Active ingredients: Carvedilol
CARAVEL 6.25 mg tablets CARAVEL 25 mg tablets
Why is Caravel used? What is it for?
This medicine contains the active substance carvedilol, which belongs to a group of medicines called beta-blockers, which relax and dilate blood vessels, lowering blood pressure and reducing the work of the heart.
CARAVEL is indicated for:
- the treatment of high blood pressure (essential arterial hypertension), also in combination with other medicines to treat high blood pressure, such as thiazide diuretics;
- the treatment of chest pain caused by heart problems (angina pectoris);
- the treatment of a disease characterized by the inability of the heart to supply an adequate amount of blood to the body (heart failure)
Contraindications When Caravel should not be used
Do not take CARAVEL
- if you are allergic to carvedilol or any of the other ingredients of this medicine (listed in section 6);
- if you have breathing problems due to lung disease (COPD - Chronic Obstructive Pulmonary Disease) or have suffered from asthma or other obstructive breathing problems (bronchospasm) in the past;
- if you have liver problems;
- if you are pregnant and breastfeeding;
- if the functionality of your heart is insufficient to ensure an adequate blood supply to the body and is not controlled in a stable way (unstable or decompensated heart failure);
- if you have heart conduction problems (2nd or 3rd degree atrioventricular block not treated with a permanent pacemaker, sick sinus node disease);
- if you have a very slow heart beat (bradycardia), less than 50 beats per minute;
- if you have very low blood pressure (maximum blood pressure below 85 mmHg);
- if you have a serious heart problem known as cardiogenic shock, which occurs when your heart does not pump enough blood around the body;
- if you have a tumor of the adrenal gland called pheochromocytoma and are not being treated;
- if your doctor has told you that your blood acidity is higher than normal (metabolic acidosis).
Precautions for use What you need to know before taking Caravel
Talk to your doctor or pharmacist before taking CARAVEL.
Take special care and talk to your doctor before taking this medicine:
- if your heart is functioning poorly and you have fluid retention (congestive heart failure);
- if your heart is functioning poorly and you have low blood pressure (maximum pressure below 100 mmHg);
- if you have blood circulation problems or have an insufficient blood supply to the heart (ischemic heart disease);
- if you have severe kidney problems (kidney failure);
- if you have recently had a heart attack;
- if you have breathing problems caused by a lung disease called COPD (Chronic Obstructive Pulmonary Disease);
- if you have diabetes or low blood sugar (hypoglycaemia). Carvedilol can mask or attenuate the initial signs and symptoms of acute hypoglycemia, especially increased heart rate (tachycardia);
- if you have problems with blood circulation in the limbs or if you have a condition called Raynaud's phenomenon, which is characterized by poor blood circulation in the fingers or toes that become painful and whitish;
- if you have thyroid problems (thyrotoxicosis), because carvedilol can hide the symptoms;
- if you are going to undergo surgery that requires the use of anesthetics. Tell the anesthetist that you are taking CARAVEL;
- if you have a very slow heart beat (bradycardia), less than 55 beats per minute;
- if you have suffered from severe allergic reactions (anaphylactic reactions) in the past or if you are undergoing desensitization therapy;
- if you have an inflammatory skin disease called psoriasis;
- if you take other medicines to lower blood pressure and treat heart problems such as verapamil or diltiazem, or if you take other anti-arrhythmic medicines; in these cases you must have your blood pressure and heart rate checked periodically;
- if you have a tumor of the adrenal gland called pheochromocytoma;
- if you suffer from a type of chest pain caused by poor blood circulation to the heart (Prinzmetal's angina);
- if you use contact lenses, as a reduction in lacrimation may occur;
- if you have sudden changes in blood pressure (labile hypertension) or have high blood pressure due to other diseases (secondary hypertension).
For those who practice sports: the use of this medicine without therapeutic need constitutes doping and can in any case determine positive anti-doping tests
Interactions Which drugs or foods can modify the effect of Caravel
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Take special care and talk to your doctor if you are taking:
- medicines used to treat changes in the heartbeat (digoxin and other digitalis glycosides);
- medicines used to treat diabetes such as insulin and oral hypoglycemic agents;
- rifampicin, a medicine used to treat tuberculosis;
- cimetidine, a medicine used to treat injuries and heartburn (ulcers);
- antidepressant medicines called monoamine oxidase inhibitors (MAOIs);
- medicines used to treat high blood pressure, such as reserpine, doxazosin
- medicines to lower blood pressure and treat heart problems such as diltiazem, verapamil and antiarrhythmic medicines (see section Warnings and precautions);
- ciclosporin, a medicine used to prevent rejection after a transplant;
- clonidine, a medicine used to treat high blood pressure. If the two drugs are administered simultaneously, clonidine should be discontinued a few days after the discontinuation of carvedilol;
- medicines used to induce anesthesia (see section Warnings and precautions).
