Active ingredients: Diltiazem
ALTIAZEM 60 mg tablets
ALTIAZEM 120 mg prolonged-release tablets
ALTIAZEM 300 mg prolonged-release hard capsules
Why is Altiazem used? What is it for?
ALTIAZEM contains a substance called diltiazem, which belongs to the category of calcium channel blocking medicines that have a direct effect on the heart.
This medicine is indicated in adults and the elderly:
- In the treatment of angina pectoris (chest pain caused by insufficient oxygen supply to the heart) caused by exertion, following a heart attack or vasospastic (Prinzmetal's angina, caused by excessive narrowing of the arteries that supply blood to the heart) .
- In the treatment of mild and moderate arterial hypertension (high blood pressure).
Contraindications When Altiazem should not be used
Do not take ALTIAZEM
- If you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6).
- In case of hypotension (pressure drop, minimum pressure below 90 mmHg).
- In case of acute myocardial infarction (death of a part of the heart tissue as a result of the "stop of blood flow) with pulmonary congestion (pathological increase in the volume of the lung caused by excessive blood supply).
- If you suffer from sinus node dysfunction (the area of the heart where the heart's electrical impulses begin) and you do not have a functioning pacemaker.
- For second or third degree sino-atrial or atrio-ventricular block (defects in the conduction system of the heart) without a functioning ventricular pacemaker.
- In case of severe bradycardia (marked reduction in heart rate).
- In case of congestive heart failure (inability of the heart to supply adequate quantities of blood to the needs of the organism).
- In case of left ventricular failure with pulmonary stasis (accumulation of fluid in the lung leading to difficulty in breathing and coughing).
- In combination with other amiodarone and dantrolene medicines (see "Other medicines and ALTIAZEM").
- In known or suspected pregnancy, lactation, women of childbearing age (see "Pregnancy, lactation and fertility").
- If you are already taking a medicine containing ivabradine to treat other heart conditions.
ALTIAZEM is contraindicated in children and adolescents (0-17 years) (see "Children and adolescents").
Precautions for use What you need to know before taking Altiazem
Talk to your doctor or pharmacist before using ALTIAZEM.
Always consult your doctor to be instructed on the correct way to administer the medicine, and undergo constant checks.
Particular caution is required at the beginning of treatment (especially a constant monitoring of the heart rate is required).
Take ALTIAZEM with caution and be closely monitored if:
- Has decreased function of the left ventricle (region of the heart).
- You suffer from bradycardia (risk of worsening).
- You have first degree atrioventricular block as evidenced by the "ECG (electrocardiogram); c" is the risk of worsening and rarely of complete block.
Calcium channel blockers, such as diltiazem, can be associated with mood changes, including depression.
Take dilitiazem with caution if you are at risk of developing intestinal obstruction as diltiazem, like other calcium channel blockers, has an inhibitory effect on intestinal motility.
Your faeces may contain residues of the prolonged-release formulations; however this fact has no clinical relevance.
Since the prolonged-release formulations of diltiazem (ALTIAZEM 120 mg prolonged-release tablets and ALTIAZEM 300 mg prolonged-release hard capsules) have a different mechanism for the release of the active substance and different rates of absorption, do not substitute a prolonged-release formulation of diltiazem with each other.
During treatment, periodic checks of hepatic (liver) and renal function should be performed.
If you are elderly or have kidney or liver failure (decreased kidney or liver function) you may see increased concentrations of the medicine in the blood. In such cases, if you are taking other antihypertensive (blood pressure lowering) medicines at the same time, use the lowest effective dose (see "Other medicines and ALTIAZEM") as the hypotensive (blood pressure lowering) effect of diltiazem may be potentiated.
In case of general anesthesia, the anesthetist should be informed that the patient is taking diltiazem. The reduction of contractility, conduction and automatism of the heart and the dilation of the vessels induced by anesthetics can be enhanced by drugs that block the channels of the heart. calcium (such as ALTIAZEM).
