Active ingredients: Chlorthalidone, Metoprolol (Metoprolol tartrate)
GROTON-LOPRESOR 25 mg + 200 mg prolonged-release tablets
Why is Igroton Lopresor used? What is it for?
Igroton-Lopresor contains two active ingredients: chlorthalidone and metoprolol tartrate.
Chlorthalidone belongs to a group of medicines that work by increasing the amount of urine produced by the kidneys called diuretics.
Metoprolol tartrate belongs to a group of medicines that work by slowing the heart beat and lowering blood pressure called beta-blockers.
Igroton-Lopresor is used in adults to treat high blood pressure (arterial hypertension).
Talk to your doctor if you don't feel better or if you feel worse.
Contraindications When Igroton Lopresor should not be used
Do not take Igroton-Lopresor
- if you are allergic to chlorthalidone or metoprolol tartrate or any of the other ingredients of this medicine
- if you are allergic to other medicines belonging to the beta-blocker class other than metoprolol)
- if you suffer from blockage of the electrical conduction of the heart (atrioventricular block)
- if you have uncompensated heart failure, severe heart disease
- if you suffer from reduced number of heart beats (sinus bradycardia)
- if you have a heart disease called "sinus knot syndrome" (characterized by heart rhythm disturbances)
- if you suffer from severe blood circulation disorders (peripheral arterial circulation)
- if you suffer from low blood pressure with severe reduction in heart function (cardiogenic shock)
- if you have untreated cancer of the adrenal gland, a gland located above the kidney which can cause high blood pressure (untreated pheochromocytoma)
- if you suffer from low blood pressure
- if you have severe bronchial asthma or have a history of severe narrowing of the bronchi which makes breathing difficult
- if you suffer from cessation or reduction of urine production by the kidney (anuria)
- if you have severe kidney problems (kidney failure)
- if you have severe liver disease (severe liver failure)
- if you suffer from low levels of potassium in the blood (hypokalaemia)
- if you suffer from low levels of sodium in the blood (hyponatremia)
- if you suffer from high levels of calcium in the blood (hypercalcaemia)
- if you have high levels of uric acid in your blood (symptomatic hyperuricaemia) and have suffered from gout or uric acid stones in the past - if you are pregnant.
Precautions for use What you need to know before taking Igroton Lopresor
Talk to your doctor or pharmacist before taking Igroton-Lopresor.
Tell your doctor if you have any of the following conditions:
- respiratory diseases (bronchospastic diseases)
- high blood sugar levels (diabetes), especially if you are being treated with insulin or medicines by mouth that lower blood sugar levels (see section "Other medicines and Igroton-Lopresor")
- untreated congestive heart failure, a disease of the heart
- disturbances in the electrical conduction of the heart (first degree atrioventricular block)
- circulation disorders in the arms and legs (e.g. Raynaud's disease or phenomenon, intermittent claudication)
- if you have a known or suspected tumor of the adrenal gland, a gland located above the kidney which can cause a rise in blood pressure (pheochromocytoma), Igroton-Lopresor should always be given at the same time as an alpha blocker and only after treatment with the alphabet blocker has been started (see "Do not take Igroton-Lopresor")
- a type of angina (chest pain) called Prinzmetal's angina
- an increase in the function of a gland called the thyroid gland (thyrotoxicosis)
- if you suffer from allergy and take beta-blockers, the allergic reactions may be more severe than normal
- liver problems, including liver cirrhosis. Minor changes in the amount of fluid and electrolytes in the blood, caused by diuretics such as chlorthalidone, can aggravate the liver disease up to hepatic coma, especially if you have liver cirrhosis. Your doctor will monitor your fluid and electrolyte levels with appropriate tests
- kidney problems (kidney failure), as you may have increased amounts of nitrogen in your blood.
Eye problems
If you experience eye or skin side effects (dry eyes and / or occasionally skin rashes under the eye) during treatment with Igroton-Lopresor, consult your doctor immediately who may decide to stop treatment. (See section "Possible side effects").
Hypokalaemia (low blood potassium levels)
In case of long-term treatment with Igroton-Lopresor you may have a reduction in the levels of potassium in the blood (hypokalaemia). This side effect varies from person to person and depends on the dose of IgrotonLopresor you take. In this case your doctor will check the amount of potassium in your blood at the start of therapy and after 3-4 weeks thereafter. Thereafter, if the potassium quantities are not affected by other factors (eg vomiting, diarrhea, changes in kidney function), the doctor's checks will be carried out every 4-6 months. If necessary, your doctor may prescribe you with Igroton-Lopresor oral treatment with potassium or potassium-sparing medicines such as triamterene, which increase the levels of potassium in the blood. In this case tell your doctor if you are taking other medicines to lower blood pressure (ACE inhibitors), because in this case the doctor will have to reduce the dose of IgrotonLopresor or stop it for 2-3 days and / or start therapy with ACE inhibitors. with a low dose (see "Other medicines and Igroton-Lopresor"). If the "hypokalaemia is accompanied by other effects such as muscle weakness, heart disturbance or changes in the rhythm of the heartbeat, the doctor will stop the treatment with Igroton-Lopresor (see section" Possible side effects "
Senior citizens
If you are elderly, use this medicine with caution. In fact, an excessive reduction in blood pressure or heart rate can lead to an inadequate blood supply to vital organs.
Also, if you are elderly, your doctor will monitor your fluid and electrolyte levels with appropriate tests.
For those who carry out sporting activities
For those who carry out sporting activities, the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Children and adolescents
The efficacy and safety in children and adolescents below 18 years of age have not been established, therefore Igroton-Lopresor is not recommended in this population (0-18 years).
