Aloneb - Package Leaflet
Active ingredients: Nebivolol, Hydrochlorothiazide
ALONEB 5 mg / 25 mg film-coated tabletsAloneb package inserts are available for pack sizes:
- ALONEB 5 mg / 25 mg film-coated tablets
- ALONEB 5 mg / 12.5 mg film-coated tablets
Why is Aloneb used? What is it for?
ALONEB contains nebivolol and hydrochlorothiazide as active ingredients.
Nebivolol is a cardiovascular drug belonging to the group of selective beta-blocking agents (ie with a selective action on the cardiovascular system). It prevents an increase in heart rate and controls the strength of the heart pump. It also exerts a dilating action on blood vessels, helping to lower blood pressure. Hydrochlorothiazide is a diuretic that works by increasing the amount of urine produced by the patient.
ALONEB combines nebivolol and hydrochlorothiazide in one tablet. It is used to treat high blood pressure (high blood pressure). It is used instead of the two separate products for those patients who are already taking them at the same time.
Contraindications When Aloneb should not be used
Do not take ALONEB:
- if you are allergic to nebivolol or hydrochlorothiazide or any of the other ingredients of this medicine (listed in section 6);
- if you are allergic (hypersensitive) to other substances derived from sulfonamide (such as hydrochlorothiazide, which is a drug derived from sulfonamide);
- if you have one or more of the following disorders:
- very low heart rate (less than 60 beats per minute);
- other severe heart rhythm disturbances (e.g. sick sinus syndrome, sino-atrial block, 2nd and 3rd degree atrioventricular block);
- recently onset or worsening heart failure, or if you are being treated for circulatory shock due to acute heart failure by intravenous administration to help the heart function;
- low blood pressure;
- severe circulation problems in the arms or legs;
- untreated pheochromocytoma, a tumor located over the kidneys (in the adrenal glands);
- severe kidney problems, complete absence of urine (anuria);
- n metabolic disturbance (metabolic acidosis), for example diabetic ketoacidosis;
- asthma or difficulty breathing (now or in the past);
- impaired liver function;
- high levels of calcium in the blood, low levels of potassium and sodium in the blood (persistent and resistant to therapy);
- high uric acid levels with gout symptoms.
Precautions for use What you need to know before taking Aloneb
Talk to your doctor or pharmacist before taking ALONEB.
- Tell your doctor if you notice or develop any of the following problems:
- a type of chest pain due to the spontaneous onset of a spasm in the blood vessels that supply the heart, called Prinzmetal's angina;
- 1st degree heart block (a mild heart conduction disorder that affects the heart rhythm);
- abnormally slow heartbeat;
- Untreated chronic heart failure;
- lupus erythematosus (disorder of the immune system, ie the body's defense system);
- psoriasis (a skin disease causing pink scaly patches) or if you have suffered from psoriasis in the past;
- overactive thyroid gland: this medicine can mask the signals of an abnormally fast heart rate caused by this condition;
- poor circulation in the arms or legs, for example Raynaud's disease or syndrome, cramps when walking;
- allergy: this medicine can intensify your reactions to pollen or other substances to which you are allergic;
- prolonged breathing difficulties;
- diabetes: this medicine may mask the warning signs of low glucose levels (e.g. palpitations, fast heart rate); your doctor will also tell you to check your blood sugar more often when taking ALONEB, as the dose of your antidiabetic medicines may need to be adjusted;
- kidney problems: your doctor will check your kidney function to make sure it doesn't get worse. If you have severe kidney problems do not take ALONEB (see section "Do not take ALONEB");
- if you tend to have a low level of potassium in your blood, and especially if you have long QT syndrome (a type of electrocardiographic abnormality) or are taking digitalis (to help your heart pump); you are more likely to have low blood potassium levels if you have liver cirrhosis, or have had rapid water loss after intense diuretic therapy, or if your potassium intake with food and drink is inadequate;
- if you are going to have surgery, always tell your anesthetist that you are being treated with ALONEB before undergoing anesthesia
- ALONEB can increase the levels of blood fats and uric acid. It can affect the levels of certain chemicals in the blood called electrolytes: your doctor will check them periodically with a blood test.
- The hydrochlorothiazide in ALONEB can make your skin hypersensitive to sunlight or artificial UV light. Stop taking ALONEB and see your doctor if a rash, itchy spots or skin sensitivity appear during therapy (see also section 4).
- Doping test: ALONEB can cause a positive doping test result.
Children and adolescents
Due to the lack of data on the use of the product in children and adolescents, the use of ALONEB is not recommended for these age groups.
Interactions Which drugs or foods can modify the effect of Aloneb
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines Always tell your doctor if you are using or have recently been given any of the following medicines in addition to ALONEB.
