Active ingredients: Perindopril (Perindopril arginine), Amlodipine
COVERLAM 5mg / 5mg tablets
COVERLAM 5mg / 10mg tablets
COVERLAM 10mg / 5mg tablets
COVERLAM 10mg / 10mg tablets
Indications Why is Coverlam used? What is it for?
Coverlam is prescribed to treat high blood pressure (hypertension) and / or to treat stable coronary artery disease (a condition in which the blood supply to the heart is reduced or blocked).
Patients already taking perindopril and amlodipine as separate tablets can take only one Coverlam tablet instead, which contains both active substances.
Coverlam is a combination of two active substances, perindopril and amlodipine. Perindopril is an ACE (angiotensin converting enzyme) inhibitor. Amlodipine is a calcium antagonist (belonging to the class of drugs called dihydropyridines). In combination, they work by dilating and relaxing blood vessels in a way that makes it easier for blood to pass through them and for the heart to maintain a good level of flow. blood
Contraindications When Coverlam should not be used
Do not take Coverlam
- if you are allergic (hypersensitive) to perindopril or any other ACE inhibitor, or to amlodipine or any other calcium channel blocker, or to any of the other ingredients of Coverlam,
- if you have been pregnant for more than three months. (COVERLAM is also best avoided in early pregnancy) (see "Pregnancy" section),
- if you have symptoms such as breathlessness, swelling of the face or tongue, intense itching or severe skin rashes related to previous treatment with ACE inhibitors or if you or a family member have experienced these symptoms in any other circumstances (a condition 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 a narrowing of the aortic heart valve (aortic stenosis) or in case of cardiogenic shock (a condition in which the heart is unable to supply the body with sufficient blood),
- if you have severe low blood pressure (hypotension),
- if you suffer from heart failure following a heart attack.
Precautions for use What you need to know before taking Coverlam
Before treatment with Coverlam, talk to your doctor if any of the following apply to you:
- if you have hypertrophic cardiomyopathy (heart muscle disease) or renal artery stenosis (narrowing of the artery that supplies blood to the kidneys),
- if you suffer from heart failure,
- if you suffer from severe increase in blood pressure (hypertensive crisis),
- if you have other heart problems,
- if you have liver problems,
- if you have kidney problems or are on dialysis,
- if you have collagen vascular disease (connective tissue disease) such as systemic lupus erythematosus or scleroderma,
- if you have diabetes,
- if you are on a diet that restricts the use of salt or uses salt substitutes containing potassium (a well-balanced blood level of potassium is essential),
- if you are elderly and the dosage needs to be increased.
- 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 Coverlam".
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Coverlam is not recommended 5 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 that stage (see "Pregnancy" section).
If you take Coverlam, tell your doctor or medical staff:
- if you are due to undergo general anesthesia and / or major surgery,
- if you have recently had diarrhea or vomiting (being sick),
- if you are to undergo LDL apheresis (the removal of cholesterol from the blood by means of a machine),
- if you need to undergo desensitization treatment to reduce the effects of an "allergy to bee or wasp stings."
Coverlam is not recommended for use in children and adolescents.
Interactions Which drugs or foods can modify the effect of Coverlam
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You must not take Coverlam with:
- lithium (used to treat mania or depression),
- estramustine (used in cancer therapy),
- potassium-sparing diuretics (spironolactone and triamterene), potassium supplements or potassium-containing salt substitutes.
Treatment with Coverlam may be affected by taking other medicines. Your doctor may need to adjust your dose and / or take other precautions. Tell your doctor if you are taking any of the following medicines as you may need special attention:
- other medicines to treat high blood pressure, including an angiotensin II receptor antagonist (AIIRA), aliskiren (see also information under "Do not take Coverlam" and "Take special care with Coverlam") or diuretics (medicines that increase the amount of urine produced by the kidneys),
- non-steroidal anti-inflammatory drugs (eg ibuprofen) for pain relief or high doses of aspirin,
- medicines to treat diabetes (such as insulin),
- medicines for the treatment of mental disorders such as depression, anxiety, schizophrenia, etc. (e.g. tricyclic antidepressants, antipsychotics, imipramine-like antidepressants, neuroleptics),
- immunosuppressants (medicines capable of depressing the body's defense mechanism) used to treat autoimmune disorders or following a surgical transplant (eg cyclosporine),
- allopurinol (for the treatment of gout),
- procainamide (to treat irregular heartbeat),
- vasodilators, including nitrates (products that dilate blood vessels),
- heparin (drug used to thin the blood),
- ephedrine, noradrenaline or adrenaline (drugs used to treat hypotension, shock or asthma),
- baclofen or dantrolene (infusion) both used to treat muscle stiffness in conditions such as multiple sclerosis; dantrolene is also used in the treatment of malignant hyperthermia during anesthesia (symptoms include very high fever and muscle stiffness),
- some antibiotics such as rifampicin, erythromycin, clarithromycin,
- antiepileptic medicines such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone,
- itraconazole, ketoconazole (medicines used to treat fungal infections),
- alpha-blockers used for the treatment of prostatic hyperplasia such as prazosin, alfuzosin, doxazosin, tamsulosin, terazosin,
- amifostine (used to prevent or reduce side effects caused by other drugs or radiotherapy in the treatment of cancer),
- corticosteroids (used to treat various conditions including severe asthma and rheumatoid arthritis),
- gold salts, especially for intravenous administration (used to treat the symptoms of rheumatoid arthritis), - ritonavir, indinavir, nelfinavir (so-called protease inhibitors used to treat HIV).