Interactions Which drugs or foods can modify the effect of Igroton Lopresor
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines
Interactions with drugs whose concomitant use must be carefully monitored
- medicines to treat certain heart disorders belonging to the class of calcium channel blockers (given into a vein) such as verapamil and diltiazem. This combination may potentiate the depressant effects of Lopresor on the heart and blood pressure
Interactions to be considered
- medicines that lower blood pressure, including: o medicines that lower the levels of catecholamines in the blood (substances produced by the body that work to control your heart rate) o other beta-blockers (also in the form of eye drops) or inhibitors monoamine oxidase (MAO) medicines used to treat depression or clonidine
- medicines to reduce blood sugar levels (antidiabetics and insulin)
- medicines to treat inflammation and pain (non-steroidal anti-inflammatory drugs), for example indomethacin
- medicines to treat certain heart disorders belonging to the class of digitalis glycosides.
- prazosin
- nitroglycerin, a medicine used to treat angina
- medicines to treat heart rhythm abnormalities (antiarrhythmics such as amiodarone, propafenone)
- medicines used to treat certain breathing problems (such as asthma and cough) or to clear the nose (nasal drops) or to treat certain eye disorders (eye drops) for example adrenaline
- rifampicin, an antibiotic
- cimetidine and carbenoxolone, medicines used to treat stomach ulcers
- medicines to induce anesthesia during surgery (general and local anesthetics such as lidocaine). If you are going to undergo surgery that requires general anesthesia, tell the anesthetist (the doctor who performs the anesthesia) that you are taking Igroton-Lopresor. Your anesthetist will choose the most suitable anesthetic for you in order to reduce any unwanted heart effects during anesthesia. Your doctor may decide to stop treatment with Igroton-Lopresor before surgery; in this case the suspension is gradual and is completed about 48 hours before the general anesthesia
- lithium, a medicine used to treat depression
- curaries, medicines used to relax muscles
- corticosteroids, medicines used to treat inflammation and / or allergies
- a hormone called "adrenocorticotropic hormone (ACTH)"
- ß2-agonists, medicines to treat respiratory diseases such as asthma
- amphotericin, a medicine to treat fungal infections
- allopurinol, a medicine used to treat gout, a joint disease
- amantadine, a medicine used in influenza
- diazoxide, a medicine used to treat blood sugar levels that are too low
- medicines to treat some cancers e.g. cyclophosphamide, methotrexate
- medicines such as atropine and biperidene, substances that act on the nervous system
- medicines to treat high blood cholesterol levels such as cholestyramine
- vitamin D
- calcium salts
- cyclosporine, a medicine that reduces the activity of the immune system, for example after an organ transplant
Igroton-Lopresor with alcohol
The use of alcohol during treatment is not recommended.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
Do not take Igroton-Lopresor during pregnancy (see section "Do not take Igroton-Lopresor").
The use of diuretics, including chlorthalidone, in pregnancy has been associated with side effects occurring in adults and children.
Both chlorthalidone and metoprolol can cause reduced blood supply to the placenta (placental hypoperfusion). Thiazide diuretics, including chlorthalidone, cross the placental barrier and have been associated with fetal or neonatal thrombocytopenia and may be associated with other effects. side effects occurring in adults Therefore, Igroton-Lopresor should not be used during pregnancy.
Feeding time
If you are breast-feeding, talk to your doctor or pharmacist before starting treatment with this medicine
Igroton-Lopresor passes into breast milk, so your doctor will decide whether to stop using this medicine or to start formula feeding / weaning.
Driving and using machines
Dizziness, fatigue or visual disturbances may occur while taking Igroton-Lopresor, especially at the start of treatment. If this happens, do not drive or use any tools or machinery.
Igroton-Lopresor contains hydrogenated polyhydric castor oil
It can cause stomach upset and diarrhea.
Dose, Method and Time of Administration How to use Igroton Lopresor: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
LIKE
Always take the tablets with a glass of water and do not chew them. The tablet can be divided into equal doses.
HOW MUCH
The recommended dose is 1 tablet a day, early in the morning. If necessary, your doctor will prescribe other medicines that lower blood pressure (for example a vasodilator or ACE inhibitor) together with Igroton-Lopresor.
Generally, your doctor will not increase the dose of this medicine as increasing the dose does not give better results and is not recommended.
Use in children and adolescents
The use of this medicine is not recommended in children and adolescents under 18 years of age
Overdose What to do if you have taken an overdose of Igroton Lopresor
If you take too much of this medicine, tell your doctor or go to a hospital straight away.
While waiting for the doctor, it may be helpful to induce vomiting and / or take activated charcoal to remove the medicine from the stomach and intestines and to lift the legs.
An overdose of this medicine can cause the following symptoms:
- excessive decrease in blood pressure (hypotension)
- reduced number of heart beats (sinus bradycardia)
- difficulty of the heart in pumping blood to the body due to an alteration in the electrical conduction system of the heart (atrioventricular block)
- severe heart disease (heart failure)
- decrease in blood pressure with severe reduction in heart function (cardiogenic shock)
- cardiac arrest
- disturbances in the rhythm of the heartbeat (cardiac arrhythmia)
- muscle spasms
- narrowing of the bronchi and difficulty in breathing (bronchospasm)
- deterioration of consciousness (or even coma)
- convulsions
- feeling of weakness
- dizziness
- drowsiness
- reduced blood flow (hypovolaemia)
- nausea
- He retched
- bluish discoloration of the body (cyanosis).