ALTIAZEM 120 mg prolonged-release tablets are coated with an insoluble polymeric membrane that allows the controlled release of the active ingredient; this membrane is not modified by the passage through the stomach and intestines; if you find it in the faeces you should not think that the product has been ineffective.
Abrupt discontinuation of treatment may be associated with worsening of angina.
Children and adolescents
The safety of use and efficacy in children and adolescents have not been established. The use of diltiazem is not recommended in children and adolescents (see "Do not take ALTIAZEM").
Interactions Which drugs or foods may change the effect of Altiazem
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Do not take ALTIAZEM with:
- DANTROLENE, muscle relaxant used in a condition called "malignant hyperthermia" (severe fever) given by perfusion. When verapamil (calcium channel blocker such as diltiazem) and dantrolene are administered simultaneously into a vein, lethal (fatal) ventricular fibrillation is constantly observed.The combination of a calcium channel blocker and dantrolene is therefore potentially dangerous (see "Do not take ALTIAZEM").
- AMIODARONE (antiarrhythmic medicine). Diltiazem is contraindicated in patients receiving amiodarone (risk of bradycardia and atrioventricular block) (see "Do not take ALTIAZEM").
Take ALTIAZEM with caution in combination with:
- Anti-hypertensive; this combination increases the hypotensive (blood pressure lowering) effect, particularly of alpha-antagonist medicines (medicines used mainly for the treatment of arterial hypertension). The combination of diltiazem with an alpha-antagonist requires close monitoring of blood pressure.
- BETA-BLOCKERS (medicines used in the treatment of cardiac arrhythmia, hypertension and angina); this association leads to the possibility of heart rhythm disturbances (marked bradycardia, sinus node arrest (block of the cardiac electrical impulse) , sino-atrial and atrio-ventricular cardiac conduction disturbances, and cardiovascular decompensation (additive effect). Such combinations should not be used unless under close clinical and electrocardiogram surveillance, particularly at the start of treatment.
- CARDIAC GLYCOSIDES (medicines that increase the contractile strength of the heart). The combination of ALTIAZEM and cardiac glycosides increases the blood concentration of digoxin (a particular cardiac glycoside) and the risk of bradycardia; caution is required in case of combination with diltiazem, especially in elderly patients and if high doses are used. diltiazem on the sinus node and on the atrioventricular node potentiate those of digitalis preparations.
- ANTIARRITHMICS (medicines used to correct abnormal heart rhythms). Since diltiazem has antiarrhythmic properties, administration with other antiarrhythmics is not recommended due to the increased additive cardiac side effects. This combination should not be used unless under close clinical and electrocardiogram surveillance.
- NITRATES; this association leads to an increase in the hypotensive effect and lipothymias (feelings of sudden weakness) due to the effect of additive dilatation of blood vessels (see "Warnings and precautions"). In all patients treated with calcium channel blockers, the prescription of nitrates should be carried out at gradually increasing doses.
- CYCLOSPORINE (medicine used to modulate the body's immune response); the simultaneous administration of these two medicines leads to an increase in the levels of free cyclosporine in the blood. It is advisable to reduce the dose of cyclosporine, check kidney function, measure levels cyclosporine in the blood and adjust the dosage both during the combination therapy and after its discontinuation.
- CARBAMAZEPINE (medicine used to treat epilepsy); this combination increases the levels of free carbamazepine in the blood. It is advisable to measure the blood levels of carbamazepine and adjust the dosage if necessary. - PHENYTHIN (medicine used for the treatment of " epilepsy). Diltiazem causes an increase in the concentration of phenytoin in the blood; phenytoin reduces the effect of diltiazem.
- ANTIDEPRESSANTS; co-administration of antidepressants and diltiazem increases the concentration of imipramine (a particular antidepressant medicine) in the blood and possibly other tricyclic antidepressant medicines as well.
- ANTIPSYCHOTICS; the combination increases the pressure reducing effect.
- THEOPHYLINE (medicine used in various respiratory diseases); this association increases the levels of free theophylline in the blood.
