cases of neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely occurs. Perindopril should be administered with extreme caution to patients with collagen disease, on therapy with immunosuppressive agents, treated with allopurinol or procainamide, or who have a combination of these complicating factors, especially in the presence of pre-existing renal impairment. Some of these patients developed severe infections, which in a few cases did not respond to broad-spectrum antibiotic therapy. If these patients are treated with perindopril, it is recommended that white blood cell counts be performed periodically and that these patients are advised to report any signs of infection (e.g. sore throat, fever).
Hypersensitivity / angioedema
Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including perindopril. This can occur at any time during therapy. In such cases, perindopril treatment should be discontinued immediately and appropriate monitoring initiated to ensure complete resolution of symptoms prior to patient discharge. In the case of edema limited to the face and lips, the reaction generally resolved without treatment, although antihistamines were helpful in relieving symptoms.
Angioedema associated with laryngeal edema can be fatal. In the event that there is involvement of the tongue, glottis or larynx that can cause airway obstruction, appropriate therapy should be given promptly, which may include a 1: 1000 (0, 0.1) subcutaneous epinephrine solution. 3 ml to 0.5 ml) and / or measures for maintaining a patent airway.
A higher incidence of angioedema has been reported in black patients treated with ACE inhibitors than in patients of other races.
Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema when treated with an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no previous facial angioedema and C-1 esterase levels were normal. Angioedema was diagnosed by means of procedures such as CT scan of the abdomen, ultrasound, or during surgery and symptoms were resolved after discontinuation of the ACE inhibitor.
Intestinal angioedema should be included in the differential diagnosis of patients treated with ACE inhibitors who present with abdominal pain.
Anaphylactoid reactions during desensitization treatment
Isolated cases of severe and life-threatening anaphylactoid reactions have been reported in patients treated with ACE inhibitors undergoing desensitizing treatment for hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in desensitized allergic patients and avoided in those undergoing venom immunotherapy. However, such reactions can be prevented with temporary withdrawal of the ACE inhibitor, at least 24 hours prior to treatment in patients requiring both ACE inhibitors and desensitization.
Anaphylactoid reactions during LDL apheresis
Rarely, cases of life-threatening anaphylactoid reactions have been reported in patients treated with ACE inhibitors undergoing low density lipoprotein (LDL) apheresis with dextran sulfate. These reactions were avoided by temporarily withholding ACE inhibitor treatment prior to each apheresis.
Patients on hemodialysis
Anaphylactoid reactions have been reported in patients on dialysis with high flux membranes (eg AN 69®) and concomitant therapy with ACE inhibitors. The use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered for these patients.
Potassium-sparing diuretics, potassium salts
The combination of perindopril with potassium-sparing diuretics, potassium salts is generally not recommended (see section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Pregnancy
ACE inhibitor therapy should not be initiated during pregnancy. For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with an ACE inhibitor is considered essential. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Related to indapamide
In case of liver disease, thiazide and related diuretics can cause hepatic encephalopathy. In these cases, the administration of the diuretic must be stopped immediately.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazides and related diuretics (see section 4.8). If the photosensitivity reaction appears during the treatment, it is recommended to stop it. In case the re-administration of the diuretic is necessary, it is recommended to protect the areas exposed to the sun or to artificial UVA rays.
Appropriate precautions for use
Common to perindopril and indapamide
Kidney failure
In case of severe and moderate renal insufficiency (creatinine clearance
In some hypertensive patients without pre-existing apparent renal lesions and for whom kidney blood tests have shown functional renal insufficiency, treatment should be stopped and possibly resumed at a reduced dose or with only one of the components.
Current practice must provide for these patients a periodic control of potassium and creatinine after two weeks of treatment and subsequently every 2 months in a period of therapeutic stability. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure, including renal artery stenosis.
The drug is generally not recommended in case of bilateral renal artery stenosis or impaired function in one kidney only.