Taking alcohol, medicines to lower blood pressure, quinidine (medicine to treat heart rhythm disturbances), or barbiturates (medicines to treat epilepsy) at the same time aggravates the signs and symptoms. The first manifestations of excessive drug intake occur 20 minutes to 2 hours after administration of the drug. The effects can also persist for several days.
If you forget to take Igroton-Lopresor
If you forget to take a tablet, do not take a double dose to make up for a forgotten tablet.
If you stop taking Igroton-Lopresor
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Abrupt discontinuation of treatment
Do not stop treatment with Igroton-Lopresor abruptly, especially if you have diseases due to a reduced oxygen supply to the heart (ischemic), such as angina pectoris (chest pain). To prevent angina pectoris from getting worse, your doctor will reduce your dose gradually over a period of 1 to 3 weeks and, if necessary, prescribe replacement therapy for you.
Your doctor will keep you under close surveillance while you are stopping treatment.
Side Effects What are the side effects of Igroton Lopresor
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience the following side effects during treatment with Igroton-Lopresor, please contact your doctor who may STOP treatment with this medicine:
- dry eyes and / or occasionally skin rashes under the eye
- low blood potassium levels accompanied by other effects such as muscle weakness, heart disease or changes in the rhythm of the heart.
In addition, you may experience the following side effects:
Very common (may affect more than 1 in 10 people)
- reduction in blood potassium levels (hypokalaemia), especially at higher doses
- increased levels of uric acid in the blood (hyperuricaemia)
- increase in blood lipids (cholesterol, triglycerides).
Common (may affect up to 1 in 10 people)
- fatigue
- dizziness
- headache
- slow heart rate (bradycardia)
- low blood pressure when moving from sitting to standing (orthostatic hypotension occasionally with syncope), which may be aggravated by alcohol, anesthetics or sedatives
- nausea
- He retched
- pain in the abdomen
- difficulty in breathing following physical exertion (exertional dyspnea)
- decreased levels of sodium in the blood (hyponatremia)
- decreased levels of magnesium in the blood (hypomagnesaemia)
- increased blood sugar levels (hyperglycaemia)
- weight loss and appetite (anorexia)
- small sufferings in the stomach and intestines
- hives and other forms of skin irritation
- erectile dysfunction.
Rare (may affect up to 1 in 1000 people)
- tingling in the arms and legs (paraesthesia)
- muscle cramps
- heart disease (heart failure)
- changes in the rhythm of the heart
- swelling (edema)
- perception of heartbeat (palpitations)
- pain in the fingers and toes that turn first whitish then bluish and finally reddish (Raynaud's phenomenon)
- depression
- reduced level of consciousness
- sleepiness or insomnia
- nightmares
- diarrhea
- constipation
- skin rashes (in the form of skin lesions, hives)
- bronchospasm (even if you have not suffered from obstructive lung disease in the past)
- increased calcium levels in the blood (hypercalcemia)
- presence of sugar in the urine (glycosuria)
- aggravation of diabetes
- joint disease from uric acid buildup (gout)
- stomach pain
- blocking the flow of bile from the liver to the intestine (intrahepatic cholestasis)
- yellowing of the skin and whites of the eyes (jaundice)
- cardiac arrhythmias
- sensitivity to sunlight (photosensitization)
- visual disturbances
- reduction in the number of platelets in the blood (thrombocytopenia)
- reduction in the number of white blood cells in the blood (leukopenia, agranulocytosis and eosinophilia).
Very Rare (may affect up to 1 in 10,000 people)
- disturbances in the electrical conduction of the heart
- chest pain
- gangrene (bluish or greenish skin on the hands or feet) if you have severe peripheral circulatory disorders
- personality disorders
- hallucinations
- dryness of the mucous membrane of the mouth
- abnormalities in liver function tests
- severe liver disease (hepatitis)
- light sensitivity reactions (photosensitivity)
- increased sweating
- hair loss
- worsening of psoriasis (skin disease)
- irritation and inflammation of the lining of the nose (rhinitis)
- sexual desire disorders
- Peyronie's disease (penile disease)
- reduced vision
- dryness and / or irritation of the eye
- ringing in the ears (tinnitus)
- hearing disturbances in case of exceeding the recommended doses
- weight gain
- joint inflammation (arthritis)
- retroperitoneal fibrosis (inflammation of the abdomen)
- lack / loss of chlorine in the blood (hypochloraemic alkalosis)
- inflammation of the pancreas (pancreatitis)
- respiratory disorders (idiosyncratic pulmonary edema)
- inflammation of the kidneys of allergic origin (allergic interstitial nephritis)
- inflammation of blood vessels (vasculitis).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not store above 25 ° C. Store in the original container to protect from moisture.
Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.
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 Igroton-Lopresor contains
Each prolonged-release tablet contains:
- The active ingredients are metoprolol tartrate 200 mg and chlorthalidone 25 mg.
- The other ingredients are: anhydrous colloidal silica; microcrystalline cellulose; dibasic calcium phosphate dihydrate; polyacrylate dispersion 30%; magnesium stearate; hypromellose; glyceryl palmitate stearate; red iron oxide; sodium starch carboxymethyl A; hydrogenated polyhydric castor oil (see paragraph "Igroton-Lopresor contains hydrogenated polyhydric castor oil"); talc; titanium dioxide.
What Igroton-Lopresor looks like and contents of the pack
Igroton-Lopresor is presented in red colored prolonged-release tablets for oral use, with a score line on both sides, and packaged in calendar blisters of 28 tablets.
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
IGROTON-LOPRESOR 25 MG + 200 MG EXTENDED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains:
Active ingredients: chlorthalidone 25 mg; metoprolol tartrate 200 mg.
For excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Prolonged-release film-coated, scored tablets
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Hypertension.