- Medicines which, like ALONEB, can affect blood pressure and / or heart function:
- Medicines to control blood pressure or for heart problems (e.g. amiodarone, amlodipine, cibenzoline, clonidine, digoxin, diltiazem, disopyramide, dofetilide, felodipine, flecainide, guanfacine, hydroquinidine, ibutilide, lacidipine, lidocaine, mexiladine, mexyloxine nicardipine, nifedipine, nimodipine, nitrendipine, propafenone, quinidine, rilmenidine, sotalol, verapamil);
- sedatives and therapies for psychosis (a mental illness), eg amisulpiride, barbiturates (also used for epilepsy), chlorpromazine, ciamemazine, droperidol, haloperidol, levomepromazine, narcotics, phenothiazine (also used for vomiting and nausea), pimozide, sulpiride, sultopride, thioridazine, thiapride, trifluoperazine;
- medicines for depression, eg amitriptyline, fluoxetine, paroxetine;
- medicines used for anesthesia during surgery;
- medicines for asthma, nasal congestion or certain eye disorders such as glaucoma (increased pressure in the eye) or dilation (widening) of the pupil;
- Baclofen (an antispasmodic drug);
- Amifostine (a protective medicine used during anti-cancer treatment).
- Medicines whose effect or toxicity may be increased by ALONEB:
- lithium (used as a mood stabilizer);
- cisapride (used for digestive problems);
- bepridil (used for angina);
- difemanil (used for excessive sweating);
- medicines used for infections: erythromycin given by infusion or injection, pentamidine and sparfloxacin, amphotericin and penicillin G sodium, halofantrine (used for malaria);
- vincamine (used for circulatory problems in the brain);
- mizolastine and terfenadine (used for allergy);
- diuretics and laxatives;
- medicines used to treat acute inflammation: steroids (eg cortisone and prednisone), ACTH (adrenocorticotropic hormone), and medicines derived from salicylic acid (eg acetylsalicylic acid / aspirin and other salicylates);
- carbenoxolone (used for heartburn and stomach ulcer);
- calcium salts (used as bone health supplements);
- medicines used to relax muscles (for example tubocurarine);
- diaxozide, used to treat hypoglycemia and hypertension;
- amantadine, an antiviral drug;
- cyclosporine, used to suppress the body's immune response;
- iodinated contrast media, used as a contrast medium in radiographs;
- anti-cancer medicines (e.g. cyclophosphamide, fluorouracil, methotrexate).
- Medicines whose effect can be reduced by ALONEB:
- Medicines that lower blood sugar levels (insulin and oral antidiabetics, metformin);
- Medicines for gout (e.g. allopurinol, probenecid and sulfinpyrazone);
- Medicines such as noradrenaline, used to treat low blood pressure or slow heart rate (bradycardia).
- Medicines for pain and inflammation (non-steroidal anti-inflammatory drugs), as these may reduce the blood pressure lowering effect of ALONEB.
- Medicines to treat excess stomach acid or ulcers (antacids), for example cimetidine: you should take ALONEB during a meal and the antacid between meals.
ALONEB with alcohol
When taking ALONEB, be careful not to drink alcohol, as you may feel confused or dizzy. If this happens to you, do not drink alcohol, including wine, beer or low-alcohol drinks.
Warnings It is important to know that:
Pregnancy and breastfeeding
You should tell your doctor if you are or think you are pregnant. As a rule, your doctor will advise you to take another medicine instead of ALONEB, as ALONEB is not recommended in pregnancy. This is because the active ingredient hydrochlorothiazide crosses the placenta. The use of ALONEB in pregnancy can cause potentially harmful effects on the fetus and newborn. Tell your doctor if you are breast-feeding or about to start breast-feeding. ALONEB is not recommended for women who are 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.
Driving and using machines
This medicine can cause dizziness or fatigue. If these conditions occur, do not drive or use machines.
ALONEB contains lactose
This product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Dosage and method of use How to use Aloneb: Dosage
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
Take one tablet a day with some water, preferably at the same time each day. ALONEB can be taken before, during or after meals, or alternatively, even without food.
Use in children and adolescents
Do not give ALONEB to children or adolescents.
If you forget to take ALONEB
If you forget to take a dose of ALONEB, but remember it shortly after, you can take that dose as usual. next, skip the missed dose and take your next normal dose at the usual time. Do not take a double dose. However, avoid repeatedly skipping doses.
If you stop taking ALONEB
You should always consult your doctor before stopping ALONEB therapy.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Aloneb
If you accidentally take too much of this medicine, tell your doctor or pharmacist immediately. The most frequent symptoms and signs of overdosing are very slow heartbeat (bradycardia), low blood pressure with possible fainting, shortness of breath as in asthma, acute heart failure, excessive passing of urine resulting in dehydration, nausea and sleepiness. , muscle spasms, heart rhythm disturbances (especially if you are also taking digitalis or medicines for heart rhythm problems).
Side Effects What are the side effects of Aloneb
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported with nebivolol:
Common side effects (may affect up to 1 in 10 people):
- unusual burning, tingling, tickling or tingling sensation
- swelling in the hands and feet.
Uncommon side effects (may affect up to 1 in 100 people):
- slow heart rate or other heart problems
- low blood pressure
- leg cramp-like pain while walking
- abnormal vision
- feeling depressed
- difficulty in digestion, gas in the stomach or intestines, vomiting
- rash, itching
- shortness of breath as in asthma, due to sudden cramps of the muscles of the airways (bronchospasm)
Very rare side effects (may affect up to 1 in 10,000 people):
- worsening of psoriasis (a skin disease causing scaly pink patches).