- ANTIULCER (ANTI-H2) such as cimetidine and ranitidine (medicines used to treat ulcer, erosion of the inner lining of the stomach and duodenum); administration of ALTIAZEM with these medicines leads to increased levels of diltiazem in the blood. Patients on diltiazem therapy should be closely monitored when starting or stopping treatment with H2 blockers.A modification of the daily dose of diltiazem may be required.
- RIFAMPICIN (antibiotic); The combination of ALTIAZEM and rifampicin leads to the risk of decreased levels of diltiazem in the blood after starting treatment with rifampicin. Patients should be monitored closely when starting or stopping rifampicin treatment.
- LITHIUM (mood stabilizer); there may be a risk of increased toxic effects of lithium in the central nervous system.
- ANESTHETICS (see "Warnings and Precautions").
- Other medicines that modify cardiac contractility or conduction, due to potential additive effects.
- Medicinal products substrates of the CYP3A4 enzyme; the combination of ALTIAZEM with inhibitors or inducers of the enzyme may lead to an increase or decrease in the concentration of diltiazem in the blood. A moderate (less than 2-fold) increase in plasma concentrations of diltiazem has been documented. when administered with a more potent CYP3A4 inhibitor. Diltiazem is also a CYP3A4 inhibitor. Co-administration may result in increased plasma concentrations of either of the two co-administered medicinal products. Co-administration of diltiazem with a CYP3A4 inducer may result in decreased plasma concentrations of diltiazem.
- BENZODIAZEPINES, such as midazolam and triazolam (psychotropic drugs used to treat anxiety and insomnia); diltiazem significantly increases midazolam and triazolam concentrations and increases their residence time in the blood. Particular caution is required when prescribing short-acting benzodiazepines metabolised by CYP3A4 in patients taking diltiazem.
- CORTICOSTEROIDS, such as methylprednisolone (anti-inflammatory); this association may lead to inhibition of methylprednisolone metabolism and inhibition of P-glycoprotein (responsible for the transport of various substances across the cell membrane). Patients should be monitored when starting treatment with methylprednisolone. The dose of methylprednisolone may need to be adjusted. methylprednisolone.
- STATINS (medicines used to control cholesterol levels in the blood); diltiazem is an inhibitor of CYP3A4 and therefore may increase the blood concentrations of some statins metabolised by this enzyme, increasing the risk of myopathy (skeletal muscle disease) and rhabdomyolysis (very severe muscle damage). If possible, a statin not metabolised by CYP3A4 should be used with diltiazem, otherwise close monitoring for signs and symptoms of potential statin toxicity is required.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
Pregnancy
The use of diltiazem is contraindicated in pregnancy (see "Do not take ALTIAZEM"). Diltiazem has shown reproductive toxicity in some animal species (rat, mouse, rabbit). In humans, very limited data are available to date. use of diltiazem in pregnancy.
Fertility
In women of childbearing age, any pregnancy must always be excluded before the start of treatment and effective contraceptive coverage must be ensured during treatment.
Feeding time
Since diltiazem is excreted in breast milk, breastfeeding while taking this medicinal product should be avoided. If the use of ALTIAZEM is considered clinically essential, an alternative method of feeding the baby should be used.
Driving and using machines
Based on reported side effects, such as sleepiness, dizziness and feeling sick, the ability to drive and use machines may be impaired. In this case, avoid driving vehicles or using machines.
ALTIAZEM 60 mg tablets contain lactose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
ALTIAZEM 60 mg tablets contain hydrogenated castor oil. It can cause stomach upset and diarrhea.
ALTIAZEM 120 mg prolonged-release tablets contain sucrose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Altiazem: Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
ALTIAZEM 60 mg tablets
Angina pectoris
The recommended dose is 1 tablet 3 times a day, at regular intervals. If necessary, the dose may be increased up to 2 tablets 3 times a day based on the doctor's advice.
Hypertension
The recommended dose is half to 1 tablet 3 times a day.
ALTIAZEM 120 mg prolonged-release tablets
Angina pectoris and hypertension
The recommended dose is 1 tablet every 12 hours.
The tablets should not be chewed, but swallowed whole with some liquid.
This formulation is indicated for maintenance therapy.