Hypotension and hydroelectrolytic depletion
There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (particularly in patients with renal artery stenosis). Therefore, clinical signs of fluid and electrolyte depletion, which may occur during an intercurrent episode of diarrhea or vomiting, should be systematically monitored and regular monitoring of the plasma electrolytes of these patients should be performed.
Marked hypotension may require an intravenous infusion of isotonic saline.
Transient hypotension is not a contraindication to continuing treatment. Once a satisfactory blood volume and blood pressure have been re-established, treatment can be resumed at a reduced dose or with only one of the components.
Potassium levels
The combination of perindopril and indapamide does not exclude the occurrence of hypokalaemia, especially in diabetic patients or patients with renal insufficiency. As with any other antihypertensive that contains a diuretic, regular monitoring of plasma potassium should be performed.
Excipients
TERAXANS should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Related to perindopril
Cough
A dry cough has been reported following administration of angiotensin converting enzyme inhibitors, the characteristics of which are persistence and disappearance after discontinuation of treatment. In the presence of this symptom, a possible iatrogenic etiology must be considered. In the event that prescription of an angiotensin converting enzyme inhibitor is nevertheless preferred, continued treatment may be considered.
Children and adolescents
The efficacy and tolerability of perindopril, alone or in combination, have not been established in children and adolescents.
Risk of arterial hypotension and / or renal failure (in case of heart failure, hydroelectrolytic depletion, etc ...)
Significant stimulation of the renin-angiotensin-aldosterone system has been observed in particular during marked water and electrolyte depletions (strict low sodium regimen or prolonged diuretic treatment) in patients with initially low blood pressure, in case of renal arterial stenosis, insufficiency congestive heart or cirrhosis with edema and ascites.
The blocking of this system by an angiotensin converting enzyme inhibitor can therefore cause, especially at the first intake and during the first two weeks of treatment, a sharp drop in blood pressure and / or an increase in plasma creatinine, a sign of a "functional renal failure. Occasionally this may be acute in onset, albeit rarely, and with a variable time interval.
In these cases, treatment should be started at a lower dose and progressively increased.
Elderly patients
Renal function and potassium levels should be checked prior to the start of treatment. The dose should be further adjusted according to the blood pressure response, particularly in the case of water and electrolyte depletion, to avoid sudden hypotension.
Patients with known atherosclerosis
The risk of hypotension is present in all patients, but particular caution is required with patients suffering from ischemic heart disease or cerebral circulatory insufficiency, starting treatment at a reduced dosage.
Renovascular hypertension
The treatment of renovascular arterial hypertension is revascularization.
However, angiotensin converting enzyme inhibitors may be useful for patients with renovascular hypertension awaiting corrective surgery or when it is not possible.
Treatment with TERAXANS is not appropriate in patients with known or suspected renal arterial stenosis, as treatment should be initiated in a hospital setting at a dose lower than that of TERAXANS.
Other patients at risk
In patients with severe heart failure (stage IV) or in patients with insulin-dependent diabetes mellitus (spontaneous tendency to increase potassium levels), treatment with TERAXANS is not appropriate as treatment must begin under close medical supervision and at a dose Initial reduced. Do not interrupt any treatment with β-blockers in the hypertensive patient with coronary insufficiency: the ACE inhibitor must be combined with the β-blocker.
Diabetic patients
In diabetic patients previously treated with oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored during the first month of therapy with an ACE inhibitor.
Ethnic differences
Like other angiotensin converting enzyme inhibitors, perindopril may be less effective in lowering blood pressure in black patients than in non-black patients, possibly due to a higher prevalence of low renin concentrations in the population. hypertensive black race.
Surgery / anesthesia
In the case of anesthesia, and even more so if the anesthesia is performed with agents with hypotensive potential, inhibitors of the angiotensin converting enzyme can cause hypotension.
Discontinuation of treatment, if possible, is therefore recommended one day before surgery for long-acting angiotensin-converting enzyme inhibitors, such as perindopril.