The following side effects have only been reported in a few isolated cases:
- widespread allergic reactions throughout the body, including generalized skin rashes (hypersensitivity reactions);
- rapid onset swelling, especially around the lips, eyes or tongue, with possible sudden difficulty in breathing (angioedema);
- a type of rash characterized by itchy, raised, light red bumps that are allergic or non-allergic in nature (hives).
The following undesirable effects have been reported with hydrochlorothiazide:
- generalized allergic reaction (anaphylactic reaction)
Heart and circulation
- heart rhythm disturbances, palpitations
- changes in the electrocardiogram
- sudden fainting on standing up, blood clots in the veins (thrombosis) and embolism, circulatory collapse (shock)
- changes in the number of blood cells, such as: decrease in white blood cells, decrease in platelets, decrease in red blood cells; reduced production of new blood cells by the bone marrow
- altered levels of body fluids (dehydration) and blood electrolytes, particularly decreased potassium, sodium, magnesium, chlorine and increased calcium
- increased uric acid levels, gout, increased blood sugar, diabetes, metabolic alkalosis (a metabolic disorder), increased cholesterol and triglycerides.
Stomach and intestines
- Lack of appetite, dry mouth, nausea, vomiting, stomach upset, abdominal pain, diarrhea, poor bowel movements (constipation), no bowel movements (paralytic ileus), flatulence
- inflammation of the glands that produce saliva, inflammation of the pancreas, increase in the level of blood amylase (a pancreatic enzyme)
- yellowing of the skin (jaundice), inflammation of the gallbladder
- Difficulty breathing, inflammation of the lungs (pneumonia), formation of fibrous tissue in the lungs (interstitial lung disease), accumulation of fluid in the lungs (pulmonary edema)
- Vertigo (spinning sensation)
- convulsions, decreased level of consciousness, coma, headache, dizziness
- apathy, confusional state, depression, nervousness, restlessness, sleep disturbances
- unusual burning, tingling, tickling, or tingling of the skin
- muscle weakness (paresis)
Skin and hair
- Itching, purple spots or patches on the skin (purpura), hives, increased sensitivity of the skin to sunlight, rash, facial rash and / or red patches that can cause scarring (cutaneous lupus erythematosus), inflammation of blood vessels with subsequent tissue death (necrotizing vasculitis), peeling, redness, laxity and blistering of the skin (toxic epidermal necrolysis)
Eyes and ears
- Yellow vision, blurred vision, worsening of myopia, reduced lacrimation.
Muscles and joints
- Muscle spasm, muscle pain
- Renal dysfunction, acute renal failure (reduced production of urine and accumulation of fluids and waste in the body), inflammation of the connective tissue inside the kidneys (interstitial nephritis), sugar in the urine.
- General / Other Erection Disorders
- General weakness, fatigue, fever, thirst.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov. it / it / responsible. 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.
This medicinal product does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. ".
The expiry date refers to the last day of that month.
Do not 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.
Deadline "> Other information
What does ALONEB
The active ingredients are nebivolol and hydrochlorothiazide.
Each tablet contains 5 mg of nebivolol (as nebivolol hydrochloride) 2.5 mg of d-nebivolol and 2.5 mg of l-nebivolol) and 25 mg of hydrochlorothiazide.
The excipients are:
- tablet core: lactose monohydrate, polysorbate 80 (E433), hypromellose (E464), corn starch, croscarmellose sodium (E468), microcrystalline cellulose (E460), colloidal anhydrous silica (E551), magnesium stearate (E572)
- tablet coating: macrogol 40 stearate type I, titanium dioxide (E171), carmine (carminic acid on aluminum lake, E120), hypromellose (E464), microcrystalline cellulose (E460)
Description of the appearance of ALONEB and contents of the package
ALONEB is available as slightly biconvex, purple, round coated tablets, debossed with "5/25" on one side in packs of 7, 14, 28, 30, 56, 90 coated tablets.
The tablets are supplied in blisters (PP / COC / PP / aluminum).
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
ALONEB 5 MG / 25 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each ALONEB tablet contains 5 mg of nebivolol (as nebivolol hydrochloride: 2.5 mg of SRRR-nebivolol or d-nebivolol and 2.5 mg of RSSS-nebivolol or l-nebivolol), and 25 mg of hydrochlorothiazide.
Excipients with known effect: each tablet contains 116.75 mg of lactose (see section 4.4).
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM -
ALONEB 5 mg / 25 mg: slightly biconvex, purplish, round coated tablets, debossed with "5/25" on one side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Treatment of essential hypertension.
The fixed dose combination ALONEB 5 mg / 25 mg is indicated in patients whose blood pressure is adequately controlled with concomitant administration of 5 mg nebivolol and 25 mg hydrochlorothiazide.
04.2 Posology and method of administration -
ALONEB 5 mg / 25 mg is indicated in patients whose blood pressure is adequately controlled with concomitant administration of 5 mg nebivolol and 25 mg hydrochlorothiazide.
The dose is one tablet (5 mg / 25 mg) per day, preferably at the same time.
Patients with renal insufficiency
ALONEB must not be administered to patients with severe renal impairment (see also sections 4.3 and 4.4).
Patients with hepatic insufficiency
Data on patients with hepatic insufficiency or impaired hepatic function are limited. For this reason the use of ALONEB in these patients is contraindicated.
In view of the limited experience with patients over 75 years of age, caution should be used and carefully monitored these patients.