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Do not take this medicine during pregnancy unless it is absolutely necessary.
The use of this medicine is not recommended if you are breastfeeding.
Driving and using machines
There are no data available to establish the effect of the medicine on the ability to drive and use machines. However, if you experience dizziness or tiredness, avoid driving and using machines, this is especially true at the start of treatment, after elevations. of the dose, following the change of the product and if you drink alcohol.
CARAVEL contains lactose and sucrose
This medicine contains lactose and sucrose, two types of sugars. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Caravel: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, consult your doctor or pharmacist.
Take the tablets with a sufficient amount of liquid, regardless of meals. However, if you suffer from heart failure, take the medicine with meals to reduce the occurrence of side effects.
Treatment of high blood pressure (essential arterial hypertension)
Adults:
The recommended starting dose is 12.5 mg once a day, for the first 2 days. Thereafter the recommended dose is 25 mg once daily. Thereafter, the dosage may be gradually increased, at intervals of not less than 2 weeks, until the maximum recommended dose of 50 mg per day is reached in one or two doses.
Treatment of chest pain caused by heart problems (angina pectoris)
Adults:
The recommended starting dose is 12.5 mg twice a day, for the first 2 days. Thereafter, the dosage can be increased to the maximum recommended dose of 25 mg, twice daily.
Treatment of heart failure
The treatment must be carried out under strict supervision of the doctor who will adjust the dosage according to your needs until the appropriate dosage is reached. The recommended starting dose is 3.125 mg (half a 6.25 mg tablet) twice a day, at least for 2 weeks. Thereafter, the dosage may be gradually increased, at intervals of not less than 2 weeks, up to a maximum of 25 mg twice a day. If the patient weighs more than 85 kg, in case of mild or moderate decompensation, the maximum recommended dose is 50 mg twice a day.
The doctor will need to monitor the patient and check their health before increasing the dosage of the medicine. If you experience worsening of heart failure or fluid retention, the dose of the other medicines or CARAVEL may need to be adjusted.
If you stop taking this medicine for more than two weeks, your therapy will need to be restarted with the minimum dose of 3.125 mg (half a 6.25 mg tablet) twice a day which can then be increased.
Use in children and adolescents
There are no data available regarding the use of this medicine in children below 18 years of age.
Use in the elderly
The recommended starting dose for the treatment of essential hypertension is 12.5 mg once daily which may be increased at intervals of not less than 2 weeks to the maximum recommended dose of 50 mg daily, to be taken in two doses of 25 mg The recommended starting dose in the treatment of angina pectoris is 12.5 mg twice daily which may be increased after an interval of at least 2 days, up to a maximum dose of 25 mg twice daily.
Overdose What to do if you have taken too much Caravel
If you take more CARAVEL than you should
If you have swallowed / taken too much of this medicine, contact your doctor or the nearest hospital immediately. If you take too much of this medicine, you may experience the following symptoms: slow heart beat ( bradycardia), decreased blood pressure (hypotension), heart failure (heart failure, cardiogenic shock and cardiac arrest) and difficulty breathing (bronchospasm), vomiting, impaired consciousness and convulsions.
If you forget to take CARAVEL
Do not take a double dose to make up for a forgotten tablet.
If you stop taking CARAVEL
Do not stop taking this medicine without consulting your doctor. You need to stop taking this medicine gradually, over 2 weeks, especially if you suffer from disturbances in the blood circulation of the heart (ischemic heart disease).
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Caravel
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects may occur:
Very common (may affect more than 1 in 10 people)
- headache and dizziness, dizziness;
- heart problems (heart failure);
- lowering of blood pressure;
- feeling of fatigue (asthenia).
Common (may affect up to 1 in 10 people)
- infections of the airways (bronchitis), lungs (pneumonia), nose and throat (upper airways);
- urinary tract infections;
- decreased number of red blood cells (anemia);
- weight gain;
- increased blood cholesterol levels (hypercholesterolemia)
- alteration of blood sugar levels in people with diabetes;
- depression;
- vision problems, dry eyes and eye irritation;
- decrease in the number of heartbeats (bradycardia);
- fluid retention which causes general swelling of the body or parts of the body such as hands, feet, ankles and legs (edema) and an increase in the amount of blood circulating (hypervolemia);
- feeling dizzy when standing up due to a rapid fall in blood pressure (postural hypotension), which may be associated with fainting;
- circulation problems in the arms and legs causing cold sensation in the hands and feet and pain in the extremities;
- tingling and pain in the fingers, followed by a sensation of heat and pain (Raynaud's phenomenon);
- difficulty moving (intermittent claudication);
- breathing difficulties, especially in patients who suffer or have suffered from asthma;
- accumulation of fluid in the lung (pulmonary edema);
- nausea, diarrhea, vomiting;
- abdominal pain and digestive problems;
- kidney problems and difficulty urinating;
- ache.