ALTIAZEM 300 mg prolonged-release hard capsules
Angina pectoris and hypertension
The recommended dose is 1 capsule per day, depending on the therapeutic response and tolerability, after starting therapy with lower doses of diltiazem.
The time of intake during the day is indifferent, but must remain constant during the course of therapy; the ideal is to take before or during a meal.
The capsules should not be chewed, but swallowed whole with some liquid.
This formulation is indicated for maintenance therapy.
Senior citizens
In elderly patients and those with renal or hepatic insufficiency or concurrently taking other antihypertensive medicinal products, use the lowest effective dose.
Particular caution is required at the beginning of treatment (see "Warnings and precautions").
Overdose What to do if you have taken too much Altiazem
The clinical effects of taking an overdose of diltiazem may include severe hypotension up to collapse, bradycardia with or without isorhythmic dissociation (reduced heart rate and heartbeats with normal or abnormal rhythm) and atrioventricular conduction disturbances (disturbances of progression of the electrical stimulus of the heart).
The treatment to be undertaken in the hospital will consist of gastric lavage (emptying and washing the stomach) and osmotic diuresis (excessive production of urine caused by a substance that is not reabsorbed by the kidney).
The automaticity and conduction disturbances (alterations of the heart rhythm due to anomalies in the formation and propagation of the electrical impulse) can be resolved with a temporary electrosystolic induction (cardiac electro-stimulation). The recommended pharmacological treatments are: atropine, vasopressor agents (agents that increase the contraction of the vessels and therefore the pressure) such as adrenaline, inotropic agents (drugs that increase the force of contraction of the heart), glucagon and calcium gluconate for infusion. If you have taken too much ALTIAZEM, notify your doctor immediately or go to the nearest hospital.
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 Altiazem
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common side effects (may affect more than 1 in 10 patients)
- Peripheral edema (fluid accumulation).
Common side effects (may affect up to 1 in 10 patients)
- Headache, dizziness.
- Atrioventricular block (first, second or third degree; branch block), palpitations.
- Hot flashes.
- Constipation (constipation), dyspepsia (digestive function disorder), stomach pain, nausea.
- Erythema.
- Malaise.
Uncommon side effects (may affect up to 1 in 100 people)
- Insomnia, nervousness.
- Bradycardia.
- Orthostatic hypotension (sharp drop in blood pressure following a transition from lying or sitting to standing).
- Vomiting and diarrhea.
- Increase in liver enzymes (AST, ALT, LDH, ALP).
Rare side effects (may affect up to 1 in 1,000 people)
- Epistaxis (nosebleed).
- Amnesia, depression, personality change, hallucinations, sleepiness.
- Paresthesia (changes in sensation in the limbs or other parts of the body), tinnitus (ringing in the ear), tremor.
- Arrhythmia, asystole (severe heart failure due to a lack of electrical activity of the heart which causes the ventricle to contract), syncope (transient loss of consciousness), angina.
- Dry mouth, taste disturbance, abdominal pain.
- Urticaria, pruritus, generalized erythema (characterized by clastic leukocyte vasculitis), petechiae (small skin spots of small size, irregularly circular and bright red in color, caused by circumscribed bleeding).
- Impotence.
- Amblyopia (altered vision), eye irritation.
- Dyspnea (labored breathing).
- Nocturia (frequent need to pass urine during rest), polyuria (increased urine output).
- Osteoarticular pain (in bones and joints).
- Anorexia (lack of appetite), weight gain.
- Increase in creatine kinase enzyme.
Very rare side effects (may affect up to 1 in 10,000 patients)
- Leukopenia (reduction in the number of white blood cells).
- Interstitial nephritis (inflammation of the kidneys).
Not known side effects (frequency cannot be estimated from the available data)
- Thrombocytopenia (reduction in the number of platelets) and lengthening of the bleeding time (bleeding).
- Mood changes (including depression).
- Extrapyramidal syndrome (gait disturbances), dizziness.
- Sino-atrial block, congestive heart failure, electrocardiogram abnormalities.