Taking Coverlam with food and drink
Coverlam must be taken before a meal.
People taking Coverlam should not consume grapefruit or drink grapefruit juice as grapefruit and grapefruit juice can cause increased levels of the active substance amlodipine in the blood, which can lead to an unpredictable increase in the hypotensive effect of Coverlam.
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 usually advise you to stop taking Coverlam before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Coverlam.
Coverlam 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 after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding. Coverlam is not recommended for mothers who are breastfeeding, and your doctor may choose another treatment for you if you wish to breastfeed, especially if your baby is just born. or was born premature
Driving and using machines
Coverlam may have an effect on the ability to drive or use machines. If the tablets make you feel unwell, dizzy, or tired, or cause you a headache, do not drive or operate machinery and contact your doctor immediately.
Important information about some of the ingredients of Coverlam
Coverlam contains lactose monohydrate (a type of sugar). If you have been given a medical diagnosis of intolerance to certain sugars, consult your doctor before taking this drug.
Dosage and method of use How to use Coverlam: Dosage
Always take Coverlam exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Take the tablet by swallowing it with water, preferably at the same time each day, in the morning and in any case before a meal. Your doctor will decide which dose is appropriate for you. Usually the dose will be one tablet a day.
Generally, Coverlam will be prescribed to patients who are already taking perindopril and amlodipine as separate tablets.
Overdose What to do if you have taken too much Coverlam
If you take more Coverlam than you should
If you have taken too many tablets, go to the nearest emergency room or consult your doctor immediately. The most likely effect of an overdose is a drop in blood pressure which can make you feel dizzy or faint. In this case, lying down with your legs elevated may help.
If you forget to take Coverlam
It is important to take the medicine every day as regular treatment is more effective. However, if you forget to take a dose of Coverlam, just take the next dose as usual. Do not take a double dose to make up for a forgotten dose.
If you stop taking Coverlam
As treatment with Coverlam is usually for life, talk to your doctor before you stop taking this medicine.
If you have any further questions on the use of Coverlam, ask your doctor or pharmacist.
Side Effects What are the side effects of Coverlam
Like all medicines, Coverlam can cause side effects, although not everybody gets them.
If you experience any of the following side effects, stop taking the medicine immediately and tell your doctor right away:
- Sudden onset of wheezing, chest pain, wheezing or difficulty in breathing,
- Swelling of the eyelids, face or lips,
- Swelling of the tongue and throat which can cause great difficulty in breathing,
- Severe skin reactions including intense skin rash, hives, skin redness all over the body, severe itching, blistering, peeling and swelling of the skin, inflammation of the mucous membranes (Stevens Johnson syndrome) or other allergic reactions,
- severe dizziness or fainting,
- myocardial infarction, arrhythmia,
- inflammation of the pancreas which may cause severe abdominal and back pain combined with feeling very unwell.
The following common side effects have been reported. If any of these effects occur or if they persist for more than a week, please contact your doctor.
- common (occurring in less than 1 in 10 but more than 1 in 100 patients): headache, dizziness, somnolence (especially at the start of treatment), dizziness, numbness or tingling sensation in the limbs, visual disturbances (including double vision), tinnitus (sensation of noise in the ear), palpitations (feeling your own heartbeat), flushing, dizziness due to hypotension, cough, shortness of breath, nausea (feeling sick), vomiting (being unwell) , abdominal pain, taste changes, dyspepsia or difficulty in digestion, diarrhea, constipation, allergic reactions (such as rash, itching), muscle cramps, tired feeling, weakness, swollen ankles (edema).
Other side effects that have been reported are included in the following list. If any of these become serious or if you notice any side effects not listed in this leaflet, please contact your doctor or pharmacist.
- uncommon (occurring in less than 1 in 100 but more than 1 in 1000 patients): mood changes, anxiety, depression, lack of sleep, sleep disturbances, tremor, fainting, loss of pain sensation, rhinitis (stuffy or runny nose), altered bowel habits, hair loss, red spots on the skin, skin discoloration, back pain, muscle or joint pain, chest pain, urinary discomfort, increased need to urinate at night, need to urinate often , pain, malaise, bronchospasm (chest tightening, wheezing and shortness of breath), dry mouth, angioedema (symptoms such as wheezing, swelling of the face or tongue), kidney problems, impotence, increased sweating, discomfort or enlargement of the breasts in the men, weight gain or loss.
- rare (occurs in less than 1 in 1,000 patients but more than 1 in 10,000 patients): confusion.
- very rare (affects less than 1 in 10,000 patients): cardiovascular disorders (irregular heartbeat, angina, heart attack and stroke), eosinophilic pneumonia (rare type of pneumonia), swelling of the eyelids, face or lips, swelling of the tongue and throat which can cause severe difficulty in breathing, severe skin reactions including intense skin rash, hives, red skin all over the body, severe itching, blistering, peeling and swelling of the skin, inflammation of the mucous membranes (Stevens Johnson syndrome) , erythema multiforme (skin rash often presenting with itchy red papules located on the face, arms or legs), sensitivity to light, blood disorders, inflammation of the pancreas which can cause severe abdominal and back pain combined with feeling very unwell, abnormal liver function, inflammation of the liver (hepatitis), yellowing of the skin (jaundice), increased liver enzymes which can lead to changes in certain medical tests, abdominal swelling (gastritis), nerve disorder which can cause weakness, tingling or numbness, increased muscle tension, vasculitis (inflammation of the blood vessels), swelling of the gums, high levels of blood sugar (hyperglycemia).