Uncommon (may affect up to 1 in 100 people)
- sleep disorders;
- feeling faint, fainting, tingling in the extremities (paraesthesia);
- disturbances in the conduction system of the heart (atrioventricular block);
- chest pain caused by heart circulation problems (angina pectoris);
- skin reactions such as rash, dermatitis, hives, itching, skin lesions;
- hair loss (alopecia);
- increased sweating;
- erection disorders (erectile dysfunction).
Rare (may affect up to 1 in 1000 people)
- decrease in blood platelets;
- stuffy nose (nasal congestion);
- constipation;
- dry mouth.
Very rare (may affect up to 1 in 10,000 people)
- decrease in white blood cells (leukopenia);
- allergic reactions;
- impaired liver function and increased levels of liver enzymes (ALT, AST, GGT);
- urinary incontinence in women, which resolves upon discontinuation of treatment.
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 about the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after "Expiry". The expiry date refers to the last day of that month.
Store below 25 ° C. Store in the original package to protect from light and moisture.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What CARAVEL contains
CARAVEL 6.25 mg tablets
- The active ingredient is carvedilol. Each tablet contains 6.25 mg of carvedilol.
- The other ingredients are: sucrose, lactose monohydrate, polyvinylpyrrolidone, colloidal anhydrous silica, crospovidone, magnesium stearate, yellow iron oxide (E 172).
CARAVEL 25 mg tablets
- The active ingredient is carvedilol. Each tablet contains 25 mg of carvedilol.
- The other ingredients are: sucrose, lactose monohydrate, polyvinylpyrrolidone, colloidal anhydrous silica, crospovidone, magnesium stearate.
Description of the appearance of CARAVEL and contents of the pack
CARAVEL 6.25 mg tablets
Round, light yellow tablets with a score line. Box of 28 divisible tablets.
CARAVEL 25 mg tablets
Round, white tablets with a score line. Box of 30 divisible 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
CARAVEL TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CARAVEL 6.25 mg tablets
One tablet contains:
Active ingredient: carvedilol 6.25 mg.
CARAVEL 25 mg tablets
One tablet contains:
Active ingredient: carvedilol 25 mg.
For excipients see 6.1.
03.0 PHARMACEUTICAL FORM
Divisible tablets of 6.25 mg and 25 mg.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of essential arterial hypertension:
carvedilol is indicated for the treatment of essential arterial hypertension. It can be used alone or in combination with other antihypertensive agents, especially with thiazide diuretics.
Treatment of angina pectoris.
Treatment of heart failure.
04.2 Posology and method of administration
The tablets should be taken with a sufficient amount of liquid. It is not necessary to take the tablets with meals; however, in patients with heart failure, carvedilol should be administered with meals to slow absorption and reduce the incidence of postural effects such as orthostatic hypotension.
Treatment of essential arterial hypertension
Adults: The recommended initiation dosage is 12.5 mg once daily for the first two days. Thereafter, the recommended dosage is 25 mg once daily. Dosage can be gradually increased at intervals if necessary. not less than two weeks, until reaching the maximum recommended dose of 50 mg per day to be taken in a single administration or divided into 25 mg twice a day.
Senior citizens: The recommended dose for initiation of therapy is 12.5 mg once a day. This dosage has allowed for adequate control of blood pressure values in some patients. If the response is inadequate, the dosage may be increased at intervals of not less than two weeks until the maximum recommended dose of 50 mg is reached, to be taken divided into 25 mg twice daily.
Treatment of angina pectoris
Adults: The recommended dosage for initiation of therapy is 12.5 mg twice daily for the first two days. Thereafter, the recommended dosage is 25 mg twice daily. It is recommended not to exceed this dosage.
Senior citizens: the recommended starting dose is 12.5 mg twice a day. Thereafter the dose can be increased, after an interval of at least two days, to 25 mg twice a day (maximum dose not to be exceeded) .
Treatment of heart failure
The decision to initiate therapy with carvedilol for heart failure should be made by a physician experienced in the management of this disease, after a "careful evaluation of the patient's condition. Patients should always be clinically stable and should not present with deterioration of clinical status or signs of decompensation since previous visit In patients receiving digitalis, diuretics and ACE inhibitors, the dosage of these drugs should be stabilized before starting treatment with carvedilol.
THE DOSAGE MUST BE CUSTOMIZED AND THE PATIENT MUST BE CAREFULLY FOLLOWED BY THE DOCTOR DURING THE WHOLE PERIOD NECESSARY TO REACH THE ADEQUATE DOSAGE.