Aortic or mitral valve stenosis / hypertrophic cardiomyopathy
ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.
Hepatic insufficiency
In rare cases, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients on ACE inhibitors who develop jaundice or marked elevation of liver enzymes should stop taking the ACE inhibitor and receive appropriate medical attention (see section 4.8).
Hyperkalemia
Increased serum potassium concentrations have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the onset of hyperkalaemia include renal failure, impaired renal function, age (> 70 years), diabetes mellitus, concomitant events, particularly dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics. (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; patients taking other drugs associated with an increase in serum potassium (e.g. heparin) are also at higher risk.
The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function, can lead to a significant increase in serum potassium. Hyperkalaemia can cause serious and sometimes fatal arrhythmias. If concomitant use of the above mentioned agents is deemed appropriate, they should be used with caution and frequent monitoring of serum potassium should be performed (see section 4.5).
Related to indapamide
Hydroelectrolytic balance
Sodium levels
They must be checked before starting treatment and at regular intervals thereafter. A diuretic treatment can in fact cause a reduction in sodium levels, with sometimes serious consequences. The drop in sodium levels may initially be asymptomatic and regular monitoring is therefore essential. Monitoring should be performed even more frequently in elderly patients and cirrhotic patients (see sections 4.8 and 4.9).
Potassium levels
Potassium depletion with hypokalaemia represents the major risk of thiazide and related diuretics. The risk of developing low potassium levels (
In these cases, in fact, hypokalaemia enhances the cardiac toxicity of digitalis and the risk of heart rhythm disturbances.
Individuals with a long QT interval, of both congenital and iatrogenic origin, are also at risk. Hypokalaemia, as well as bradycardia, acts as a predisposing factor for the onset of severe heart rhythm disturbances, especially torsades de pointes, which can be fatal.
In all these cases, more frequent monitoring of potassium levels is necessary. The first plasma potassium check should be done during the first week of treatment.
If low potassium levels are found, their correction is required.
Calcium Levels
Thiazide and related diuretics can reduce urinary excretion of calcium and cause a slight and transient increase in plasma calcium levels. A marked increase in calcium levels may be related to undiagnosed hyperparathyroidism. In these cases, treatment should be stopped. before exploring the parathyroid function.
Glycemia
It is important, in diabetic patients, to check blood glucose especially in the presence of low potassium levels.
Uric acid
In hyperuricaemic patients, the tendency to gout attacks may increase.
Renal function and diuretics
Thiazide and related diuretics are fully effective only if renal function is normal or minimally impaired (creatinine levels below values of the order of 25 mg / l, or 220 mmol / l in adults).
In the elderly, the value of plasma creatinine levels must be adjusted taking into account the age, weight and sex of the patient, according to the Cockroft formula:
C1cr = (140-age) x weight / 0.814 x plasma creatinine value
with: the age expressed in years
the weight expressed in Kg
the plasma creatinine value expressed in micromol / l
This formula is valid for elderly male subjects and must be corrected for women by multiplying the result by 0.85.
Hypovolemia, due to the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. This can result in an increase in blood urea and creatinine levels. This transient functional renal insufficiency does not cause consequences in the patient with normal renal function, but can instead aggravate a pre-existing "renal insufficiency".
Sportsmen
The attention of athletes is drawn to the fact that this product contains an active ingredient that can induce a positive reaction to doping control tests
04.5 Interactions with other medicinal products and other forms of interaction -
Common to perindopril and indapamide
Associations not recommended
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. The concomitant use of thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity with ACE inhibitors. The combination of perindopril and indapamide with lithium is not recommended but if this combination is necessary, a check should be carried out. strict serum lithium levels (see section 4.4).
Associations that require special precautions for use
• Baclofen: Potentiation of the antihypertensive effect. Control of blood pressure and renal function and adjustment of the antihypertensive dose if necessary.