- Patients taking Coverlam have also reported the following side effects: hypoglycaemia (low blood sugar levels), disorders related to stiffness, tremor and / or movement disorders.
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 out of the reach and sight of children.
Do not use Coverlam 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 from moisture. Store in the original package.
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.
What Coverlam contains
- The active ingredients are perindopril arginine and amlodipine.
Coverlam 5mg / 5mg: One tablet contains 5mg of perindopril arginine and 5mg of amlodipine.
Coverlam 10mg / 5mg: One tablet contains 10mg of perindopril arginine and 5mg of amlodipine.
Coverlam 5mg / 10mg: one tablet contains 5mg of perindopril arginine and 10mg of amlodipine.
Coverlam 10mg / 10mg: One tablet contains 10mg of perindopril arginine and 10mg of amlodipine.
- The other ingredients contained in the tablet are: lactose monohydrate, magnesium stearate (E470B), microcrystalline cellulose (E460), anhydrous colloidal silica (E551).
Description of the appearance of Coverlam and contents of the package
Coverlam 5mg / 5mg tablets are white, elongated in shape, with 5/5 imprinted on one face and logo on the other.
Coverlam 10mg / 5mg tablets are white in color, triangular in shape, with the indication 10/5 embossed on one face and the logo on the other.
Coverlam 5mg / 10mg tablets are white, square-shaped with the indication 5/10 embossed on one face and the logo on the other.
Coverlam 10mg / 10mg tablets are white in color, round in shape with 10/10 imprinted on one face and logo on the other.
The tablets are available in bottles of 5, 7, 10, 14, 20, 28, 30, 50, 56, 60, 90, 100, 120 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
COVERLAM TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 3.395 mg of perindopril equivalent to 5 mg of perindopril arginine and 6.935 mg of amlodipine besylate equivalent to 5 mg of amlodipine.
[One tablet contains 3.395 mg of perindopril equivalent to 5 mg of perindopril arginine and 13.870 mg of amlodipine besylate equivalent to 10 mg of amlodipine]
[One tablet contains 6.790 mg of perindopril equivalent to 10 mg of perindopril arginine and 6.935 mg of amlodipine besylate equivalent to 5 mg of amlodipine]
[One tablet contains 6.790 mg of perindopril equivalent to 10 mg of perindopril arginine and 13.870 mg of amlodipine besylate equivalent to 10 mg of amlodipine]
Excipient: lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
White, elongated tablet with 5/5 marked on one side.
[White, square shaped tablet with 5/10 marked on one side].
[White colored, triangular shaped tablet with 10/5 marked on one side].
[White, round tablet with 10/10 marked on one side].
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Coverlam is indicated as replacement therapy for the treatment of essential hypertension and / or stable coronary artery disease, in patients already controlled on the combination of perindopril and amlodipine, administered concurrently at the same dose level.
04.2 Posology and method of administration
Oral use.
One tablet a day as a single dose, to be taken preferably in the morning and in any case before a meal.
The fixed dose combination is not suitable for initial therapy.
If a change in dosage is required, the dose of Coverlam may be changed or an individual adjustment with a free combination may be considered.
Special populations
Patients with renal insufficiency and the elderly
Elimination of perindoprilat is reduced in the elderly and in patients with renal insufficiency. Therefore the usual medical follow-up will include frequent monitoring of creatinine and potassium.
Coverlam can be administered to patients with Clcr ≥ 60ml / min and is not suitable for patients with Clcr
Amlodipine used at similar dosages in elderly and young patients is equally well tolerated. Normally used dosages are recommended in elderly patients, but dose escalation should be considered with caution (see sections 4.4 and 5.2). Changes in plasma concentrations of amlodipine are not correlated with the degree of renal impairment. Amlodipine is not dialysable.
Patients with hepatic insufficiency
No specific dosages have been established for patients with mild to moderate hepatic impairment; therefore the choice of dosage should be made with caution and should start with the lowest dose (see sections 4.4 and 5.2). To identify the optimal starting dose and maintenance dose in patients with hepatic impairment, patients should be individually titrated using the free combination of amlodipine and perindopril. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. In patients with severe hepatic impairment, amlodipine treatment should be initiated at the lowest dose followed by gradual dose adjustment.
Pediatric population
Coverlam should not be administered to children and adolescents as the efficacy and tolerability of perindopril and amlodipine in combination have not been established in the latter.
04.3 Contraindications
Related to perindopril
• Hypersensitivity to perindopril or any other ACE inhibitor,
• History of angioedema associated with previous ACE inhibitor therapy,
• Hereditary or idiopathic angioedema,
• Second and third trimester of pregnancy (see sections 4.4 and 4.6),
• Concomitant use of Coverlam with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).
Related to amlodipine
- Hypersensitivity to dihydropyridine derivatives, to amlodipine and to any of the excipients
• Severe hypotension
• Shock (including cardiogenic shock)
• Left ventricular outflow obstruction (eg high grade aortic stenosis)
• Heart failure with haemodynamic instability after acute myocardial infarction.