The recommended dose for initiation of therapy is 3.125 mg (1/2 tablet of 6.25 mg) twice daily for at least two weeks. If this dosage is well tolerated, the dosage may subsequently be increased at intervals. not less than two weeks, and increased first to 6.25 mg twice daily, then to 12.5 mg twice daily and finally to 25 mg twice daily. The dosage should be increased to the highest tolerated dose. by the patient.
The maximum recommended dose is 25 mg twice daily in all patients with severe heart failure and in patients with mild or moderate heart failure with a body weight of less than 85 kg. In patients with mild or moderate heart failure who weigh more than 85 kg the maximum recommended dose is 50 mg twice daily.
Before each dose increase, the patient should be examined by the physician for any signs of worsening heart failure or vasodilatation.Temporary worsening of heart failure or fluid retention should be treated with an increase in the dosage of diuretics, although occasionally it may be necessary to decrease the dose of carvedilol or temporarily stop taking it.
In the event that carvedilol treatment is discontinued for more than two weeks, therapy should be restarted with 3.125 mg (1/2 tablet of 6.25 mg) twice daily and thereafter the posology should be increased taking into account the previous recommendations.
Symptoms of vasodilation can initially be treated with a reduction in the dosage of diuretics. If symptoms persist the dose of ACE inhibitor (if used) may be decreased and, if deemed necessary, a reduction in the carvedilol dose may subsequently be made. In such circumstances, the carvedilol dose should not be increased until symptoms of worsening heart failure or vasodilation have stabilized.
The tolerability and efficacy of carvedilol in patients under 18 years of age have not been established.
04.3 Contraindications
Hypersensitivity to carvedilol or to any of the excipients.
Unstable / decompensated heart failure.
Clinically manifest liver dysfunction.
2nd and 3rd degree atrioventricular block (unless a permanent pacemaker has been placed).
Severe bradycardia (
Sino-atrial node dysfunction (sick sinus syndrome, including sino-atrial block).
Severe hypotension (systolic pressure
Cardiogenic shock.
History of bronchospasm, chronic obstructive pulmonary disease (COPD) with a bronchospastic component.
Asthma.
Pregnancy and lactation (see section 4.6).
Pheochromocytoma not controlled with alpha-blockers.
Metabolic acidosis.
04.4 Special warnings and appropriate precautions for use
Chronic congestive heart failure
In patients with congestive heart failure, worsening of heart failure or water retention may occur during the carvedilol titration phase. If these symptoms occur, the dosage of diuretics should be increased and the carvedilol dose should not be increased up to when stabilization of symptoms and clinical signs has not been achieved. Occasionally, it may be necessary to reduce the dose of carvedilol or, in rare cases, to temporarily stop taking it. Such episodes do not preclude the possibility of a subsequent effective titration of carvedilol.
In patients with digitalis controlled heart failure, diuretics and / or ACE inhibitors, carvedilol should be used with caution as both digitalis and carvedilol slow atrioventricular conduction.
Renal function in congestive heart failure
Reversible worsening of renal function has been observed during carvedilol therapy in chronic heart failure patients with low blood pressure (systolic ischemic heart disease, diffuse vascular disease, and / or underlying renal insufficiency. such risk factors, renal function should be monitored during the phases of increasing the carvedilol dosage and treatment should be suspended, or the dosage reduced, if worsening of renal function is observed.
Left ventricular dysfunction after acute myocardial infarction
Before starting carvedilol treatment, the patient must be clinically stable and must have received an ACE inhibitor for at least the past 48 hours, and the ACE inhibitor dose must be stable for at least the past 24 hours.
Chronic obstructive pulmonary disease
Carvedilol should be used with caution in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who are not taking oral or inhaled medicinal products and only if the potential benefits outweigh the potential risks. In patients with a predisposition to bronchospasm, respiratory distress may occur as a result of a possible increase in airway resistance. Patients should be closely monitored during the initial and dose adjustment phases of carvedilol, and if bronchospasm is observed, the carvedilol dose should be reduced.
Diabetes
Carvedilol should be administered with caution to patients with diabetes mellitus, as the initial signs and symptoms of acute hypoglycaemia may be masked or attenuated.
In patients with insulin-dependent diabetes mellitus, however, alternative drugs to beta-blockers are preferred.
In diabetic patients with chronic heart failure, the use of carvedilol may be associated with worsening of blood glucose control. Regular blood glucose control is therefore necessary in diabetics both when carvedilol therapy is initiated and when its dosage is increased; hypoglycemic therapy should be adjusted accordingly.
Peripheral vascular disease
Carvedilol should be used with caution in patients with peripheral vascular disease as beta-blockers can precipitate or aggravate the symptoms of arterial insufficiency.