• Non-steroidal anti-inflammatory drugs (including high-dose acetylsalicylic acid): when ACE inhibitors are administered concomitantly with non-steroidal anti-inflammatory drugs (eg acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-NSAIDs selective), "attenuation of the antihypertensive effect" may occur. The concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including acute renal failure, and to an increase in serum potassium, particularly in patients with pre-existing renal insufficiency; this combination should be administered with caution, particularly in elderly patients. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter.
Associations to be monitored
• Imipramine-like antidepressants (tricyclics), neuroleptics: potentiation of the antihypertensive effect and potentiation of the risk of orthostatic hypotension (additive effect).
• Corticosteroids, tetracosactide: Reduction of the antihypertensive effect (salt and water retention by corticosteroids)
• Other antihypertensives: The use of other antihypertensives with perindopril / indapamide may induce an additional blood pressure lowering effect.
Related to perindopril
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).
Associations not recommended
• Potassium-sparing diuretics (spironolactone, triamterene, alone or in combination), potassium salts: ACE inhibitors decrease the potassium loss induced by diuretics. Potassium-sparing diuretics, such as spironolactone, triamterene or amiloride, potassium supplements or potassium-containing salt substitutes can lead to significant increases in serum potassium (life-threatening). If concomitant use of these drugs is prescribed for the presence of documented hypokalaemia, they should be taken with caution and with frequent monitoring of serum potassium and by ECG.
Associations that need special precautions
• Antidiabetics (insulin, hypoglycemic sulfonamides): described for captopril and enalapril.
The use of angiotensin converting enzyme inhibitors may cause an enhancement of the blood glucose lowering effect in diabetic treated with hypoglycemic insulin or sulfonamides. The occurrence of hypoglycaemic episodes is very rare (improving glucose tolerance leads to a reduction in insulin requirements).
Associations to be monitored
• Allopurinol, cytostatics or immunosuppressive agents, systemic corticosteroids or procainamide: concomitant administration with ACE inhibitors may lead to an increased risk of leukopenia.
• Anesthetic drugs: ACE inhibitors can potentiate the hypotensive effect of some anesthetic drugs.
• Diuretics (thiazides or loop diuretics): Prior treatment with high dose diuretics may lead to volume depletion and a risk of hypotension when initiating therapy with perindopril.
• Gold: Nitritoid reactions (symptoms include flushing of the face, nausea, vomiting and hypotension) have been reported rarely in patients receiving injectable gold (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including perindopril.
Related to indapamide
Associations that require special precautions for use
- Drugs that cause torsades de pointes: due to the risk of hypokalaemia, indapamide should be administered with caution in combination with drugs that induce torsades de pointes such as class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide); class III antiarrhythmics (amiodarone, dofetilide, ibutilide, bretilium, sotalol); some neuroleptics (chlorpromazine, ciamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyroperzide (other pyroperzide), pyroperidrophols other substances such as bepridil, cisapride, dihemanyl, iv erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, iv vincamine, methadone, astemizole, terfenadine. QT.
• Hypokalaemic drugs: amphotericin B (iv route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulating laxatives: potentiation of the risk of reduction of potassium levels (additive effect).
Control of potassium levels and possible correction; cases treated with digitalis require particular attention. Use non-stimulant laxatives.
• Digitalis: reducing potassium levels favors the toxic effects of digitalis. Monitoring of potassium levels and ECG is necessary and treatment should be reconsidered if necessary.
Associations to be monitored
• Metformin: lactic acidosis due to metformin triggered by a possible functional renal insufficiency linked to diuretics and more specifically to loop diuretics. Do not use metformin if plasma creatinine levels exceed 15 mg / liter (135 micromol / liter) in men and 12 mg / liter (110 micromol / liter) in women.
• Iodine contrast media: in the case of dehydration caused by diuretics, there is an increased risk of acute renal failure, particularly with high doses of iodinated contrast media. Rehydration should be performed prior to administration of the iodinated medium.
• Calcium (salts of): risk of an increase in calcium levels due to reduced urinary elimination of calcium.