04.2 Posology and method of administration
The tablets should not be chewed.
They can be divided in half and allow a dosage adjustment to the individual needs of the patient.
The normal dose is 1 tablet a day, early in the morning. If necessary, another antihypertensive drug, for example a vasodilator or an ACE inhibitor, can be combined.
Generally, an increase in the dosage does not give better results and is not recommended.
The safety and efficacy of Igroton-Lopresor in children have not been established.
04.3 Contraindications
Hypersensitivity to the active substances, to related derivatives (including beta blockers other than metoprolol), or to any of the excipients.
Metoprolol
Second or third degree atrioventricular block uncompensated heart failure; clinically relevant sinus bradycardia (heart rate less than 45-50 beats / minute); sick sinus syndrome; severe disturbances of the peripheral arterial circulation; cardiogenic shock; untreated pheochromocytoma (see section 4.4); hypotension; severe bronchial asthma or a history of severe bronchospasm.
Chlorthalidone
Anuria; renal insufficiency with creatinine clearance less than 30 ml / min; severe liver failure; refractory hypokalaemia or conditions causing increased potassium loss; hyponatremia; hypercalcaemia; symptomatic hyperuricaemia (history of gout or uric acid stones); pregnancy.
04.4 Special warnings and appropriate precautions for use
Igroton-Lopresor should be used with caution in patients with diabetes mellitus. Chlorthalidone can adversely affect glucose tolerance, although diabetes mellitus occurs very rarely during chlorthalidone treatment.
Beta-blockers may alter the effects of insulin and oral hypoglycemic agents (see section 4.5). Diabetic patients should be advised that beta-blockers may mask tachycardia from hypoglycemia; however, other manifestations of hypoglycemia, such as dizziness and sweating, they may not be eliminated significantly and sweating may be increased.
Igroton-Lopresor should also be used with caution in patients with impaired liver function or progressive liver disease. Minor changes in fluid and electrolyte balance caused by thiazide diuretics can precipitate hepatic coma, especially in patients with liver cirrhosis.
In addition, metoprolol undergoes significant first pass hepatic metabolism and is eliminated primarily via hepatic metabolism. Therefore, liver cirrhosis may increase the systemic bioavailability of metoprolol and may reduce its total clearance, resulting in increased plasma concentrations.
Metoprolol
In general, beta-blockers should not be given to patients with bronchospastic conditions. However, due to the relative cardioselectivity of metoprolol, Igroton-Lopresor can be administered with caution to patients with mild or moderate bronchospastic disease in cases where other indicated drugs are not tolerated or are not effective. Since b1-selectivity is not absolute, the lowest possible dose of Lopresor should be used and a b2-agonist administered concurrently. Beta-blockers should not be used in patients with untreated congestive heart failure (see section 4.3); heart failure should be stabilized first.
Due to their negative effect on atrioventricular conduction, beta-blockers should only be used, with caution, in patients with first degree atrioventricular block (see section 4.3). If the patient experiences progressive bradycardia (heart rate less than 50-55 beats / minute), the dosage should be gradually reduced, or treatment discontinued gradually (see section 4.3).
Igroton-Lopresor should be used with caution in patients with peripheral arterial disorders (e.g. Raynaud's disease or phenomenon, intermittent claudication), as treatment with beta-blockers may aggravate these conditions.
If the drug is prescribed to patients with known or suspected pheochromocytoma, an a-blocker should always be administered at the same time (see section 4.3).
Caution is indicated in the treatment of elderly patients. An excessive decrease in blood pressure or heart rate can cause inadequate blood supply to vital organs.
Prior to surgery requiring general anesthesia, the anesthetist should be informed that the patient is being treated with a beta blocker. An anesthetic with the least possible cardiodepressive effect should be used (see section 4.5). beta-blocker prior to surgery, it must occur gradually and be completed approximately 48 hours before general anesthesia.
Abrupt discontinuation of treatment should be avoided, especially in patients with ischemic heart disease. To prevent an exacerbation of angina pectoris, Igroton-Lopresor should be withdrawn gradually over a period of 1 to 3 weeks and, if necessary, replacement therapy initiated at the same time.
In patients treated with beta-blockers, anaphylactic reactions caused by other agents may be particularly severe and resist normal doses of adrenaline. Whenever possible, the use of beta-blockers should be avoided in patients at increased risk of anaphylaxis.
Beta-blockers can increase the number and duration of angina attacks in patients with Prinzmetal's angina (a variant of angina pectoris). Relatively selective beta-blockers, such as metoprolol, can be used in such patients, but only with extreme caution.
Beta blockers mask some of the clinical symptoms of thyrotoxicosis. Therefore, when Igroton-Lopresor is administered to patients with known or suspected thyrotoxicosis, both thyroid and cardiac function should be closely monitored.
Oculomucocutaneous syndrome in its complete variant, described with practolol, has not been reported with metoprolol. However, partial manifestations of this syndrome (dry eyes and / or occasionally skin rash) have also been described with metoprolol. In most cases the symptoms disappeared upon discontinuation of metoprolol treatment. Patients should be carefully observed for potential ocular effects. If such effects occur, consideration should be given to discontinuing Igroton-Lopresor.
Chlorthalidone
Treatment with thiazides and related diuretics has been associated with changes in serum electrolytes such as hypokalaemia, hypomagnesaemia, hypercalcaemia and hyponatremia. Hypokalaemia can sensitize the heart or dramatically increase its response to the toxic effects of digitalis.