- Vasculitis (inflammation of the blood vessels), including leukocytoclastic vasculitis, and edema (especially in the lower limbs).
- Gingival hyperplasia (enlargement of the gum tissue).
- Hepatitis (inflammation of the liver).
- Photosensitivity (including lichenoid keratosis in sun-exposed skin areas), angioedema (allergic skin reaction), rash, erythema multiforme (including Steven-Johnson syndrome and toxic epidermal necrolysis or Lyell's syndrome), sweating, exfoliative dermatitis, exanthematous pustular dermatitis acute generalized, occasionally desquamative erythema with or without fever (skin disorders).
- Gynecomastia (breast development in humans).
- Asthenia (lack of strength).
- Hyperglycemia (increase in the concentration of glucose in the blood).
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. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. 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.
ALTIAZEM 60 mg tablets
- No special storage precautions are required.
ALTIAZEM 120 mg prolonged-release tablets
- Do not store above 25 ° C.
ALTIAZEM 300 mg prolonged-release hard capsules
- Do not store above 30 ° C.
Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to the last day of that month and to the product in intact packaging, correctly stored.
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.
Other information
What ALTIAZEM contains
ALTIAZEM 60 mg tablets
Each tablet contains:
- Active ingredient: diltiazem hydrochloride 60 mg.
- Other components: lactose, hydrogenated castor oil, macrogol 6000, magnesium stearate.
ALTIAZEM 120 mg prolonged-release tablets
Each tablet contains:
- Active ingredient: diltiazem hydrochloride 120 mg.
- Other components: Core: monosodium citrate, sucrose, povidone, magnesium stearate, macrogol 6000.
- Coating: sucrose, coating polymer, acetyltributyl citrate, polymerized castor oil, sodium bicarbonate, ethylvanillin, titanium dioxide (E 171).
ALTIAZEM 300 mg prolonged-release hard capsules
- Each capsule contains:
- Active ingredient: diltiazem hydrochloride 300 mg.
- Other components: microcrystalline cellulose, sodium carmellose, acrylic copolymer and methacrylic esters, ethylcellulose, diacetylated monoglycerides, magnesium stearate.
- Composition of the capsule: gelatin, titanium dioxide (E 171), yellow iron oxide (E 172).
What ALTIAZEM looks like and contents of the pack
ALTIAZEM 60 mg tablets
- Tablets.
- Box of 50 white divisible tablets contained in 2 blisters of 25 tablets each.
ALTIAZEM 120 mg prolonged-release tablets
- Prolonged-release tablets.
- Box of 24 white coated tablets contained in 2 blisters of 12 tablets each.
ALTIAZEM 300 mg prolonged-release hard capsules
- Prolonged-release hard capsules.
- Box of 14 hard gelatin capsules, white for the body, yellow for the head, contained in blister packs.
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
ALTIAZEM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
ALTIAZEM 60 mg tablets
Each tablet contains:
Active principle : diltiazem hydrochloride 60 mg.
Excipients : lactose, hydrogenated castor oil.
ALTIAZEM 120 mg prolonged-release tablets
Each tablet contains:
Active principle : diltiazem hydrochloride 120 mg.
Excipients : sucrose.
ALTIAZEM 300 mg prolonged-release hard capsules
Each capsule contains a blend of immediate-release and sustained-release microgranules
Each capsule contains:
Active principle: diltiazem hydrochloride 300 mg.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use
Each bottle contains:
Active principle: diltiazem hydrochloride 50 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Divisible tablets.
Prolonged-release coated tablets.
Prolonged-release hard capsules.
Powder and solvent for solution for injection for intravenous use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ALTIAZEM 60 mg tablets, ALTIAZEM 120 mg prolonged-release tablets, ALTIAZEM 300 mg prolonged-release capsules, hard :
• Treatment of exertional, post-infarct and vasospastic angina pectoris (Prinzmetal's angina).
• Treatment of mild and moderate arterial hypertension.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection :
Protection of the myocardium in acute ischemia from coronary artery spasm or from non-functional coronary occlusion.
Protection of the myocardium during cardiac surgery in extracorporeal circulation.