The safety and efficacy of Aloneb in children and adolescents below 18 years of age is not established. No data are available. Therefore, its use in children and adolescents is not recommended.
Method of administration
The tablets can be taken with meals.
04.3 Contraindications -
- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
- Hypersensitivity to other sulfonamide derivatives (because hydrochlorothiazide is a sulfonamide derivative medicine).
- Hepatic failure or impaired liver function.
- Anuria, severe renal insufficiency (creatinine clearance
- Acute heart failure, cardiogenic shock or acute heart failure episodes requiring inotropic intravenous therapy.
- Sinus node syndrome, including sino-atrial node block.
- Second and third degree atrioventricular block (without pacemaker).
- Bradycardia (heart rate
- Hypotension (systolic blood pressure
- Severe peripheral circulatory disorders.
- History of bronchospasm and bronchial asthma.
- Untreated pheochromocytoma.
- Metabolic acidosis.
- Refractory hypokalemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.
04.4 Special warnings and appropriate precautions for use -
All the warnings relating to each of the two components, listed below, also apply to the fixed combination ALONEB. See also section 4.8.
The following warnings and precautions for use reflect those generally applicable to beta-adrenergic antagonist drugs.
• Anesthesia - Maintaining beta blockade reduces the risk of arrhythmias during induction and intubation. If, in anticipation of surgery, it is decided to interrupt the beta receptor blockade, therapy with beta-adrenergic antagonists should be stopped at least 24 hours beforehand.
Particular care should be taken in the use of certain anesthetic drugs that cause myocardial depression. The patient can be protected against vagal reactions by intravenous administration of atropine.
• Cardio-vascular system - In general, beta-adrenergic antagonists should not be used in patients with untreated congestive heart failure (CHF) unless their condition has stabilized.
In patients with ischemic heart disease, treatment with beta-adrenergic antagonists should be discontinued gradually, i.e. over 1-2 weeks. If necessary, replacement therapy should be started at the same time to prevent an "exacerbation of" angina pectoris. Beta-adrenergic antagonists can induce bradycardia: if the rate falls below 50-55 bpm at rest and / or the patient exhibits symptoms attributable to bradycardia, the dosage should be reduced.
Beta adrenergic antagonists should be used with caution in:
- patients with peripheral circulatory diseases (Raynaud's syndrome or disease, intermittent claudication), as worsening of these disorders may occur;
- patients with first degree atrioventricular block, due to the negative effect of beta-blockers on conduction time;
- patients with Prinzmetal's angina due to coronary vasoconstriction due to non-contrasted alpha-adrenergic stimulation: beta-adrenergic antagonists can increase the number and duration of angina attacks.
Administration of nebivolol in combination with calcium channel blockers of the verapamil and diltiazem type, with Class I antiarrhythmic drugs and centrally acting antihypertensive drugs is generally not recommended, for details see section 4.5.
• Metabolism and the endocrine system - Nebivolol does not interfere with blood glucose in diabetic patients. However, it should be used with caution in diabetic patients, as nebivolol may mask some symptoms of hypoglycaemia (tachycardia, palpitations).
Beta-adrenergic antagonist drugs may mask the symptoms of tachycardia in hyperthyroidism. Abrupt discontinuation of administration may intensify these symptoms.
• Respiratory system - In patients with chronic obstructive pulmonary disorders, beta-adrenergic antagonists should be used with caution, as the constriction of the airways may be aggravated.
• Other - In patients with a history of psoriasis beta-adrenergic antagonists should only be administered after careful consideration.
Beta-adrenergic antagonists may increase sensitivity to allergens and the severity of anaphylactic reactions.
• Kidney failure - Maximum benefits can be obtained from thiazide diuretics only if renal function is not impaired. In patients with renal dysfunction thiazides may increase azotemia. In patients with impaired renal function accumulation effects of this active substance may develop. If there is a progressive decrease in renal function, as indicated by the increase in non-protein nitrogen, a careful review of the therapy is necessary, evaluating the possibility of interrupting diuretic therapy.
• Metabolism and the endocrine system. Thiazide therapy may decrease glucose tolerance. Dosage adjustments of insulin or oral hypoglycaemic agents may be necessary (see section 4.5). Latent diabetes mellitus may become manifest during therapy with thiazide.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Such therapy can precipitate hyperuricaemia and gout in certain patients.
• Electrolyte imbalance - As with any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause an imbalance of fluids or electrolytes (hypokalemia, hyponatremia and hypochloraemic alkalosis). Symptoms that suggest a water and electrolyte imbalance are: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness , muscle aches or cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
The risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients with excessive diuresis, in patients receiving inadequate amounts of electrolytes by mouth and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5). Patients with a long QT syndrome, either congenital or iatrogenic, are at particularly high risk for hypokalemia. Hypokalaemia increases the cardiotoxicity of digitalis glucosides and the risk of cardiac arrhythmia. More frequent plasma potassium monitoring is indicated in patients at risk of hypokalaemia, starting within one week after initiation of therapy.
In the case of very high ambient temperatures, dilution hyponatremia can occur in oedematous patients. Chloride deficiency is generally mild and does not usually require treatment.