As with all thiazide diuretics, the potassium excretion induced by chlorthalidone is dose dependent and varies in extent from one subject to another. With 25-50 mg per day the decrease in serum potassium concentrations averages 0.5 mmol / l. In the case of chronic treatment, serum potassium concentrations should be monitored at the start of therapy and subsequently after 3-4 weeks. Thereafter, checks should be performed every 4-6 months, if the electrolyte balance of potassium is not affected by additional factors (e.g. vomiting, diarrhea, change in renal function).
If necessary, Igroton-Lopresor can be combined with oral potassium therapy or a potassium-sparing diuretic (e.g. triamterene). In both cases, serum potassium levels should be monitored. If hypokalaemia is accompanied by clinical signs (eg muscle weakness, ECG changes), Igroton-Lopresor should be discontinued.
The association between Igroton-Lopresor and potassium salts or potassium-sparing diuretics should be avoided in patients already receiving ACE inhibitors.
Monitoring of serum electrolytes is particularly important in elderly patients and in those with liver cirrhosis.
Chlorthalidone can increase serum uric acid levels, however gout attacks are rarely seen during chronic treatment.
Modest and partially reversible increases in plasma concentrations of total cholesterol, triglycerides, or LDL-cholesterol have been reported in patients on chronic treatment with thiazide or thiazide-like diuretics. The clinical relevance of these findings is under discussion.
Chlorthalidone should be used with caution in patients with severe renal insufficiency. In such patients, thiazide diuretics can precipitate azotaemia and the effects of repeated administration can be cumulative.
Chlorthalidone and thiazide diuretics lose their diuretic effect when creatinine clearance is
In patients with severe coronary or cerebral arteriosclerosis, a prudent dosing schedule should be adopted.
The antihypertensive effect of ACE inhibitors is potentiated by agents that increase the activity of circulating renin (diuretics). It is recommended to reduce the dosage of the diuretic or to discontinue it for 2-3 days and / or to initiate therapy with ACE inhibitors with a low starting dose.
Keep this medicine out of the reach of children.
04.5 Interactions with other medicinal products and other forms of interaction
The effect of Igroton-Lopresor and other antihypertensives on blood pressure is additive.
In the treatment of diabetics, caution is indicated, and the dosage of the antidiabetic should be readjusted.
In diabetic patients using insulin, treatment with beta-blockers may be associated with more pronounced or prolonged episodes of hypoglycaemia. Beta-blockers may also antagonize the hypoglycemic effect of sulfonylureas. The risk of these effects is lower with a b1-selective drug such as metoprolol than with non-cardioselective beta-blockers. Diabetic patients receiving Igroton-Lopresor should be closely monitored to ensure safety. control of diabetes (see section 4.4).
Concurrent treatment with non-steroidal anti-inflammatory drugs (eg indomethacin) may decrease the antihypertensive effect of Igroton-Lopresor. There have been isolated cases of deterioration of renal function in patients predisposed to associated therapy with a diuretic and an NSAID.
The simultaneous use of digitalis glycosides and beta-blockers can cause excessive bradycardia and / or prolongation of the atrioventricular conduction time. In addition, hypokalaemia or hypomagnesaemia due to thiazide diuretics may favor the onset of digitalis-induced cardiac arrhythmias.
Metoprolol
The acute postural hypotension that may follow the first dose of prazosin may be accentuated in patients already treated with a beta blocker.
Patients on concomitant treatment with drugs that cause catecholamine depletion, other beta-blockers (including eye drops) or monoamine oxidase inhibitors (MAOIs) should be kept under surveillance.
If a patient is being treated concomitantly with clonidine and metoprolol and the clonidine treatment must be discontinued, the beta-blocker must be discontinued several days before the clonidine. This is because the hypertension that may follow clonidine withdrawal may be increased in patients treated concomitantly with beta-blockers.
Nitroglycerin may increase the hypotensive effect of metoprolol.
Metoprolol may modify the pharmacokinetic parameters of alcohol. Calcium antagonists of the verapamil and diltiazem type may potentiate the depressant effects of beta-blockers on blood pressure, heart rate and contractility, and atrioventricular conduction. A calcium antagonist of the verapamil type (phenylalkylamine) should not be administered intravenously to patients receiving Igroton-Lopresor, as there is a risk of cardiac arrest Patients receiving oral therapy with a calcium channel blocker of the verapamil type in combination with Igroton-Lopresor should be closely monitored.
Amiodarone, propafenone and other class I antiarrhythmics may potentiate the effect of beta-blockers on heart rate and atrioventricular conduction.
Adrenaline or other substances with sympathomimetic activity (eg those contained in antitussives or nasal and ophthalmic drops) can cause hypertensive reactions when administered simultaneously with beta-blockers; however, this is less likely with therapeutic doses of beta-selective drugs than with beta-blockers not cardioselective.
Enzyme inducers and inhibitors can alter plasma concentrations of metoprolol. For example, the plasma concentration of metoprolol is lowered by rifampicin and can be increased by cimetidine.
Metoprolol may reduce the clearance of lidocaine, causing an increase in the effects of lidocaine.
Some inhalation anesthetics may potentiate the cardiodepressive effect of beta blockers (see section 4.4).
Chlorthalidone
Since diuretics elevate lithemia, this should be controlled in patients treated with lithium combined with chlorthalidone. Where lithium has induced polyuria, diuretics can have a paradoxical antidiuretic effect.
Diuretics enhance the action of curare derivatives.
The hypokalaemic effect of chlorthalidone may be enhanced by corticosteroids, ACTH, β2 agonists, amphotericin and carbenoxolone. Concomitant administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol, increase the risk of adverse events caused by amantadine, increase the hyperglycemic effect of diazoxide and reduce the renal excretion of cytotoxic agents (eg cyclophosphamide, methotrexate) and thus enhance their myelosuppressive effects.