• Cyclosporine: risk of increased creatinine levels without changing the circulating rates of cyclosporine, even in the absence of salt and water depletion.
04.6 Pregnancy and breastfeeding -
Pregnancy
Related to perindopril
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester 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. For patients planning pregnancy, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with an ACE inhibitor is considered essential.
When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitors during the second and third trimester of pregnancy 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 ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken ACE inhibitors should be carefully observed for hypotension (see sections 4.3 and 4.4).
Related to indapamide
Prolonged exposure to thiazide during the third trimester of pregnancy may reduce maternal plasma volume as well as uteroplacental blood flow which can result in fetal placental ischaemia and growth retardation. In addition, rare cases of hypoglycemia and thrombocytopenia have been reported in newborn infants. following exposure at the end of pregnancy.
Feeding time
TERAXANS is contraindicated during lactation.
. The use of perindopril is not recommended during breastfeeding.
Indapamide is excreted in breast milk. Indapamide is very similar to thiazide diuretics which have been associated with decreased or even suppression of breast milk production during lactation. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia and nuclear jaundice may occur.
Since serious adverse reactions in nursing infants may occur with either drug, a decision must be made whether to discontinue breastfeeding or to discontinue treatment, taking into account the importance of therapy to the mother.
04.7 Effects on ability to drive and use machines -
Related to perindopril, indapamide and TERAXANS
The two components and TERAXANS do not change the level of supervision; however, individual reactions due to a drop in blood pressure may occur in some patients, especially at the start of treatment or when combining with another antihypertensive drug.
As a result, the ability to drive or use machines may be impaired.
04.8 Undesirable effects -
Administration of perindopril inhibits the renin-angiotensin-aldosterone system and tends to reduce indapamide-induced potassium loss. Hypokalaemia (potassium levels) has been observed in 6% of patients receiving TERAXANS
The following side effects that may be observed during treatment have been classified according to the following frequency:
very common (≥1 / 10); common (≥1 / 100,
Disorders of the blood and lymphatic system
Very rare:
• Thrombocytopenia, leukopenia / neutropenia, agranulocytosis, aplastic anemia, haemolytic anemia.
• Anemia has been reported in special patients (kidney transplant, hemodialysis) under treatment with angiotensin converting enzyme inhibitors (see section 4.4).
Psychiatric disorders
Uncommon: Mood or sleep disturbances.
Nervous system disorders
Common: Paresthesia, headache, dizziness, vertigo.
Very rare: Confusion
Eye disorders
common: Changes in vision.
Ear and labyrinth disorders
common: tinnitus.
Vascular pathologies
Common: Hypotension, orthostatic or not (see section 4.4)
Cardiac pathologies
Very rare: arrhythmia including bradycardia, ventricular tachycardia, atrial fibrillation, angina pectoris and myocardial infarction possibly secondary to marked hypotension in high-risk patients (see section 4.4)
Respiratory, thoracic and mediastinal disorders
Common:
• With the use of angiotensin converting enzyme inhibitors, the onset of dry cough characterized by its persistence and its disappearance upon discontinuation of treatment has been reported. An iatrogenic etiology should be considered in the presence of this symptom. Dyspnea
Uncommon: bronchospasm.
Very rare: eosinophilic pneumonia, rhinitis
Gastrointestinal disorders
common: constipation, dry mouth, nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhea.
Very rare: pancreatitis
Hepatobiliary disorders
Very rare: hepatitis, both cytolytic and cholestatic (see section 4.4)
Not known: In case of hepatic insufficiency, possibility of development of hepatic encephalopathy (see sections 4.3 and 4.4)
Skin and subcutaneous tissue disorders
common: skin rash, pruritus, maculopapular eruptions
Uncommon:
• angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx, urticaria (see section 4.4)
• hypersensitivity reactions, mainly at a dermatological level, in subjects predisposed to allergic and asthmatic manifestations
• purple
Possibility of aggravation of pre-existing acute systemic lupus erythematosus
Very rare: erythema multiforme, toxic epidermal necrolysis, Stevens Johnson syndrome.