Thiazides can reduce the excretion of calcium in the urine and cause a slight and intermittent increase in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Administration of thiazides should be discontinued prior to performing the parathyroid function test.
Thiazides have been shown to increase urinary excretion of magnesium, which can cause hypomagnesaemia.
• Lupus erythematosus - Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
• Doping test - The hydrochlorothiazide contained in this drug can give a positive result in a doping test.
• Other - Sensitization reactions can occur in patients with or without a history of allergy or bronchial asthma.
In rare cases, photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reactions occur during treatment, it is recommended to stop the treatment. If it is deemed necessary to re-administer the drug, it is recommended to protect exposed areas from the sun or artificial UVA light.
• Iodine-protein bond - Thiazides can reduce serum protein bound iodine levels without signs of thyroid dysfunction.
Nebivolol / hydrochlorothiazide combination
In addition to the warnings relating to the individual components, there is also a "warning that applies specifically to ALONEB:
• Galactose intolerance, Lapp-lactase deficiency, glucose-galactose malabsorption - This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this drug.
04.5 Interactions with other medicinal products and other forms of interaction -
The following interactions reflect those that are generally described for beta-adrenergic antagonists.
- Combinations not recommended
Class I antiarrhythmics (quinidine, hydroquinidine, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine, propafenone): the effect on atrio-ventricular conduction time can be potentiated and the negative inotropic effect increased (see section 4.4).
Calcium channel blockers such as verapamil / diltiazem: negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block (see section 4.4).
Centrally acting antihypertensives (clonidine, guanfacine, monoxidine, methyldopa, rilmenidine): Concomitant use of centrally acting antihypertensives may aggravate heart failure by decreasing central sympathetic tone (reduced heart rate and cardiac output, vasodilation) (see section 4.4). Sudden discontinuation, particularly if prior to discontinuation of the beta-blocker, may increase the risk of "rebound arterial hypertension".
- Combinations to be used with caution
Class III antiarrhythmics (amiodarone): May potentiate the effect on atrioventricular conduction time.
Volatile halogenated anesthetics: Concomitant use of beta-adrenergic antagonists and anesthetics may attenuate reflex tachycardia and increase the risk of hypotension (see section 4.4). As a general rule, avoid abrupt discontinuation of beta-blocker treatment. The anesthetist should be informed about the patient's intake of ALONEB.
Insulin and oral antidiabetic drugs: although nebivolol has no influence on blood glucose, concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia).
Baclofen (an antispasmodic agent), amifostine (in addition to antineoplastics): concomitant use with antihypertensive agents is likely to may increase the fall in blood pressure, therefore the dosage of the antihypertensive drug should be adjusted accordingly.
- Associations to be taken into consideration
Digitalis glycosides: Concomitant use may increase atrioventricular conduction time. Clinical studies with nebivolol have provided no clinical evidence of interaction. Nebivolol has no effect on digoxin kinetics.
Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine): Concomitant use may increase the risk of hypotension and, in patients with heart failure, an increase in the risk of further deterioration of ventricular pump function cannot be excluded.
Antipsychotics, antidepressants (tricyclics, barbiturates and phenothiazines): concomitant use may potentiate the hypotensive effect of beta-blockers (additive effect).
Non-steroidal anti-inflammatory drugs (NSAIDs): no interference on the hypotensive effect of nebivolol.
Sympathomimetic drugs: concomitant use may counteract the effect of beta-adrenergic antagonists. Beta-adrenergic drugs can lead to non-counteracted alpha-adrenergic activity of sympathomimetic drugs with both alpha and beta-adrenergic effects (risk of hypertension, severe bradycardia and heart block).
Potential interactions related to hydrochlorothiazide:
- Concomitant use not recommended
Lithium: Renal clearance of lithium is reduced by thiazides and, consequently, the risk of lithium toxicity may increase when used concomitantly with hydrochlorothiazide. The use of ALONEB in combination with lithium is therefore not recommended. If the use of this combination proves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium levels: The potassium-depleting effect of hydrochlorothiazide (see section 4.4) can be potentiated by concomitantly administering other medicinal products associated with potassium loss and hypokalemia (eg other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or derivatives of salicylic acid). Such concomitant use is therefore not recommended.
- Concomitant use requiring caution
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs (ie acetylsalicylic acid (> 3 g / day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics.
Calcium salts: Thiazide diuretics may increase serum calcium levels due to reduced excretion. If calcium supplements are to be prescribed, serum calcium levels should be monitored and the calcium dosage adjusted accordingly.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may favor the onset of digitalis-induced cardiac arrhythmias.
Medicinal products affected by changes in serum potassium: Periodic monitoring of serum potassium and an ECG are recommended when ALONEB is given together with drugs whose effects are affected by changes in serum potassium (e.g. digitalis glycosides and antiarrhythmics) and together with medicinal products (including some antiarrhythmics) that induce torsades de pointes (ventricular tachycardia), since hypokalemia is a predisposing factor for torsades de pointes (ventricular tachycardia):
- class Ia antiarrhythmics (eg quinidine, hydroquinidine, disopyramide);
- class III antiarrhythmics (for example amiodarone, sotalol, dofetilide, ibutilide);
- some antipsychotics (e.g. thioridazine, clopromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, sultopride, amilsulpride, thiapride, pimozide, haloperidol, droperidol);
- others (e.g. bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Nondepolarizing muscle relaxants (e.g. tubocurarine): hydrochlorothiazide may potentiate the effect of non-depolarising muscle relaxants.