Raynaud's phenomenon
Carvedilol should be used with caution in patients with peripheral circulatory disorders (e.g. Raynaud's phenomenon) as worsening of symptoms may occur.
Thyrotoxicosis
Carvedilol, like other beta-blocking drugs, can mask the symptoms of thyrotoxicosis.
Anesthesia and major surgery
Particular attention should be paid in patients undergoing surgery due to the synergy between the negative inotropic and hypotensive effects of carvedilol and anesthetics.
Bradycardia
Carvedilol can induce bradycardia. Carvedilol dosage should be reduced if the patient's pulse rate falls below 55 beats per minute.
Hypersensitivity
Carvedilol should be administered with caution to patients with a history of severe hypersensitivity reactions and to patients undergoing desensitization therapy as beta-blockers may increase both sensitivity to allergens and the severity of an anaphylactic reaction.
Psoriasis
In patients with a history of psoriatic phenomena associated with beta-blocker treatment, carvedilol should only be administered after a "careful benefit / risk assessment".
Concomitant use of calcium channel blockers
In patients in whom it is necessary to use carvedilol in combination with calcium channel blockers of the verapamil or diltiazem type, or other antiarrhythmic drugs, careful monitoring of electrocardiographic (ECG) and blood pressure is necessary.
Pheochromocytoma
In patients with pheochromocytoma, treatment with an alpha-blocker should be started before using any beta-blocking agent. Although carvedilol possesses both alpha and beta blocking pharmacological properties, there is no experience with its use in this condition. Therefore, particular caution should be exercised in administering carvedilol to patients with suspected pheochromocytoma.
Prinzmetal's variant angina
Drugs with non-selective beta-blocking activity may cause chest pain in patients with Prinzmetal's variant angina. There are no data on clinical experience with carvedilol in these patients, although the alpha-blocking activity of carvedilol can prevent these symptoms. However, care should be taken in administering carvedilol to patients with suspected Prinzmetal's variant angina.
Contact lenses
Contact lens wearers should be aware of the possibility of reduced lacrimation.
Withdrawal syndrome
Carvedilol treatment should not be stopped abruptly, especially in patients with ischemic heart disease. Withdrawal of carvedilol treatment should occur gradually (over 2 weeks).
As with other drugs with beta-blocking activity:
Carvedilol should be used with caution in patients with labile or secondary hypertension until further clinical experience is available.
If in the course of heart failure therapy, deterioration in clinical status or signs of worsening of heart failure occur compared to the previous visit, alternative therapy should be instituted.
This product contains sucrose: patients with rare hereditary problems of fructose intolerance, or with glucose-galactose malabsorption syndrome, or with sucrase-isomaltase deficiency should not take this medicine.
The product also contains lactose: patients with lactase deficiency, rare hereditary problems of galactose intolerance or glucose-galactose malabsorption syndrome should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacokinetic interactions
Digoxin: Following the concomitant administration of carvedilol and digoxin in hypertensive patients, steady state trough concentrations of digoxin were increased by approximately 16%. Both digoxin and carvedilol slow atrioventricular conduction. Closer monitoring of digoxinaemia is recommended whenever carvedilol treatment is initiated, modified or discontinued.
Insulin or oral hypoglycemic agents: The effects of insulin or oral hypoglycaemics may be potentiated by agents with beta-blocking properties. The signs and symptoms of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycemic agents, a regular blood glucose control.
Inducers and inhibitors of hepatic metabolism: rifampicin reduced plasma concentrations of carvedilol by approximately 70%. Cimetidine increased the AUC by approximately 30% but caused no change in Cmax.
Particular attention should be paid both in patients treated with mixed function oxidase inducers (e.g. rifampicin), as serum levels of carvedilol may be reduced, and in patients treated with mixed function oxidase inhibitors (e.g. cimetidine). ), as the plasma levels of carvedilol can be increased.
However, given the relatively small effect of cimetidine on carvedilol levels, the likelihood of a clinically important interaction is minimal.
Agents that reduce catecholamines: Patients taking both agents with beta-blocking properties and a medicinal product that can reduce catecholamines (e.g. reserpine, and monoamine oxidase inhibitors), should be carefully monitored for signs of hypotension and / or severe bradycardia.
Cyclosporine: Modest increases in mean trough concentrations of cyclosporine were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In approximately 30% of patients, the dose of cyclosporine was reduced. to keep cyclosporin concentrations within the therapeutic range, while in the rest of the patients no adjustment was necessary. On average, the cyclosporin dose in these patients was reduced by approximately 20%. Individual variability in dose adjustment required, it is recommended that cyclosporin plasma concentrations be closely monitored following initiation of carvedilol therapy and that the cyclosporine dose be adjusted as appropriate.