Cases of photosensitivity reactions have been reported (see section 4.4)
Musculoskeletal and connective tissue disorders
Common: muscle cramps
Renal and urinary disorders
Uncommon: kidney failure
Very rare: acute renal failure
Diseases of the reproductive system and breast
Uncommon: impotence
General disorders and administration site conditions
common: asthenia
Uncommon: sweating
Diagnostic tests
• potassium depletion particularly with a significant reduction in potassium levels in some patients at risk (see section 4.4)
• decreased sodium levels with hypovolaemia causing dehydration and orthostatic hypotension
• increased uric acid and blood sugar levels during treatment
• moderate increase in urea and plasma creatinine levels, reversible upon stopping treatment, more often reported in case of renal artery stenosis, arterial hypertension treated with diuretics, renal failure
• increase in potassium levels, usually transient
Rare: elevation of plasma calcium levels
04.9 Overdose -
The most recurrent effect in overdose is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, somnolence, confusional state, oliguria which can progress to anuria (due to hypovolemia).
Disturbances in the salt and water balance may also occur (reduced sodium levels, reduced potassium levels).
The first measures to be taken consist in rapidly eliminating the ingested product (s) with gastric lavage and / or administration of activated charcoal and rapidly restoring the hydroelectrolytic balance until normalization in a specialized center.
In case of marked hypotension, it is advisable to place the patient in the supine position, with the legs raised and, if necessary, to carry out an intravenous infusion of isotonic sodium chloride solution or any other means of volume expansion.
Perindoprilat, the active metabolite of perindopril, is dialysable (see section 5.2).
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: perindopril and diuretics, ATC code: C09BA04
TERAXANS consists of the combination of perindopril arginine salt, an inhibitor of the angiotensin converting enzyme, and indapamide, a chlorosulfonamide diuretic. Its pharmacological properties derive from those of each of its components, to which the properties are added. due to the synergistic action of the two associated products.
Mechanism of action
Related to perindopril
Perindopril is an inhibitor of the conversion enzyme (ACE) of angiotensin I to angiotensin II, a vasoconstrictor substance; in addition, the angiotensin converting enzyme stimulates the secretion of aldosterone by the adrenal cortex and the degradation of bradykinin, a vasodilator substance into an inactive heptapeptide.
It follows:
• a reduction in aldosterone secretion,
• an increase in plasma renin activity, since aldosterone no longer exerts a negative feedback,
• a decrease in total peripheral vascular resistance with a preferential activity at the muscle and renal level, not accompanied by salt and water retention or reflex tachycardia, in chronic treatment.
The antihypertensive action of perindopril also occurs in subjects with low or normal concentrations of renin.
Perindopril acts by means of its active metabolite, perindoprilat; the other metabolites are inactive.
Perindopril reduces the workload of the heart:
• with a venous vasodilatory effect, probably due to a change in prostaglandin metabolism: reduction in preload,
• with a reduction of the total peripheral resistances: reduction of the afterload.
Studies conducted in patients with heart failure have shown:
• a drop in left and right ventricular filling pressure,
• a reduction in total peripheral vascular resistance,
• an increase in cardiac flow and an improvement in the cardiac index,
• an increase in regional muscle blood flows.
Stress tests are also improved.
Related to indapamide
Indapamide is a sulfonamide derivative with an indole nucleus, pharmacologically related to the group of thiazide diuretics. Indapamide inhibits sodium reabsorption at the dilution cortical segment level. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thus increasing diuresis and exerting an antihypertensive action.
Characteristics of the antihypertensive activity
Related to TERAXANS
In hypertensive patients of any age, TERAXANS exerts a dose-dependent antihypertensive effect on diastolic and systolic blood pressure in the supine and standing position.
PICXEL, a multicentre, randomized, double-blind, active-controlled study evaluated by echocardiography the effect of the combination perindopril / indapamide on left ventricular hypertrophy (IVS) compared to enalapril monotherapy.