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperidene), apparently due to a decrease in gastrointestinal motility and stomach emptying rate.
Absorption of thiazide diuretics is impaired in the presence of anion exchange resins such as cholestyramine. A decrease in pharmacological effect can be expected.
Administration of thiazide diuretics with Vitamin D or with calcium salts can potentiate the increase in serum calcium levels.
Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-like complications.
04.6 Pregnancy and lactation
Both chlorthalidone and metoprolol can cause placental hypoperfusion. Thiazide diuretics, including chlorthalidone, cross the placental barrier and have been associated with fetal or neonatal thrombocytopenia and may be associated with other undesirable effects occurring in adults. Therefore, Igroton-Lopresor should not be used during pregnancy.
Since both of its active ingredients pass into breast milk, you will have to choose between discontinuing the drug or weaning.
04.7 Effects on ability to drive and use machines
Metoprolol may cause dizziness, fatigue or visual disturbances (see section 4.8); chlorthalidone may worsen the patient's ability to react, especially at the start of treatment. Therefore, Igroton-Lopresor may interfere with the ability to drive or use machines.
04.8 Undesirable effects
Interpretation of frequencies: very common: ≥10%; common: ≥1% a
Metoprolol
Central and peripheral nervous system
Common: fatigue, dizziness, headache.
Rare: paraesthesia, muscle cramps.
Cardiovascular system
Common: bradycardia, postural hypotension (occasionally with syncope).
Rare: heart failure, cardiac arrhythmias, edema, palpitations, Raynaud's phenomenon.
Very rare: cardiac conduction disturbances, precordial pain, gangrene in patients with previous severe peripheral circulatory disorders.
Psyche
Rare: depression, decreased mental alertness, drowsiness or insomnia, nightmares.
Very rare: personality disorders, hallucinations.
Gastrointestinal tract
Common: nausea, vomiting, abdominal pain.
Rare: diarrhea, constipation.
Very rare: dry mouth, liver function test abnormalities, hepatitis.
Skin and appendages
Rare: skin rash (in the form of urticaria, psoriasiform and dystrophic skin lesions).
Very rare: photosensitivity, increased sweating, hair loss, worsening of psoriasis.
Respiratory tract
Common: exertional dyspnea.
Rare: bronchospasm (which can occur in patients with no history of obstructive pulmonary disease).
Very rare: rhinitis.
Urogenital system
Very rare: libido and sexual potency disorders, Peyronie's disease (relationship with metoprolol has not been definitively established).
Sensory organs
Very rare: vision disturbances, eye irritation and / or dryness, tinnitus, hearing difficulties in case of exceeding the recommended doses.
Endocrine system and metabolism
Very rare: weight gain.
Blood
Very rare: thrombocytopenia.
Miscellaneous
Very rare: arthritis, retroperitoneal fibrosis (relationship with metoprolol has not been definitively established).
Chlorthalidone
Electrolyte and metabolic disorders
Very common: hypokalaemia, especially at higher doses, hyperuricaemia and increased plasma lipids.
Common: hyponatremia, hypomagnesemia and hyperglycemia.
Rare: hypercalcemia, glycosuria, aggravation of metabolic diabetes and gout.
Very rare: hypochloraemic alkalosis.
Gastrointestinal tract
Common: anorexia and minor gastrointestinal pains.
Rare. mild nausea and vomiting, gastric pain, diarrhea, constipation, intrahepatic colostasis, jaundice.
Very rare: pancreatitis.
Cardiovascular system
Common: orthostatic hypotension, which may be aggravated by alcohol, anesthetics or sedatives.
Rare: cardiac arrhythmias
Skin
Common: urticaria and other forms of skin rash.
Rare: photo-awareness.
Central and peripheral nervous system
Common: dizziness.
Rare: headache, paraesthesia.
Urogenital system
Common: impotence.
Sensory organs
Rare: visual disturbances.
Blood
Rare: thrombocytopenia, leukopenia, agranulocytosis and eosinophilia.
Miscellaneous
Very rare: idiosyncratic pulmonary edema, allergic interstitial nephritis and vasculitis.
04.9 Overdose
Signs and symptoms
Poisoning due to metoprolol overdose can lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, deterioration of consciousness (or even coma), seizures, nausea, vomiting and cyanosis.
The simultaneous intake of alcohol, antihypertensives, quinidine, barbiturates aggravates the signs and symptoms. The first manifestations of metoprolol overdose appear after 20 minutes - 2 hours. The effects of a massive overdose can persist for several days, despite decreasing concentrations plasma tests of metoprolol.
Nausea, feeling of weakness, dizziness, somnolence, hypovolaemia, hypotension and electrolyte disturbances associated with cardiac arrhythmia and muscle spasms have been observed in overdose with chlorthalidone.
Treatment
Patients must always be hospitalized and, generally, in intensive care, in order to continuously monitor their vital functions (cardiac function, blood gas analysis, biochemical parameters). Intravenous fluid and electrolyte replacement may be indicated. If appropriate, emergency supportive measures, such as artificial ventilation or heart rate regulation, should be instituted. Although apparently in good condition, patients who have taken doses that cause a modest overdose should be closely observed for at least 4 hours for evidence of symptoms of poisoning.
In the event of a potentially life-threatening overdose, induction of vomiting (if the patient is conscious), gastric lavage and / or administration of activated charcoal to remove the drug from the gastrointestinal tract. Hemodialysis is unlikely to make a useful contribution to the elimination of metoprolol.