Verapamil, diltiazem or other antiarrhythmics: in combination with carvedilol may increase the risk of AV conduction disturbances (see section 4.4).
Pharmacodynamic interactions
Clonidine: Concomitant administration of clonidine and agents with beta-blocking properties may potentiate the blood pressure and heart rate lowering effects.
Should it be necessary to discontinue the treatment of carvedilol and clonidine, used in combination, carvedilol must be stopped first, a few days before starting to gradually decrease the dosage of clonidine.
Calcium channel blockers (see section 4.4)
Isolated cases of conduction disturbance (rarely with haemodynamic impairment) have been observed when carvedilol is administered in combination with diltiazem. As observed for other agents with beta-blocking properties, if carvedilol is administered orally with calcium channel blockers of the verapamil or diltiazem type, ECG and blood pressure monitoring is recommended.
As observed for other beta-blocking drugs, carvedilol may also potentiate the action of other drugs administered in combination with antihypertensive activity (eg alpha1 receptor antagonists) or that of drugs that can cause hypotension as an undesirable side effect.
Particular attention should be paid during anesthesia due to the synergy between the negative inotropic and hypotensive effects of carvedilol and anesthetics.
04.6 Pregnancy and lactation
There is no adequate clinical experience with the use of carvedilol in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy, embryonal / fetal development, parturition and postnatal development (see section 5.3).
The potential risk for humans is unknown.
Carvedilol should not be given during pregnancy unless the potential benefits outweigh the potential risks.
Beta-blockers reduce placental perfusion, which can cause intrauterine fetal death and immature and premature births. In addition, adverse reactions (especially hypoglycaemia and bradycardia) may occur in the fetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the newborn in the postnatal period.
Animal studies have shown no substantial evidence of teratogenicity with carvedilol (see also section 5.3).
Animal studies have shown that carvedilol or its metabolites are excreted in human milk. It is not known whether carvedilol is excreted in human breast milk.
Carvedilol intake is contraindicated during breastfeeding.
04.7 Effects on ability to drive and use machines
No studies on the effects of carvedilol on patients' fitness to drive or operate machinery have been performed.
Due to variable individual reactions (e.g. dizziness, tiredness), the ability to drive, operate machinery or work without solid support may be impaired. This is particularly true at the start of treatment, after dose increases, with product changes and in combination with alcohol.
04.8 Undesirable effects
(a) Summary of the safety profile
The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.
(b) List of adverse reactions
The risk of most adverse reactions associated with carvedilol is similar across all indications.
The exceptions are described in subsection (c).
The categories of attendance are as follows:
Very common ≥ 1/10
Common ≥ 1/100 e
Uncommon ≥1 / 1,000 and
Rare ≥ 1 / 10,000 e
Very rare
Infections and infestations
Common: bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections
Disorders of the blood and lymphatic system
Common: anemia
Rare: thrombocytopenia
Very rare: leukopenia
Disorders of the immune system
Very rare: hypersensitivity (allergic reaction)
Metabolism and nutrition disorders
Common: hypoglycaemia, weight gain, hypercholesterolaemia, impaired glycemic control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes
Psychiatric disorders
Common: depression, depressed mood
Uncommon: sleep disturbances
Nervous system disorders
Very common: dizziness, vertigo, headache
Uncommon: pre-syncope, syncope, paraesthesia
Eye disorders
Common: visual impairment, reduced lacrimation (dry eyes), eye irritation
Cardiac pathologies
Very common: heart failure
Common: Bradycardia, edema (including: generalized edema, peripheral edema, edema of the genitals, edema of the lower extremities), hypervolemia, excess fluid
Uncommon: atrioventricular block, angina pectoris
Vascular pathologies
Very common: hypotension
Common: orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Raynaud's phenomenon)
Respiratory, thoracic and mediastinal disorders
Common: dyspnoea, pulmonary edema, asthma in predisposed patients
Rare: nasal congestion
Gastrointestinal disorders
Common: nausea, diarrhea, vomiting, dyspepsia, abdominal pain
Rare: constipation, dry mouth
Hepatobiliary disorders
Very rare: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT)
Skin and subcutaneous tissue disorders
Uncommon: skin reactions (e.g. allergic rash, dermatitis, urticaria, pruritus, psoriatic skin lesions, which where present may be exacerbated by treatment, and similar lichen planus), alopecia, increased sweating
Musculoskeletal and connective tissue disorders
Common: pain in the extremities
Renal and urinary disorders
Common: renal failure and changes in renal function in patients with diffuse vascular disease and / or baseline renal failure, urination disturbances
Very rare: urinary incontinence in women
Diseases of the reproductive system and breast
Uncommon: erectile dysfunction
General disorders and administration site conditions
Very common: asthenia (fatigue)
Common: pain
(c) Description of selected adverse reactions
Vertigo, syncope, headache and asthenia are usually mild and are more likely to occur at the start of treatment.