Paroxysmal junctional tachycardia. Rapid atrial fibrillation and flutters.
04.2 Posology and method of administration
ALTIAZEM 60 mg tablets :
Angina pectoris :
1 tablet three times a day, at regular intervals. If necessary, the dose may be increased up to two tablets three times a day based on the doctor's advice.
Hypertension :
Half to one tablet three times a day.
In elderly patients and in those with renal or hepatic insufficiency or who require two anti-hypertensive drugs the starting dose will be half a tablet three times a day.
ALTIAZEM 120 mg prolonged-release tablets :
Angina pectoris and hypertension :
One tablet every twelve hours.
ALTIAZEM 300 mg prolonged-release hard capsules :
Angina pectoris and hypertension :
The dose is one capsule per day, depending on the therapeutic response and tolerability, after starting therapy with lower doses of diltiazem.
In elderly patients and those with renal or hepatic insufficiency or who require two antihypertensive drugs, lower doses should be started.
The time of intake during the day is indifferent, but must remain constant for the same patient; the ideal is to take before or during a meal.
The capsules and tablets should not be chewed, but swallowed whole with some liquid.
ALTIAZEM 120 mg prolonged-release tablets and ALTIAZEM 300 mg prolonged-release hard capsules are pharmaceutical forms indicated for maintenance therapy.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection :
Acute ischemia of the myocardium :
0.15 mg / kg by direct intravenous route (in 1-2 minutes).
If necessary, treatment can be followed by continuous intravenous infusion at a constant rate.
In this case the maximum dosage will be 10 mg / h for 24 hours. Administration must be carried out under continuous electrocardiographic control and diluting the product in 5% physiological or glucose solution. In any case, the total dose of 240 mg of diltiazem per day should not be exceeded.
Cardiac surgery in extracorporeal circulation :
Add 0.05 to 0.2 mg / kg (total dose) to solutions commonly used in cardioplegia.
The recommended dose is 0.1 mg / kg, administered as an intravenous infusion at a constant rate starting 30 minutes prior to induction of anesthesia.
Treatment should continue during the postoperative period, particularly when the patient regains consciousness and returns to normal temperature.
In the case of coronary artery bypass grafting, the infusion should be maintained for at least 24 hours after the interruption of extra-corporeal circulation. Intravenous treatment should be continued until previous antianginal therapy can be resumed.
Junctional tachycardia :
0.25 to 0.30 mg / kg by direct intravenous route (in 1-2 minutes).
Rapid atrial fibrillation and flutters :
A direct intravenous dose of 0.25 to 0.30 mg / kg (over 1-2 minutes) is often sufficient to slow the heart rate below 100 beats / minute.
For continuation of therapy beyond 24 hours it is recommended to use the oral form.
Special populations :
Pediatric age
The safe use and efficacy in children have not been established. The use of diltiazem is not recommended in children.
Elderly patients
In elderly patients and those with renal or hepatic insufficiency or concurrently taking other antihypertensive drugs, use the lowest effective dose.
Particular caution is required at the start of treatment (see section 4.4.).
04.3 Contraindications
For oral formulations :
• Hypersensitivity to diltiazem or to any of the excipients
• Hypotension (systolic blood pressure below 90 mmHg)
• Acute myocardial infarction with pulmonary congestion
• Sinus node syndrome, conduction disturbances (sino-atrial block, second or third degree atrial ventricular block in patients without a functioning ventricular pacemaker), severe bradycardia (less than 40 bpm)
• Congestive heart failure
• Left ventricular failure with pulmonary stasis
• Combination with amiodarone and dantrolene (infusion) (see section 4.5.)
• Known or suspected pregnancy, lactation, women of childbearing potential (see section 4.6.)
• Generally contraindicated in pediatric age (see section 4.2.)