To neutralize the effects of excessive beta blockade, the following measures may be necessary:
In case of significant bradycardia, atropine can be administered intravenously. An intravenous beta-agonist (eg, prenalterol, isoprenaline) should be used to control bradycardia and hypotension; very high doses may be required to overcome the beta blockade.
Dopamine, dobutamine or noradrenaline can be given to maintain blood pressure.
Glucagon has positive inotropic and chronotropic effects on the heart, independent of β-adrenergic receptors and has been shown to be effective in the treatment of resistant hypotension and heart failure associated with beta-blocker overdose.
Diazepam is the drug of choice to control seizures. A 2-agonist or aminophylline can be administered to counter bronchospasm; during and after administration of the bronchodilator, patients should be monitored to monitor for the onset of cardiac arrhythmias.
Beta blocker withdrawal may occur after an episode of overdose (see section 4.4).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: cardioselective beta-blockers and diuretics.
ATC code: C07CB02
Pharmacodynamic effects and mechanism of action
Igroton-Lopresor contains two components with different mechanisms of action and whose blood pressure lowering effects are complementary.
Metoprolol
Metoprolol is a cardioselective beta-blocker that acts on 1-adrenergic receptors, located mainly in the heart, at doses lower than those needed to block b2-receptors, located mainly in the peripheral vessels and bronchi.
Metoprolol has no membrane stabilizing effect, nor does it exhibit partial antagonistic activity (ISA).
The stimulating effect of catecholamines on the heart is reduced or inhibited by metoprolol. This causes a decrease in heart rate, contractility and output.
It lowers high blood pressure both in the ortho and in the supine position and reduces the extent of blood pressure increases in response to physical exertion.
Treatment results in an initial increase in peripheral resistance, which normalizes or in some cases decreases during long-term treatment. As with all beta-blockers, the precise mechanism of the antihypertensive effect of metoprolol is not fully known. However, the long-term reduction in blood pressure observed with metoprolol appears to be directly proportional to the gradual reduction in total peripheral resistance.
Long-term treatment with metoprolol may reduce insulin sensitivity. However, metoprolol interferes with insulin release and carbohydrate metabolism less than non-selective beta-blockers.
In short-term studies it has been observed that metoprolol can alter the blood lipid profile, increasing triglycerides and decreasing free fatty acids; in some cases it causes a slight decrease in the HDL fraction, although to a lesser extent than non-selective beta-blockers. In a long-term study conducted over several years, cholesterol levels fell.
Chlorthalidone
Chlorthalidone is a benzothiazide diuretic related to thiazide diuretics with a long duration of action.
Thiazide and thiazide-like diuretics act primarily at the level of the distal renal tubule (first convoluted tract), and inhibit the reabsorption of NaCl (by antagonizing the Na + -Cl- cotransporter) and promoting the reabsorption of Ca ++ (through an unknown mechanism). The increased release of Na + and water at the level of the cortical tract of the collecting tubule and / or the increased flow velocity produce an increase in the secretion and excretion of K + and H +.
The increased urinary excretion of sodium and chloride and the lower urinary potassium increase induced by chlorthalidone are dose-dependent. In people with normal renal function, diuresis is induced following the administration of 12.5 mg of chlorthalidone. The diuretic effect is established after about 2-3 hours, reaches its maximum after about 4-24 hours and can persist for 2-3 days.
Diuresis induced by thiazide diuretics initially results in a decrease in plasma volume, cardiac output and systemic pressure. The renin-angiotensin-aldosterone system can become activated. In hypertensive patients, chlorthalidone moderately reduces blood pressure. In case of continuous administration, the hypotensive effect is maintained, presumably due to the fall in peripheral resistance; cardiac output returns to the values it had before treatment, plasma volume remains somewhat reduced and circulating renin activity may be increased.
Following chronic administration, the antihypertensive effect of chlorthalidone is dose dependent for doses between 12.5 and 50 mg / day. Increasing the dose beyond 50 mg increases metabolic complications and there is rarely a beneficial therapeutic effect.
05.2 "Pharmacokinetic properties
Metoprolol
Metoprolol is absorbed throughout the intestinal tract.
Peak plasma concentrations are reached after approximately 4-5 hours in case of metoprolol administered with controlled release formulations and the extent of absorption is complete, as with a conventional tablet. Plasma concentrations of metoprolol increase almost dose proportionally over the range of 50 - 200 mg.
Due to a massive first pass effect only about 50% of a single oral dose of metoprolol reaches the systemic circulation. The extent of presystemic elimination differs at the individual level, due to genetic differences in oxidative metabolism. Although the plasma profile shows a "wide variability between subjects, it is however well reproducible in the" context of the single individual. After repeated administration, the percentage of drug available systemically is greater than that obtained after single administration. Ingestion of the drug with food can increase the systemic availability of a single oral dose by approximately 20-40%.
Metoprolol is rapidly distributed, with a volume of distribution of 3.2-5.6 l / kg. The half-life is not dose dependent and does not change with repeated administration. Approximately 10% of plasma metoprolol is bound to proteins. Metoprolol crosses the placenta and is found in breast milk (see section 4.6). In patients with hypertension. CSF concentrations of metoprolol are similar to plasma concentrations.
Metoprolol is extensively metabolised by hepatic enzymes of the cytochrome P450 system. The oxidative metabolism of metoprolol is genetically controlled. No metabolites of metoprolol contribute significantly to its beta-blocking effect.
The mean elimination half-life of metoprolol is 3-4 hours; in slow metabolising subjects it may be 7-9 hours. Approximately 95% of a dose can be recovered in the urine. In the majority of (extensively metabolised) subjects, less than 5% of an oral dose is excreted unchanged. In subjects with slow metabolization, up to 40% of the dose may be excreted unchanged.