In patients with congestive heart failure, worsening of heart failure and fluid retention may occur in the carvedilol dose titration phase (see section 4.4).
Heart failure is a commonly reported event in both placebo and carvedilol-treated patients (14.5% and 15.4%, respectively, in patients with left ventricular dysfunction after acute myocardial infarction).
Reversible worsening of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischemic heart disease and diffuse vascular disease and / or underlying renal insufficiency (see section 4.4).
As a class effect, beta-adrenergic receptor antagonists can cause latent diabetes, worsening of overt diabetes, and inhibition of blood glucose counter-regulation.
Carvedilol can cause urinary incontinence in women which resolves upon discontinuation of treatment.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms and signs
Severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest can occur in the event of overdose. In addition, breathing difficulties and problems, bronchospasm, vomiting, altered consciousness and generalized convulsions may occur.
Treatment
In addition to normal intervention protocols, vital signs should be monitored and brought back to normal if necessary under intensive care conditions.
The following supportive therapies can be used:
Atropine: 0.5 to 2 mg i.v. (in case of excessive bradycardia)
To support ventricular function, use:
glucagon: initially 1 to 10 mg i.v., then 2 to 5 mg / h by long-term infusion or
sympathomimetic drugs to be administered according to body weight and the effect obtained: dobutamine, isoprenaline, orciprenaline or adrenaline.
If a positive inotropic effect is required, phosphodiesterase inhibitors (PDEs) should be considered.
In the event that the prevailing manifestations of overdose are represented by a peripheral vasodilatation, norfenephrine or noradrenaline should be administered under constant monitoring of the conditions of the circulatory system.
In case of bradycardia resistant to drug therapy, pacemaker treatment should be initiated.
In case of bronchospasm, beta-sympathomimetic drugs (by aerosol or, if ineffective, also intravenously) or intravenous aminophylline, administered by injection or slow infusion, should be administered.
In case of seizures, slow IV administration is recommended. of diazepam or clonazepam.
Note:
In case of severe intoxication with symptoms of shock, supportive treatment with antidotes should be continued for a sufficiently long period of time, in view of the prolonged elimination half-life and redistribution of carvedilol from deeper compartments. The duration of antidote therapy is related to the extent of the overdose; therapy and supportive measures should be continued until the patient has stabilized.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: alpha and beta-adrenergic receptor blockers.
ATC code: C07AG02.
Carvedilol is a non-selective beta-blocker that exerts vasodilating activity mediated mainly through a selective block of alpha1-adrenergic receptors, and is endowed with antioxidant properties.
Carvedilol reduces peripheral vascular resistance by vasodilation and depresses the renin-angiotensin-aldosterone system by beta-blockade. Plasma renin activity is reduced and fluid retention is rare.
Carvedilol has no intrinsic sympathomimetic activity and, like propranolol, has membrane stabilizing activity.
Carvedilol is a racemic mixture of two stereoisomers. In animal models, both enantiomers possess blocking activity against alpha adrenergic receptors.
The beta-adrenergic receptor blocking properties are not selective for beta-1 or beta-2 adrenoceptors and are associated with the levorotatory enantiomer of carvedilol.
Carvedilol is a powerful antioxidant and has a "scavenger" activity against oxygen radicals.
The anti-oxidant properties of carvedilol and its metabolites have been demonstrated in studies in vitro and in vivo in animal models, ed in vitro in different types of human cells.
Clinical studies have shown that the combined vasodilation and beta-blocking activities possessed by carvedilol produce the following effects:
In hypertensive patients, the reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as is observed with pure beta-blocker drugs. Heart rate decreased slightly. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained, therefore cold extremities (often seen with beta-blocking drugs) are a rare event.
Acute hemodynamic studies have shown that carvedilol is able to reduce ventricular pre- and afterload.
In patients with heart failure, carvedilol has been shown to produce favorable effects on hemodynamics and improve both the ejection fraction and the size of the left ventricle.
The normal ratio of high and low density lipoproteins (HDL / LDL) is not changed. The plasma electrolyte picture is not changed.
In a large, multicenter, double-blind, placebo-controlled study (COPERNICUS), 2289 patients with stable severe heart failure of ischemic or non-ischemic origin, on standard therapy, were randomized to receive carvedilol (1156 patients) or placebo (1133 patients).
Patients had left ventricular systolic dysfunction with a mean ejection fraction of less than 20%. In the carvedilol group, mortality was reduced by 35% compared to the placebo group (12.8% vs 19.7%, p = 0.00013). In the carvedilol group, the reduction in mortality was observed in all patient subgroups studied; furthermore, sudden deaths were reduced by 41% compared to the placebo group (4.2% vs 7.8%).