In the PICXEL study, hypertensive patients with IVS (defined as left ventricular mass index (IMVS)> 120 g / m² in men and> 100g / m² in women) were randomized to perindopril tert-butylamine 2 mg / indapamide 0.625 mg. or enalapril 10 mg once daily for one year of therapy The dose was titrated on the basis of blood pressure to 8 mg perindopril tert-butylamine and 2.5 mg indapamide or 40 mg enalapril once daily. Only 34% of patients remained on treatment with perindopril tert-butylamine 2mg (equivalent to 2.5mg perindopril arginine) / indapamide 0.625mg (versus 20% with enalapril 10mg).
At the end of treatment, the left ventricular mass index (IMVS) decreased significantly in the perindopril / indapamide group (-10.1 g / m²) compared to the enalapril group (-1.1 g / m²) in the whole randomized patient population. The difference between groups on the change in left ventricular mass index (IMVS) was -8.3 (95% CI (-11.5, -5.0), p
A better effect on left ventricular mass index (IMVS) was achieved with doses of perindopril 8 mg (equivalent to 10 mg perindopril arginine) / indapamide 2.5 mg.
For blood pressure, the estimated mean differences between groups in the randomized population were -5.8 mmHg (95% CI (-7.9, -3.7), systolic blood pressure and -2.3, respectively. mmHg (95% CI (-3.6, -0.9), p = 0.0004) for systolic blood pressure, in favor of the perindopril / indapamide group.
Related to perindopril
Perindopril is active in all stages of arterial hypertension: from mild to moderate to severe. A reduction in systolic and diastolic blood pressure has been observed in supine and standing positions.
The peak of the antihypertensive effect occurs 4-6 hours after a single administration and the antihypertensive efficacy is maintained for at least 24 hours.
The residual inhibition of the angiotensin converting enzyme at the 24th hour is high and is around 80%.
In responding patients, blood pressure normalization is achieved after one month of treatment and is maintained without tachyphylaxis.
Discontinuation of treatment is not accompanied by rebound phenomena.
Perindopril possesses vasodilatory and restorative properties of the elastic qualities of large arterial trunks, corrects structural changes in arterial resistance and determines a reduction in left ventricular hypertrophy.
If necessary, the addition of a thiazide diuretic produces additive synergy.
The combination of an angiotensin converting enzyme inhibitor and a thiazide diuretic also reduces the risk of hypokalaemia induced by the diuretic given alone.
Related to indapamide
Indapamide, alone, produces an antihypertensive effect that lasts for 24 hours; this effect occurs at doses at which the diuretic effect is not very evident.
Its antihypertensive activity is expressed through an improvement in arterial compliance and a reduction in total and arteriolar peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
Beyond a certain dose, there is a plateau of the antihypertensive effect of thiazide diuretics and similar, with a simultaneous increase in undesirable effects; in case of ineffectiveness of the treatment, the dose should not be increased.
It has also been shown in the short, medium and long term in hypertension that indapamide:
• has no effect on lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol,
• it has no effect on glucose metabolism, even in diabetic hypertensive patients.
Clinical trial data on dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA Nephron-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.
These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.
ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.
05.2 "Pharmacokinetic properties -
Related to TERAXANS
The administration of the combination perindopril and indapamide does not modify the pharmacokinetic parameters of the two drugs taken separately.
Related to perindopril
Orally, the absorption of perindopril is rapid and the peak concentration is reached within one hour. The plasma half-life of perindopril is one hour.
Perindopril is a prodrug. 27% of the administered perindopril dose reaches the bloodstream as perindoprilat as the active metabolite. In addition to the active perindoprilat, perindopril produces five metabolites, all of which are inactive. The peak plasma concentration of perindoprilat is reached in 3-4 hours.
Since food intake reduces conversion to perindoprilat, and hence bioavailability, perindopril arginine salt should be administered orally in a single daily dose in the morning before a meal.