Related to Coverlam
All contraindications relating to each component, as listed above, must also be applied to the fixed dose combination of Coverlam.
• Hypersensitivity to any of the excipients.
04.4 Special warnings and appropriate precautions for use
All warnings relating to each component, as listed below, must also be applied to the fixed dose combination of Coverlam.
Related to perindopril
Special warnings
Hypersensitivity / Angioedema
Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx has been rarely reported in patients treated with an angiotensin converting enzyme inhibitor, including perindopril (see section 4.8); this can occur at any time during therapy . In such cases, Coverlam treatment should be discontinued immediately and appropriate monitoring initiated and continued until symptoms have resolved completely. In cases where the edema was confined to the face and lips, the condition typically resolved without treatment, although antihistamines have been helpful in relieving symptoms.
Angioedema associated with laryngeal edema can be fatal. In the case of edema of the tongue, glottis or larynx, which can cause airway obstruction, emergency therapy should be instituted promptly. It may include the administration of adrenaline and / or the maintenance of a patent airway. The patient should be kept under close medical supervision until complete and sustained resolution of symptoms.
Patients with a history of angioedema unrelated to the intake of an ACE inhibitor may be at increased risk of developing angioedema during administration of an ACE inhibitor (see section 4.3).
Intestinal angioedema has been reported rarely in patients receiving ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases in the absence of a history of prior facial angioedema and C-1 esterase levels were normal. Angioedema was diagnosed via procedures that included abdominal CT scan or ultrasound or surgery and symptoms 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 (see section 4.8).
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, patients on ACE inhibitor therapy during low-density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid reactions during desensitization
Patients treated with ACE inhibitors undergoing desensitization treatment (e.g. hymenoptera venom) have reported anaphylactoid reactions. In the same patients, these reactions were avoided by temporarily withholding ACE inhibitor therapy, but reappeared upon accidental patient re-exposure.
Neutropenia / Agranulocytosis / Thrombocytopenia / Anemia
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be administered with extreme caution in patients with collagen vascular disease, on immunosuppressive therapy, on allopurinol or procainamide, or with a combination of these complicating factors, especially with impaired pre-existing renal function. Some of these patients developed severe infections which, in a few cases, did not respond to intensive antibiotic therapy. If perindopril is used in these patients, periodic checks of the white blood cell count are advised and these patients should be advised to report any signs of infection (e.g. sore throat, fever) immediately.
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).
Precautions for use
Hypotension
ACE inhibitors can cause a drop in blood pressure. Symptomatic hypotension is rarely observed in patients with uncomplicated hypertension and is more likely to occur in hypovolaemic patients, e.g. following diuretic treatment, a salt-reduced diet, dialysis, diarrhea or vomiting, or suffering from severe renin-dependent hypertension (see sections 4.5 and 4.8). In patients at high risk for symptomatic hypotension, blood pressure, renal function and serum potassium levels should be closely monitored during treatment with Coverlam.
Similar considerations apply to patients with ischemic heart disease or cerebrovascular disorders in whom an excessive drop in blood pressure can lead to myocardial infarction or to a cerebrovascular event.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg / ml (0.9%) solution. The occurrence of a transient hypotensive response is not an indication. a contraindication to the administration of further doses, which generally can occur without difficulty after an increase in blood pressure due to volume expansion.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
Like other ACE inhibitors, perindopril should be administered with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction such as aortic stenosis or hypertrophic cardiomyopathy.
Renal impairment
In cases of renal insufficiency (creatinine clearance individualized dose titration with monocomponents (see section 4.2).
In patients with renal insufficiency, regular monitoring of potassium and creatinine are part of current medical practice (see section 4.8).
In some patients with bilateral renal artery stenosis or artery stenosis of a solitary kidney treated with ACE inhibitors, an increase in blood urea and serum creatinine has been observed, usually reversible on discontinuation of treatment. This is especially likely in patients with renal insufficiency. The simultaneous presence of renovascular hypertension increases the risk of severe hypotension and renal insufficiency. Generally mild and transient increases in blood urea and serum creatinine have been observed in some hypertensive patients with no apparent previous renovascular disease, especially when perindopril was administered concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment.
Hepatic insufficiency
Rarely, ACE inhibitor treatment has 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 unknown. Patients treated with ACE inhibitors who experience jaundice or a significant increase in liver enzymes should discontinue the ACE inhibitor and be placed under appropriate medical supervision (see section 4.8).
Race
ACE inhibitors cause angioedema more frequently in black patients than in non-black patients.
Like other ACE 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 black hypertensive population.
Cough
Cough has been reported following administration of ACE inhibitors. This characteristic cough is dry, persistent and resolves upon discontinuation of treatment. ACE inhibitor-induced cough should be considered when making differentiated diagnoses of cough.
Surgery / anesthesia
In patients undergoing major surgery or undergoing anesthesia with agents that cause hypotension, Coverlam may block angiotensin II formation secondary to compensatory renin release. Treatment should be stopped one day before surgery. If hypotension occurs and is thought to be related to the above mechanism, it should be corrected by volume expansion.