Antidiabetic drugs (oral agents and insulin): treatment with a thiazide can affect glucose tolerance. Dosage adjustment of the antidiabetic drug may be necessary (see section 4.4).
Metformin: Metformin should be used with caution, due to the risk of lactic acidosis induced by possible renal failure related to hydrochlorothiazide.
Beta-blockers and diazoxide: the hyperglycemic effect of beta-blockers other than nebivolol and diazoxide may be potentiated by thiazides.
Pressor amines (e.g. norepinephrine): the effect of the pressor amines can be reduced.
Drugs used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol): The dosage of uricosuric drugs may need to be adjusted, because drochlorothiazide may increase the level of serum uric acid. The dosage of probenecid or sulfinpyrazone may need to be increased. Co-administration of a thiazide may increase the incidence of drug reactions. hypersensitivity to allopurinol.
Amantadina: Thiazides may increase the risk of adverse effects caused by amantadine.
Salicylates: in case of high doses of salicylates, hydrochlorothiazide can potentiate the toxic effect of salicylates on the central nervous system.
Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.
Iodine contrast media: in case of diuretic-induced dehydration there is an increased risk of acute renal failure, especially in the presence of high doses of iodized products. Patients should be rehydrated prior to administration.
Potential interactions related to both nebivolol and hydrochlorothiazide
- Concomitant use which may be considered
Other antihypertensive drugs: Additional hypotensive effects or their enhancement may occur during concomitant treatment with other antihypertensive drugs.
Antipsychotics, tricyclic antidepressants, barbiturates, narcotics and alcohol: concomitant administration of ALONEB with these drugs can potentiate the hypotensive effect and / or cause postural hypotension.
Since the CYP2D6 isoenzyme is involved in the metabolism of nebivolol, concomitant administration of substances that inhibit this enzyme, particularly paroxetine, fluoxetine, thioridazine and quinidine - may lead to increased plasma levels of nebivolol associated with an increased risk of excessive bradycardia and adverse events.
Concomitant administration of cimetidine increased the plasma levels of nebivolol without changing the clinical effect. Concomitant administration of ranitidine did not affect the pharmacokinetics of nebivolol. If ALONEB is taken with meals and antacid drugs are taken between meals and "other, the two treatments can be prescribed at the same time. The combination of nebivolol with nicardipine weakly increased the plasma levels of both drugs, without changing the clinical effect. Concomitant intake of alcohol, furosemide or hydrochlorothiazide had no effect on the pharmacokinetics of nebivolol. Nebivolol had no effect on the pharmacokinetics and pharmacodynamics of warfarin.
The absorption of hydrochlorothiazide is reduced in the presence of ion exchange resins (eg. cholestyramine and colestipol).
Cytotoxic agents: with the concomitant use of hydrochlorothiazide and cytotoxic agents (eg cyclophosphamide, fluorouracil, methotrexate) an increase in bone marrow toxicity (in particular granulocytopenia) is to be expected.
04.6 Pregnancy and breastfeeding -
There are no adequate data on the use of ALONEB in pregnant women. Animal experiments with the two components are insufficient to elucidate the reproductive effects of the combination of nebivolol and hydrochlorothiazide (see section 5.3).
There are insufficient data on the use of nebivolol in human pregnancy to establish its potential toxicity. However, nebivolol has pharmacological effects that may cause harmful effects on pregnancy and / or the fetus / newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, and this has been associated with growth retardation, intrauterine death, abortion, premature birth Undesirable effects (eg hypoglycaemia and bradycardia) may occur in the fetus and newborn.
If treatment with beta-adrenergic antagonists is deemed necessary, beta1-selective antagonists are preferable.
Nebivolol should not be used during pregnancy unless absolutely necessary. If treatment with nebivolol is deemed necessary, uteroplacental blood flow and fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus, alternative treatment should be considered. Newborns must be carefully monitored. Symptoms of hypoglycemia and bradycardia are generally to be expected within the first 3 days of birth.
Experience with the use of hydrochlorothiazide during pregnancy, especially during the first trimester, is limited. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can impair fetal-placental perfusion and cause fetal and neonatal effects such as jaundice, electrolyte disturbance. and thrombocytopenia.
Hydrochlorothiazide should not be used in gestational edema, in pregnancy hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without favorable effects on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in those rare situations where no other treatment can be used.
It is not known whether or not nebivolol is excreted in human breast milk. Animal studies have shown that nebivolol is excreted in breast milk. Most beta-blockers, particularly lipophilic compounds such as nebivolol and its active metabolites, pass into breast milk albeit to varying degrees. Hydrochlorothiazide is excreted in human milk in small quantities. Thiazides in high doses, causing intense diuresis, can inhibit milk production. The use of ALONEB while breastfeeding is not recommended. If ALONEB is used during breastfeeding. , doses should be kept as low as possible.
04.7 Effects on ability to drive and use machines -
No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines it should be taken into account that antihypertensive therapy may occasionally cause dizziness and fatigue.
04.8 Undesirable effects -
Side effects are listed separately for each of the two active substances.