The combined secondary endpoints of mortality or hospitalizations for heart failure, mortality or hospitalization for cardiovascular causes and mortality or hospitalizations from all causes were all significantly lower in the carvedilol group than in the placebo group (with reductions of 31%, 27% and 24%, p
During the study, the incidence of serious adverse events was lower in the carvedilol group (39% vs 45.4%). At the start of treatment, the incidence of worsening heart failure was similar in both groups. L "incidence of severe worsening of heart failure was lower in the carvedilol group (14.5% vs 21.1%).
05.2 "Pharmacokinetic properties
The absolute bioavailability of carvedilol in humans is approximately 25%. Peak plasma is reached approximately 1 hour after oral administration. There is a linear relationship between dose and plasma concentration. Meals do not change bioavailability or maximal plasma concentration, although the time to reach maximum plasma concentration is delayed. Carvedilol is highly lipophilic; approximately 98% - 99% of the drug is bound to plasma proteins. The volume of distribution is approximately 2 L / kg and increases in patients with liver cirrhosis. L "first pass effect" after oral administration is about 60-75%; entero-hepatic recirculation of the unchanged drug was demonstrated in the animal.
The mean elimination half-life of carvedilol is between 6 and 10 hours.
Plasma clearance is approximately 590 mL / min. Elimination occurs primarily via the biliary route. The major route of excretion is via the faeces. A smaller amount is eliminated by the kidney in the form of various metabolites.
In all animal species studied and also in humans, carvedilol is extensively metabolised to produce various metabolites which are mainly eliminated with the bile.
In patients with impaired liver function, bioavailability may be increased by up to 80% due to a reduced first pass effect.
Carvedilol is extensively metabolised by the liver; one of the main metabolic mechanisms is represented by glucuroconjugation. Demethylation and hydroxylation of the phenolic ring produce three active metabolites with beta-blocking activity. The 4 "-hydroxyphenol metabolite was found, in preclinical trials, about thirteen times more active than carvedilol in terms of beta-blocking activity. The three active metabolites show, when compared to carvedilol, a weak vasodilator action. In humans, their concentrations. they are about ten times lower than that of carvedilol. Furthermore, two of the hydroxy-carbazole metabolites are particularly potent antioxidants, with an antioxidant activity 30 to 80 times greater than that of carvedilol.
Pharmacokinetics in special populations
The pharmacokinetics of carvedilol change with age; plasma levels of carvedilol in elderly patients are approximately 50% higher than those seen in young patients. In a study conducted in patients with liver cirrhosis, the bioavailability of carvedilol was found to be was four times higher and the plasma peak was five times higher than that observed in healthy volunteers.
In hypertensive patients with moderate (creatinine clearance 20-30 ml / min) to severe (creatinine clearance) renal impairment
05.3 Preclinical safety data
In carcinogenicity studies performed in rats and mice using doses up to 75 mg / kg / day and 200 mg / kg / day, respectively (38 to 100 times the maximum recommended human dose), carvedilol was not found to be carcinogenic.
Carvedilol has been shown not to possess mutagenic activity in tests conducted on mammals and non-mammals either in vitro is in vivo.
Administration of carvedilol to pregnant female rats at maternally toxic dosages (200 mg / kg equal to more than 100 times the maximum recommended human dose) resulted in impaired fertility (poor mating, fewer corpora lutea and fewer implants , and embryos) Dosages 60 mg / kg (30 times the maximum recommended dose in humans) caused a delay in the growth and development of the offspring. An embryotoxic effect (increased post-implantation losses) was observed but no malformations were observed in rats and rabbits up to doses of 200 mg / kg and 75 mg / kg, respectively (100 times and 38 times the maximum recommended dose in the " man).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
CARAVEL 6.25 mg tablets: sucrose; lactose monohydrate; polyvinylpyrrolidone; anhydrous colloidal silica; crospovidone; magnesium stearate; yellow iron oxide (E 172).
CARAVEL 25 mg tablets: sucrose; lactose monohydrate; polyvinylpyrrolidone; anhydrous colloidal silica; crospovidone; magnesium stearate.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
36 months.
06.4 Special precautions for storage
Store the product in the original packaging to protect it from moisture and light; store at a temperature not exceeding 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
The tablets are packed in PVC / PVDC-Al blisters.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
SPA - Antibiotic Products Company S.p.A. - Via Biella, 8 - 20143 Milan.
08.0 MARKETING AUTHORIZATION NUMBER
CARAVEL 6.25 mg tablets - 28 divisible tablets AIC 036339012
CARAVEL 25 mg tablets - 30 divisible tablets AIC 036339024
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
5 October 2005/5 October 2010.
10.0 DATE OF REVISION OF THE TEXT
April 2015.