Hyperkalemia
Increased plasma potassium concentrations have been reported in some patients treated with ACE inhibitors, including perindopril. Risk factors for the onset of hyperkalaemia include renal failure, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute heart failure, metabolic acidosis and concomitant use of potassium-sparing diuretics ( e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or salt substitutes containing potassium or patients taking other drugs associated with an increase in plasma potassium (e.g. heparin). The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes, particularly in patients with impaired renal function, may result in a significant increase in plasma potassium. Hyperkalaemia can lead to severe, sometimes fatal arrhythmias. . If concomitant use of perindopril and the above-mentioned drugs is deemed appropriate, they should be used with caution and with frequent monitoring of plasma potassium (see section 4.5).
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, blood glucose should be carefully monitored during the first month of therapy with an ACE inhibitor (see section 4.5).
Related to amlodipine
Precautions for use
The safety and efficacy of amlodipine during hypertensive crisis have not been evaluated.
Use in patients with heart failure
Patients with heart failure should be treated with caution.
In a long-term, placebo-controlled clinical study in patients with severe heart failure (NYHA class III and IV) amlodipine was associated with more cases of pulmonary edema than placebo (see section 5.1).Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Use in patients with hepatic insufficiency
The plasma half-life of amlodipine is prolonged and AUC values are higher in patients with impaired hepatic function; no specific dosages have been established for these patients. Amlodipine should therefore be initially taken at the lowest dose and used with caution both at the start of treatment and when increasing the dose. Gradual dosage adjustment and careful monitoring may be required in patients with severe hepatic impairment.
Use in elderly patients
In elderly patients, dose escalation should be considered with caution (see sections 4.2 and 5.2).
Use in patients with renal insufficiency
Amlodipine can be used at normal dosages in such patients. The degree of renal impairment is not related to changes in plasma concentrations of amlodipine. Amlodipine is not dialysable.
Related to Coverlam
All the warnings relating to each single component, listed above, must be considered applicable to the fixed association COVERLAM.
Precautions for use
Excipients
The product contains lactose; therefore patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome or the Lapp lactase deficiency should not take this medicinal product.
Interactions
The combination of Coverlam and lithium, potassium-sparing diuretics or potassium supplements, or dantrolene is not recommended (see section 4.5).
04.5 Interactions with other medicinal products and other forms of interaction
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).
Concomitant use not recommended
Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes
Although serum potassium usually remains within limits, hyperkalaemia may occur in some patients treated with perindopril. Potassium-sparing diuretics (eg spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may result in significant increases in serum potassium. Therefore, the combination of perindopril with these drugs is not recommended (see section 4.4). 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.
Lithium
Reversible increases in serum concentrations and in lithium toxicity (severe neurotoxicity) have been observed during concomitant administration of lithium and ACE inhibitors. The combination of perindopril and lithium is not recommended. If the combination proves necessary, careful monitoring of plasma lithium levels should be performed (see section 4.4).
Estramustine
Risk of increased adverse effects such as angioneurotic edema (angioedema).
Concomitant use requiring special attention
Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin ≥3 g per day
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-selective NSAIDs), attenuation of the antihypertensive effect may occur. ACE inhibitors and NSAIDs 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 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.
Antidiabetics (insulin, hypoglycemic sulfonamides)
Administration of angiotensin converting enzyme inhibitors (ACE inhibitors) may induce a hypoglycemic effect in diabetic patients receiving hypoglycemic insulin or sulfonamides. The occurrence of hypoglycaemic episodes is very rare (there is probably an improvement in glucose tolerance with a resulting reduction in insulin requirements).
Concomitant use to be kept under surveillance
Diuretics
Patients treated with diuretics, and especially those with volume and / or salt depletion, may experience an excessive reduction in blood pressure after the initiation of therapy with ACE inhibitors. The occurrence of hypotensive effects can be reduced by discontinuing the diuretic. expanding blood volume or increasing salt intake before starting perindopril therapy, at low and progressive doses.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Gold
Nitritoid reactions have been reported rarely in patients receiving injectable gold salts (sodium aurothiomalate) and concomitant therapy with ACE inhibitors, including perindopril (symptoms include facial hyperaemia, nausea, vomiting and hypotension).
Related to amlodipine
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors: Concomitant use of amlodipine with potent or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may cause a significant increase in amlodipine exposure. Clinical significance. of these pharmacokinetic changes may be more pronounced in the elderly, therefore clinical monitoring and dosage adjustment may be required.
CYP3A4 inducers: There are no data available regarding the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (eg rifampicin, Hypericum perforatum) may decrease plasma concentrations of amlodipine. Amlodipine should be used with caution when co-administered with CYP3A4 inducers.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as the bioavailability of amlodipine may increase and consequently potentiate the antihypertensive effect of amlodipine in some patients.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse associated with hyperkalaemia have been observed following intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalaemia, it is recommended to avoid concomitant administration of calcium channel blockers such as amlodipine in patients prone to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effects of amlodipine on other medicinal products
The effects of amlodipine on the decrease in blood pressure add to the effects of the decrease in pressure exerted by other antihypertensive agents.
In clinical interaction studies, amlodipine did not alter the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporine.
Related to Coverlam
Concomitant use requiring special attention
Baclofen. Potentiation of the antihypertensive effect. Control of blood pressure and renal function and adjustment of the antihypertensive dosage if necessary.