The table below presents the adverse events reported following administration of nebivolol alone, which in most cases are mild to moderate in intensity. These events are classified by organ and by order of frequency.
In addition, the following adverse reactions have been reported with some beta-adrenergic antagonists: hallucinations, psychosis, confusion, cold / cyanotic extremities, Raynaud's phenomenon, dry eyes and oculocutaneous toxicity like practolol.
The undesirable effects reported with the use of hydrochlorothiazide alone are the following:
- Blood and lymphatic system disorders: leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, bone marrow failure.
- Immune system disorders: anaphylactic reaction.
- Metabolism and nutrition disorders: anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricaemia, electrolyte imbalance (includes hyponatremia, hypokalemia, hypomagnesaemia, hypochloraemia, hypercalcemia), hyperglycemia, hyperamylasemia.
- Psychiatric disorders: apathy, confusion, depression, nervousness, restlessness, sleep disturbances.
- Nervous system disorders: convulsions, decreased level of consciousness, coma, headache, dizziness, paraesthesia, paresis.
- Eye disorders: xanthopsia, blurred vision, worsening of myopia, reduced lacrimation.
- Ear and labyrinth disorders: vertigo
- Cardiac disorders: cardiac arrhythmias, palpitations.
- Vascular disorders: orthostatic hypotension, thrombosis, embolism, shock.
- Respiratory, thoracic and mediastinal disorders: respiratory distress, pneumonia, interstitial lung disease, pulmonary edema.
- Gastrointestinal disorders: dry mouth, nausea, vomiting, gastric disturbances, diarrhea, constipation, abdominal pain, paralytic ileus, flatulence, sialoadenitis, pancreatitis.
- Hepato-biliary disorders: cholestatic jaundice, cholecystitis.
- Skin and subcutaneous tissue disorders: pruritus, purpura, urticaria, photosensitization reaction, rash, cutaneous lupus erythematosus, necrotizing vasculitis, toxic epidermal necrolysis.
- Musculoskeletal, connective tissue and bone disorders: muscle spasms, myalgia.
- Renal and urinary disorders: renal dysfunction, acute renal failure, interstitial nephritis, glycosuria.
- Reproductive system and breast disorders: erectile dysfunction.
- General disorders and administration site conditions: asthenia, pyrexia, fatigue, thirst.
- Investigations: electrocardiographic changes, increased blood cholesterol, increased blood triglycerides.
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 www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
There is no data on nebivolol overdose. Symptoms of overdose with beta-blockers are: bradycardia, hypotension, bronchospasm and acute heart failure.
Overdose of hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloraemia, hyponatremia) and dehydration following excessive diuresis. The most common signs and symptoms of hydrochlorothiazide overdose are nausea and somnolence. Hypokalemia can cause muscle spasm and / or acute cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
In case of overdose or hypersensitivity the patient should be kept under close surveillance and treated in an intensive care unit. Blood glucose levels should be monitored and serum electrolytes and creatinine monitored frequently. Absorption of drug residues still present in the gastrointestinal tract can be avoided by gastric lavage and administration of activated charcoal and a laxative. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma / plasma substitutes and, if necessary, with catecholamines. Electrolyte imbalances should be corrected. The beta-blocking effect can be counteracted by slowly intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 mcg / minute, or dobutamine, starting with a dose of 2.5 mcg / minute, until the required effect is achieved. In refractory cases it is possible to combine isoprenaline and dopamine. If this does not produce the desired effect, it can be considered the intravenous administration of glucagon 50-100 mcg / kg. If necessary, the injection can be repeated within one hour and should be followed - if necessary - by an intravenous infusion of glucagon of 70 mcg / kg / h. In extreme cases of treatment-resistant bradycardia, a pacemaker can be inserted.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: beta-blocking agents, selective, and thiazides.
ATC code: C07BB 12.
ALONEB is a combination of nebivolol (a selective beta-adrenergic receptor antagonist) and hydrochlorothiazide (a thiazide diuretic). The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater extent than either of the two components used alone.
Nebivolol is a racemate of two enantiomers, SRRR-nebivolol (or d-nebivolol) and RSSS-nebivolol (or l-nebivolol). It is a drug with dual pharmacological activity:
• it is a competitive and selective antagonist of beta-receptors: this effect is attributed to the enantiomer SRRR (d-enantiomer);
• has mild vasodilatory properties due to the interaction with the L-arginine / nitric oxide pathway.
Nebivolol administered in single and repeated doses reduces heart rate and blood pressure, at rest and during exercise, in both normal and hypertensive patients. The antihypertensive effect is maintained during chronic treatment.
At therapeutic dosages, nebivolol is devoid of alpha-adrenergic antagonism.
Systemic vascular resistance decreases during acute and chronic treatment with nebivolol in hypertensive patients. The reduction in cardiac output at rest or under exertion can be contained, despite the reduction in heart rate, due to an increase in systolic output. The clinical relevance of these haemodynamic differences relative to other beta-1 antagonists has not been fully established. In hypertensive patients, nebivolol increases the vascular -nitroxide-mediated- response to acetylcholine (ACh), which is reduced in patients with endothelial dysfunction.
Experimental in vitro and in vivo animal studies have shown that nebivolol is devoid of intrinsic sympathomimetic activity.