A linear correlation has been demonstrated between the dose of perindopril taken and the relative plasma concentration. The volume of distribution of free perindoprilat is approximately 0.2 l / kg. Plasma protein binding of perindoprilat is 20%, mainly to angiotensin converting enzyme, but is concentration dependent.
Perindoprilat is eliminated in the urine and the final half-life of the free fraction is approximately 17 hours, with steady state attainment within 4 days.
Elimination of perindoprilat is reduced in the elderly, as well as in patients with heart or renal insufficiency. In renal insufficiency, dosage adjustment is desirable according to the degree of insufficiency (creatinine clearance).
The dialysis clearance of perindoprilat is 70ml / min.
In the cirrhotic patient, the kinetics of perindopril are changed: the hepatic clearance of the parent molecule is reduced by half. However, the amount of perindoprilat formed is not reduced and therefore no dosage adjustment is necessary (see sections 4.2 and 4.4).
Related to indapamide
Indapamide is rapidly and totally absorbed from the digestive tract.
The maximum plasma peak is reached in humans approximately one hour after oral administration of the drug. The plasma protein binding rate is 79%.
The elimination half-life is between 14 and 24 hours (average 18 hours). Repeated administrations do not cause accumulation. Elimination occurs essentially via the urine (70% of the dose) and faecal (22%) in the form of inactive metabolites.
Pharmacokinetic parameters do not change in the patient with renal insufficiency.
05.3 Preclinical safety data -
The perindopril / indapamide combination has slightly higher toxicity than its components. Renal manifestations do not appear to be potentiated in the rat; however, the combination has shown digestive toxicity in dogs and greater maternal toxic effects in rats. (compared to perindopril).
These side effects, however, occurred at high doses, significantly higher than those used in therapy.
Related to perindopril
In chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
No mutagenicity was observed in studies in vitro or in vivo.
Reproductive toxicology studies (rats, mice, rabbits and monkeys) showed no signs of embryotoxicity or teratogenicity. However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects in the later stages of fetal development that can lead to fetal death and birth defects in rodents and rabbits: kidney and rabbit lesions have been observed. an increase in perinatal and postnatal mortality.
No carcinogenicity was observed in long-term studies in rats and mice.
Related to indapamide
The higher doses (40 to 8000 times the therapeutic dose) administered orally to various animal species have shown an exacerbation of the diuretic properties of indapamide. The main symptoms of poisoning during acute toxicity studies with intravenous or intraperitoneal indapamide were related to the pharmacological action of indapamide, ie bradypnea and peripheral vasodilation.
Regarding the mutagenic and carcinogenic properties of indapamide, the tests were negative.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Nucleus:
Lactose monohydrate
Magnesium stearate (E470B)
Maltodextrin
Anhydrous colloidal silica (E551)
Sodium starch glycolate (type A)
Coating film:
Glycerol (E422)
Hypromellose (E464)
Macrogol 6000
Magnesium stearate (E470B)
Titanium dioxide (E171)
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
2 years
06.4 Special precautions for storage -
Keep the container tightly closed to protect the product from moisture.
06.5 Nature of the immediate packaging and contents of the package -
14, 20, 28, 30 or 50 tablets in a polypropylene container equipped with a low density polyethylene flow reducer and a low density polyethylene cap containing a white desiccant gel.
Package contents: 1 x 14, 1 x 20, 1 x 28, 1 x 30 or 1 x 50 tablets
2 x 28, 2 x 30 or 2 x 50 tablets
3 x 30 tablets
10 x 50 tablets
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
I.F.B. STRODER S.r.l.
Via Luca Passi, 85
00166 Rome
08.0 MARKETING AUTHORIZATION NUMBER -
A.I.C. n ° 039227044 - "10 mg / 2.5 mg film-coated tablets" 30 x 1 tablets in PP container
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
January 12, 2011
10.0 DATE OF REVISION OF THE TEXT -
07/2015