Concomitant use to be kept under surveillance
• Antihypertensive agents (such as beta-blockers) and vasodilators:
concomitant use of these agents may increase the hypotensive effects of perindopril and amlodipine. Concomitant use of nitroglycerin and other nitrates or vasodilators may further reduce blood pressure and should therefore be considered with caution.
• Corticosteroids, tetracosactide: reduction of the antihypertensive effect (retention of water and salt by corticosteroids).
• Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increased antihypertensive effect and increased risk of orthostatic hypotension.
• Amifostine: may potentiate the antihypertensive effect of amlodipine.
• Tricyclic antidepressants / antipsychotics / anesthetics: increased antihypertensive effect and increased risk of orthostatic hypotension.
04.6 Pregnancy and lactation
Given the effects of the individual components of this combination on pregnancy and lactation COVERLAM is not recommended during the first trimester of pregnancy. COVERLAM is contraindicated during the second and third trimester of pregnancy.
COVERLAM is not recommended during breastfeeding. A decision must therefore be made whether to discontinue breastfeeding or to discontinue COVERLAM considering the importance of this therapy to the mother.
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 regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. 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. 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 trimesters is known to induce foetotoxicity (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 closely monitored for hypotension (see sections 4.3 and 4.4).
Related to amlodipine
The safety of amlodipine during pregnancy has not been established.
In animal studies, reproductive toxicity effects were observed following administration of high doses (see section 5.3).
Use in pregnancy is only recommended if there is no safer alternative and when the disorder carries major risks for the mother and fetus.
Feeding time
Related to perindopril
Since no data are available regarding the use of perindopril during lactation, perindopril is not recommended and alternative treatments with a proven safety profile for use during lactation are preferred, especially when nursing a newborn or preterm infant.
Related to amlodipine
It is not known whether amlodipine is excreted in human milk. The decision to continue / discontinue breastfeeding or to continue / discontinue amlodipine therapy must be considered taking into account the benefits of breastfeeding for the infant and the benefits of therapy with amlodipine for the mother.
Fertility
Reversible biochemical changes in the head of spermatozoa have been reported in patients treated with calcium channel blockers. There are insufficient clinical data on the potential effect of amlodipine on fertility. In a rat study, undesirable effects on male fertility were reported (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects of Coverlam on the ability to drive and use machines have been performed. Amlodipine has mild or moderate effects on the ability to drive or use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue, or nausea, their ability to react may be impaired. Caution is recommended especially at the start of treatment.
04.8 Undesirable effects
During treatment with perindopril or amlodipine administered separately, the following undesirable effects have been reported, which have been classified according to the MedDRA system organ class, according to the following frequency:
very common (≥1 / 10); common (≥1 / 100,
Additional information related to amlodipine
Exceptional cases of extrapyramidal syndrome have been reported.
04.9 Overdose
There is no information on Coverlam overdose in humans.
For amlodipine, human experience with intentional overdose is limited.
Symptoms
available data suggest that strong peripheral vasodilation and possible reflex tachycardia may occur following overdose. Marked and possibly prolonged systemic hypotension has been reported up to and including cases of shock with a fatal outcome.
Treatment
Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of the lower limbs, and attention to circulating fluid volume and diuresis.
For the restoration of vascular tone and arterial pressure, a vasoconstrictor can be of help if there are no contraindications for its use. Intravenous administration of calcium gluconate may prove useful in neutralizing the effects of calcium channel blocking.
Gastric lavage can be helpful in some cases. Administration of charcoal to healthy volunteers, either immediately or within two hours of taking 10 mg amlodipine, has been shown to significantly reduce the absorption of amlodipine.
Since amlodipine is largely protein bound, dialysis is unlikely to be useful.
For perindopril, limited clinical data are available regarding overdose in humans. Symptoms associated with ACE inhibitor overdose may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety. and cough.
In the event of an overdose, treatment with an "intravenous infusion of saline is recommended. If hypotension occurs, the patient should be positioned as in shock. If available, treatment with an" infusion of angiotensin may also be considered. II and / or of catecholamines. Perindopril can be removed from the systemic circulation by hemodialysis (see section 4.4). The use of a pacemaker is indicated in the case of therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, ATC code: C09BB04.
Perindopril
Perindopril is an angiotensin I to angiotensin II converting enzyme inhibitor (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that enables the conversion of angiotensin I to the vasoconstrictor agent angiotensin II, and the degradation of the vasodilating agent bradykinin into an inactive heptapeptide. Inhibition of ACE causes a reduction of angiotensin II in plasma, which leads to an increase in plasma renin activity (by inhibition of the negative feedback mechanism of renin release) and a reduced secretion of aldosterone. inactivates bradykinin, the inhibition of ACE also determines an increase in the activity of the kallikrein-kinin system at the circulatory and local level (and therefore also an "activation of the prostaglandin system). It is possible that this mechanism contributes to the reduction of blood pressure by ACE inhibitors and that it is partially responsible for certain side effects (eg cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites do not show in vitro inhibition of ACE activity.
Hypertension
Perindopril is active at all stages of hypertension: mild, moderate, severe; a reduction in systolic and diastolic blood pressure in supine and standing position has been observed.
Perindopril reduces peripheral vascular resistance causing a reduction in blood pressure. As a result, there is an increase in peripheral blood flow, with no effect on heart rate.
Renal blood flow usually increases, while glomerular filtration rate (GFR) generally remains unchanged.