In vitro and in vivo experimental studies on animals have shown that nebivolol does not possess membrane stabilizing activity at pharmacological doses.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
Hydrochlorothiazide is a thiazide diuretic. Thiazides act on the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chloride in approximately equivalent quantities. The diuretic action of hydrochlorothiazide reduces plasma volume, increases blood volume. "Plasma renin activity and aldosterone secretion, resulting in increases in urinary loss of potassium and bicarbonate, and decreases in serum potassium. With hydrochlorothiazide, diuresis occurs after about 2 hours and the maximum effect appears about 4 hours after the dose, while the action persists for about 6-12 hours.
05.2 "Pharmacokinetic properties -
Concomitant administration of nebivolol and hydrochlorothiazide has no effect on the bioavailability of the two active substances. The combination tablet is bioequivalent to the concomitant administration of the two separate components.
Both enantiomers of nebivolol are rapidly absorbed after oral administration. Absorption of nebivolol is not affected by simultaneous food intake: nebivolol can be taken with or without food.
The oral bioavailability of nebivolol averages 12% in extensive metabolisers and is practically complete in poor metabolisers. At steady state and at the same dose, the peak plasma concentration of unchanged nebivolol is approximately 23-fold higher in poor metabolisers than in extensive metabolisers. When the sum of the concentrations of the parent drug and the active metabolites are considered, the difference in the peak plasma concentrations is 1.3-1.4 times.
Due to the variability in the rate of metabolism, the dosage of nebivolol must always be individually adapted to the needs of the individual patient: poor metabolisers may therefore require lower dosages.
Plasma concentrations are dose proportional in the range of 1 to 30 mg. The pharmacokinetics of nebivolol are not affected by age.
In plasma, both enantiomers of nebivolol are predominantly bound to albumin. The plasma protein binding is 98.1% for SRRR-nebivolol and 97.9% for RSSS-nebivolol.
Nebivolol is extensively metabolised, partly to active hydroxymetabolites. Nebivolol is metabolised via aromatic and alicyclic hydroxylation, N-dealkylation and glucuronidation, with further formation of glucuronides of the hydroxymetabolites. The metabolism of nebivolol by aromatic hydroxylation is subject to CYP2D6-dependent genetic oxidative polymorphism.
In rapid metabolisers, the elimination half-lives of the enantiomers of nebivolol average 10 hours. In slow metabolisers they are 3-5 times longer. In rapid metabolisers, plasma levels of the RSSS enantiomer are slightly higher than those of the SRRR enantiomer. In poor metabolisers this difference is greater. In rapid metabolisers, the elimination half-lives of hydroxymetabolites of both enantiomers average 24 hours, and about twice as long in poor metabolisers. In most subjects (extensive metabolisers) it is. steady state is achieved within 24 hours for nebivolol and within a few days for hydroxymetabolites.
After one week of administration, 38% of the dose is excreted in the urine and 48% in the faeces. The urinary excretion of unchanged nebivolol is less than 0.5% of the dose.
Hydrochlorothiazide is well absorbed (65-75%) after oral administration. Plasma concentrations are linearly related to the administered dose. The absorption of hydrochlorothiazide depends on the intestinal transit time, ie it increases when the intestinal transit time is slow, for example when given with food. Following plasma levels over at least 24 hours, the plasma half-life was observed to vary between 5.6 and 14.8 hours, and peak plasma levels were observed within 1 and 5 hours after administration.
Hydrochlorothiazide is 68% bound to plasma proteins, and its apparent volume of distribution is 0.83-1.14 l / kg. Hydrochlorothiazide crosses the placental barrier but not the blood brain barrier.
The metabolism of hydrochlorothiazide is very poor. Almost all hydrochlorothiazide is excreted unchanged in the urine.
Hydrochlorothiazide is eliminated primarily by the kidney. More than 95% of hydrochlorothiazide appears unchanged in the urine within 3-6 hours after an oral dose. In patients with renal dysfunction, plasma concentrations of hydrochlorothiazide are higher and the elimination half-life. is prolonged.
05.3 Preclinical safety data -
Non-clinical data reveal no special hazard for humans of a combination of nebivolol and hydrochlorothiazide. This is based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential of the individual components.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet
Polysorbate 80 (E433)
Croscarmellose sodium (E468)
Microcrystalline cellulose (E460)
Anhydrous colloidal silica (E551)
Magnesium stearate (E572)
Microcrystalline cellulose (E460)
Macrogol 40 stearate type I
Titanium dioxide (E171)
Carmine (carminic acid on aluminum lake, E120)
06.2 Incompatibility "-
06.3 Period of validity "-
06.4 Special precautions for storage -
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
The tablets are supplied in blisters (PP / COC / PP / aluminum).
Packs of 7.14, 28, 30, 56, 90 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Menarini International Operations Luxembourg S.A. 1, Avenue de la Gare L-1611 Luxembourg
Dealer for sale :
Istituto Luso Farmaco d "Italia S.p.A. - Milanofiori - Road 6 - Building L, Rozzano (MI)
08.0 MARKETING AUTHORIZATION NUMBER -
5 mg / 25 mg film-coated tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 30 March 2010
Date of last renewal: November 31, 2012
10.0 DATE OF REVISION OF THE TEXT -