There are no significant changes in metoprolol plasma concentrations in elderly subjects compared to younger subjects.
Impaired renal function is unlikely to affect the bioavailability of metoprolol or its elimination. However, excretion of metabolites is reduced. Significant accumulation of metabolites has been observed in patients with creatinine clearance of approximately 5 ml / min or less, but this accumulation does not affect the beta-blocking properties of metoprolol.
Cirrhosis of the liver can increase the bioavailability of unchanged metoprolol and reduce its total clearance. Patients with porta-cava anastomosis, in case of intravenous administration, have a systemic clearance of approximately 0.3 l / min and AUC values up to 6 times higher than those found in healthy volunteers.
Inflammatory diseases do not affect the pharmacokinetics of metoprolol, while hyperthyroidism may increase its presystemic clearance.
Chlorthalidone
The bioavailability of an oral dose of 50 mg of chlorthalidone is approx. 64%. and peak blood concentrations are reached approximately 8-12 hours after ingestion. For doses of 25 and 50 mg, the mean Cmax values are respectively 1.5 mcg / ml (4.4 mcmol / l) and 3 , 2 mcg / ml (9.4 mcmol / l). For doses up to 100 mg c "is a proportional increase in AUC. In response to repeated daily dosing of 50 mg, steady-state mean blood concentrations (measured at the end of the 24-hour interval between doses) of 7.2 mcg / ml (21.2 mcmol / l) are reached after 1 - 2 weeks.
Due to the high accumulation in erythrocytes and binding to plasma proteins, there is only a small fraction of free chlorthalidone in the blood. Having a high degree of binding affinity to erythrocyte carbonic anhydrase during treatment with 50 mg doses only about 1.4% of the total amount of chlorthalidone present in the blood is found in steady-state plasma. In vitro, plasma protein binding of chlorthalidone is approximately 76% and most is bound to albumin.
Chlorthalidone crosses the placental barrier and passes into breast milk. In mothers who were given 50 mg of chlorthalidone daily before and after delivery, the levels of chlorthalidone in whole fetal blood were approximately 15% of those found in maternal blood. The concentration of chlorthalidone in amniotic fluid and breast milk is equivalent to about 4% of that in the corresponding maternal blood.
Metabolism and hepatic excretion via the bile represent a minor route of elimination. Within 120 hours, approximately 70% of the dose is excreted in the urine and faeces, mostly unchanged.
Chlorthalidone is eliminated from the entire blood and plasma circulation with an elimination half-life of approximately 50 hours. The elimination half-life is unaltered after chronic administration. Most of the absorbed dose of chlorthalidone is excreted via the kidney, with a mean renal plasma clearance of 60 ml / min.
Changes in renal function do not alter the pharmacokinetics of chlorthalidone, the affinity of the drug to the carbonic anhydrase of the erythrocytes being the limiting factor in the rate of elimination of the drug from the blood or plasma. Elimination of chlorthalidone occurs more slowly in elderly patients than in healthy young adults, although absorption is the same. Therefore, close medical supervision of elderly patients being treated with chlorthalidone is indicated.
05.3 Preclinical safety data
Metoprolol
Reproductive toxicity studies in mice, rats and rabbits revealed no teratogenic potential of metoprolol tartrate. High doses have been associated with some maternal toxicity and growth retardation of the offspring, both in utero and after birth. There was no evidence of damage to fertility in rats at oral doses up to 500 mg / kg.
In the Ames test with bacterial cells, and in the in vivo tests with mammalian somatic cells or male mouse germ cells, metoprolol tartrate was found to be devoid of mutagenic / genotoxic potential.
After oral administration of doses up to 800 mg / kg for 21-24 months, metoprolol tartrate was not carcinogenic in mice and rats.
Chlorthalidone
Experiments on the induction of gene mutations in bacteria or cultured mammalian cells have yielded negative results. At highly cytotoxic assays, chromosomal aberrations are induced in hamster ovary cell cultures. However, experiments conducted on the self-healing induction capacity of DNA. in rat hepatocytes or in mouse bone marrow micronuclei or rat liver did not reveal any evidence for the induction of chromosomal damage. Therefore it is believed that the results of the hamster ovary cell assays are derived from considerations related to cytotoxicity rather than genotoxicity. It can be concluded that chlorthalidone does not present a risk of mutagenesis in humans.
Long-term carcinogenicity studies have not been conducted with chlorthalidone.
Teratogenic studies in rats and rabbits did not reveal any teratogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Microcrystalline cellulose; dibasic calcium phosphate dihydrate; magnesium stearate; anhydrous colloidal silica; talc; titanium dioxide; red iron oxide; hypromellose; polyacrylate dispersion 30%; glyceryl palmitate stearate; hydrogenated polyhydric castor oil; sodium starch carboxymethyl A.
06.2 Incompatibility
None known.
06.3 Period of validity
4 years
06.4 Special precautions for storage
Store at a temperature not exceeding 25 ° C. Store the tablets in the original container to keep them away from moisture.
06.5 Nature of the immediate packaging and contents of the package
ALU / PVC or ALU / PVC / PVDC non-toxic blisters
Carton of 28 prolonged-release film-coated tablets in calendar blisters
06.6 Instructions for use and handling
None.
07.0 MARKETING AUTHORIZATION HOLDER
Daiichi Sankyo Italy S.p.A.
Via Paolo di Dono, 73 - 00142 Rome
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n .: 024769022
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Authorization: 20.12.1984; renewal: 1.6.2005
10.0 DATE OF REVISION OF THE TEXT
April 2008