The antihypertensive activity is maximum between 4 and 6 hours after single administration and the antihypertensive efficacy is maintained for at least 24 hours the minimum effects are between 87 and 100% of the maximum effects.
The reduction in blood pressure occurs rapidly. In responding patients, blood pressure normalization is reached after one month of treatment and is maintained without the occurrence of tachyphylaxis.
The stopping of the treatment is not accompanied by rebound phenomena (rebound).
Perindopril reduces left ventricular hypertrophy.
In humans, perindopril has been confirmed to possess vasodilating properties. It improves the elasticity of large arterial trunks and reduces the media / lumen ratio of small arteries.
Patients with stable coronary artery disease
The EUROPA study is a 4-year, multi-center, international, randomized, double-blind, placebo-controlled clinical trial.
Twelve thousand two hundred and eighteen patients over 18 years of age were randomized to receive 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n = 6110) or placebo (n = 6108).
The study population had coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of patients had a previous myocardial infarction and / or a previous coronary revascularization. Most patients were taking study drug in addition to conventional therapy which included antiplatelet, lipid-lowering and beta-blockers.
The main efficacy criterion was the combination of cardiovascular mortality, non-fatal myocardial infarction and / or cardiac arrest with successful resuscitation. Treatment with 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) once daily demonstrated a significant absolute reduction of the primary endpoint of 1.9% (relative risk reduction of 20%, 95% Cl [9.4; 28.6] - p
In patients with a history of myocardial infarction and / or revascularisation, an absolute reduction of the primary endpoint relative to placebo of 2.2% was observed, corresponding to an RRR of 22.4% (95% CI [12.0; 31 , 6] - p
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.
Amlodipine
Amlodipine is an inhibitor of the calcium ion flux of the dihydropyridine group (calcium ion antagonist) and inhibits the transmembrane flux of calcium ions to the heart and smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not yet been fully determined but amlodipine reduces the total ischemic load based on the following two mechanisms of action:
• Amlodipine dilates peripheral arterioles, thereby reducing the total peripheral resistance (afterload) against which the heart works. Since heart rate remains stable, this reduction in cardiac afterload reduces myocardial energy consumption and demands of oxygen.
• The mechanism of action of amlodipine probably also involves dilation of the main coronary arteries and coronary arterioles, both in the normally oxygenated and in the ischemic regions. This dilation increases the oxygen supply to the myocardium in patients with coronary artery spasm (Prinzmetal's or variant angina).
In hypertensive patients, once daily dosing results in clinically significant reductions in both supine and standing blood pressure over 24 hours. Due to the slow onset of action, acute hypotension is not a feature of administration of amlodipine.
In patients with angina, daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment elevation, and reduces both angina attack frequency and consumption. of nitroglycerin tablets.
Amlodipine has not been associated with adverse metabolic events or changes in plasma lipid levels, and is suitable for use in patients with asthma, diabetes and gout.
Use in patients with coronary artery disease (CAD)
The efficacy of amlodipine in the prevention of clinical events in patients with coronary artery disease (CAD) was evaluated in an independent, multicenter, randomized, double-blind, placebo-controlled clinical study in 1997 patients: the CAMELOT study (Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis - Comparison between amlodipine and enalapril in reducing thrombotic events). Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard treatment with statins, beta-blockers, diuretics and aspirin. , for 2 years. The main efficacy results are shown in Table 1. These results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with coronary artery disease.
Use in patients with heart failure
Hemodynamic studies and controlled clinical trials on exercise tolerance in patients with NYHA class II - IV heart failure have shown that amlodipine does not aggravate their clinical condition with regard to exercise tolerance, left ventricular ejection fraction and clinical symptoms.
A placebo-controlled clinical trial (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure treated with digoxin, diuretics and ACE inhibitors, demonstrated that amlodipine does not increase the risk of mortality or the risk of mortality and morbidity. , considered jointly, in patients with heart failure.
In a long-term, placebo-controlled follow-up study (PRAISE 2) conducted in patients with NYHA class III and IV heart failure, treated with amlodipine, without clinical symptoms or objective findings suggesting the presence of ischemic disease, in fixed dose therapy with ACE inhibitors, digitalis and diuretics, the use of amlodipine had no effect on overall cardiovascular mortality. In the same population, amlodipine was associated with an increase in pulmonary edema.
Heart Attack Prevention Treatment Clinical Study (ALLHAT)
The double-blind randomized mortality study, ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was conducted in order to compare the most innovative pharmacological therapies: amlodipine 2.5-10 mg / d (calcium channel blocker) or lisinopril 10-40 mg / d (ACE inhibitor) as first-line therapies compared to those of thiazide diuretic, chlorthalidone 12.5-25 mg / d in mild to moderate hypertension.
A total of 33,357 hypertensive patients over 55 years of age were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for coronary heart disease (CHD), including: previous myocardial infarction or stroke> 6 months prior to enrollment or documentation of other atherosclerotic cardiovascular disease (CVD) (overall 51.5%), type 2 diabetes (36.1%), HDL-C left ventricular hypertrophy diagnosed with EKG or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was the combination of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and
chlorthalidone therapy: RR 0.98 (95% CI (0.90-1.07) p = 0.65). Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group than in the chlorthalidone group (10.2% vs 7.7%, RR 1.38 , (95% CI [1.25-1.52] p
05.2 Pharmacokinetic properties
The rate and extent of absorption of Coverlam's perindopril and amlodipine are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine from single tablet formulations.
Perindopril
After oral administration, the absorption of perindopril is rapid and the maximum concentration is reached within 1 hour. The plasma half-life of perindopril is 1 hour.
Perindopril is a prodrug. 27% of the administered dose of perindopril reaches the bloodstream as its active metabolite, perindoprilat. In addition to the active perindoprilat, perindopril produces five metabolites, all of which are inactive. The peak plasma concentration of perindoprilat is reached within 3-4 hours.
Since food intake reduces conversion to perindoprilat, and hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning, before a meal.
A linear relationship between the perindopril dose and its plasma concentration has been demonstrated.
The volume of distribution is approximately 0.2 l / kg for free perindoprilat. 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 being reached within 4 days.
Elimination of perindoprilat is reduced in the elderly, as well as in patients with heart or renal insufficiency (see section 4.2). Therefore the usual medical follow-up will include frequent monitoring of creatinine and potassium.
The dialysis clearance of perindoprilat is 70 ml / min.
In the cirrhotic patient, the kinetics of perindopril are modified: 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).
Amlodipine
Absorption, distribution, binding to plasma proteins: After oral administration of therapeutic doses, amlodipine is absorbed gradually with peak plasma levels within 6-12 hours after dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 L / kg. Studies in vitro showed that amlodipine is approximately 97.5% bound to plasma proteins.
Food intake does not alter the bioavailability of amlodipine.
Biotransformation / elimination
The terminal plasma elimination half-life is approximately 35-50 hours, which justifies once-daily administration. Amlodipine is extensively metabolised by the liver to inactive compounds and 10% is eliminated in the urine as the base molecule and 60% in the metabolised form. .
Use in hepatic insufficiency
Very limited clinical data are available regarding the administration of amlodipine in patients with hepatic insufficiency. Patients with hepatic insufficiency have a lower clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
Use in the elderly
The time to reach peak plasma concentrations of amlodipine in elderly and younger subjects is similar.In elderly patients the clearance of amlodipine tends to decrease causing increases in the AUC and elimination half-life of the drug. Increases in AUC and elimination half-life comparable to those predicted for this patient population were observed in heart failure patients.
05.3 Preclinical safety data
Perindopril
In chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
No mutagenesis was observed in the studies performed in vitro or in vivo.
In reproductive toxicity studies (rats, mice, rabbits and monkeys) no signs of embryotoxicity or teratogenesis were shown. However, the class of angiotensin converting enzyme inhibitors has been shown to cause undesirable effects on late fetal development leading to fetal death and birth defects in rodents and rabbits: kidney injury and increased peri- and postnatal mortality.
Carcinogenesis was not observed in long-term studies in rats and mice.
Amlodipine
Reproductive toxicology
Reproduction studies in rats and mice have shown delayed parturition, prolonged labor and reduced neonatal survival at doses approximately 50 times the maximum recommended human dose based on the mg / kg ratio.
Reduction of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females for 14 days before mating) at doses up to 10 mg / kg / day (equivalent to 8 times the maximum dose of 10 mg on a recommended mg / m2 basis in humans *). Another study conducted in male rats treated with amlodipine besylate for 30 days at a dose comparable to that administered to humans (mg / kg), showed a decrease in testosterone and follicle-stimulating hormones in plasma, as well as decreases in density. sperm and the number of mature sperm cells and Sertoli cells.
Carcinogenesis, mutagenesis
Rats and mice treated for two years with dietary amlodipine, at concentrations calculated to provide daily levels of 0.5, 1.25 and 2.5 mg / kg / day, showed no evidence of carcinogenicity. The highest dose (for rats equal to twice the maximum clinical dose of 10 mg on a mg / m2 basis recommended in humans * and for mice similar to this maximum recommended dose) was close to the maximum tolerated dose by mice but not from rats.
Mutagenicity studies did not reveal any drug-related effects on either the genetic or chromosomal level.
* Calculated on a patient weighing 50 kg
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Microcrystalline cellulose (E460)
Colloidal anhydrous silica (E551)
Magnesium stearate (E470B)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Keep the container tightly closed to protect it from humidity.
Store in the original packaging.
06.5 Nature of the immediate packaging and contents of the package
5, 7, 10, 14, 20, 28, 30 or 50 tablets in a polypropylene container equipped with a flow reducer and a low density polyethylene cap containing a white desiccant gel.
Box of 1 container of 5, 7, 10, 14, 20, 28, 30 or 50 tablets.
Box of 2 containers of 28, 30 or 50 tablets.
Box of 3 containers of 30 tablets.
Box of 4 containers of 30 tablets.
Box of 10 containers of 50 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
LES LABORATOIRES SERVIER
50, rue Carnot
92284 Suresnes cedex (France)
08.0 MARKETING AUTHORIZATION NUMBER
AIC n.038477079 / M - 5 mg / 5 mg tablets 1 pp container of 30 tablets
AIC n.038477218 / M - 5 mg / 10 mg tablets 1 pp container of 30 tablets
AIC n.038477358 / M - 10 mg / 5 mg tablets 1 pp container of 30 tablets
AIC n.038477497 / M - 10 mg / 10 mg tablets 1 pp container of 30 tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
29 December 2010
10.0 DATE OF REVISION OF THE TEXT
07/2015