• Combination with ivabradine (see section 4.5)
For injectable formulation :
• Hypersensitivity to diltiazem or to any of the excipients
• Sinus dysfunction without a functioning pacemaker
• Second or third degree atrioventricular block without a functioning ventricular pacemaker
• Atrial fibrillation or flutter with ventricular pre-excitation syndrome, particularly when the refractory period of the accessory pathway is short
• Severe bradycardia
• Hypotension (systolic blood pressure below 90 mmHg), associated with hypovolaemia and / or heart failure
• Wide complex ventricular tachycardia (QRS ≥ 0.12 sec.)
• Cardiogenic shock
• Congestive heart failure
• Left ventricular failure with pulmonary stasis
• Combination with amiodarone and dantrolene (see section 4.5.)
• Known or suspected pregnancy, lactation, women of childbearing potential (see section 4.6.)
• Generally contraindicated in pediatric age (see section 4.2.)
• Combination with ivabradine (see section 4.5)
Diltiazem i.v. it must not be given to patients with accessory bypass (Wolf-Parkinson-White syndrome or short PR syndrome) and who develop atrial fibrillation or flutter.
04.4 Special warnings and appropriate precautions for use
The safety of use and efficacy in children have not been established. The use of diltiazem is not recommended in children (see section 4.3.).
For oral formulations :
Careful monitoring is required in patients with impaired left ventricular function, bradycardia (risk of exacerbations) or with first degree atrioventricular block as evidenced by ECG (risk of exacerbation and rarely complete block).
During treatment, periodic checks of liver and kidney function should be performed.
Increased plasma concentrations of diltiazem may be observed in the elderly and in patients with renal or hepatic insufficiency. Concomitant administration of other antihypertensive agents may potentiate the hypotensive effect of diltiazem. Therefore, in all these cases, a modification of the posology may be necessary.
Contraindications and precautions must be strictly observed and there must be constant monitoring, particularly of heart rate, at the start of treatment.
Abrupt discontinuation of treatment may be associated with worsening of angina.
Calcium channel blockers, such as diltiazem, can be associated with mood changes, including depression.
Like other calcium channel blockers, diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing intestinal blockage. Residues of the prolonged-release formulations may be present in the stools of patients; however this fact has no clinical relevance.
In case of general anesthesia, the anesthetist should be informed that the patient is taking diltiazem. Depression of cardiac contractility, conductivity and automatism and vasodilation associated with anesthetics can be potentiated by calcium channel blocking drugs.
Since controlled-release formulations of diltiazem are characterized by a different mechanism for the release of the active substance and by different dissolution rates, they are unlikely to have the same pharmacokinetic profile. Therefore, the substitution of one controlled release formulation of diltiazem with another is not recommended.
The tablets of ALTIAZEM 120 mg prolonged-release tablets they are coated with an insoluble polymeric membrane that allows the controlled release of the active ingredient; this membrane is not modified by the passage in the gastrointestinal tract, its possible finding in the faeces is therefore not to be interpreted as a sign of ineffectiveness of the product.
ALTIAZEM 60 mg tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
ALTIAZEM 60 mg tablets contain hydrogenated castor oil therefore may cause stomach upset and diarrhea.
ALTIAZEM 120 mg prolonged-release tablets contain sucrose, so if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
For injectable formulation :
It is recommended to use ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection in a hospital setting; this recommendation is to be considered mandatory with regard to perfusion use.
The injectable formulation of diltiazem should be used with caution in patients with first degree atrioventricular block.
In case of cardiomegaly or heart failure or hypotension (when not associated with hypovolaemia and / or heart failure), treatment should only be undertaken in a hospital setting.
The injectable formulation is not recommended in cases of severe bradycardia, unless the benefit outweighs the risk. In any case, the patient must be closely monitored.
Elderly patients and patients with renal or hepatic insufficiency: No information is available on the use of injectable diltiazem in such patients. However, an increase in plasma levels of diltiazem in such patients is possible after oral administration.
In elderly patients and those with renal or hepatic insufficiency or concurrently taking other antihypertensive drugs, use the lowest effective dose.
Particular caution is required at the beginning of the treatment.
In case of general anesthesia, the anesthetist should be informed that the patient is taking diltiazem. Depression of cardiac contractility, conductivity and automatism and vasodilation associated with anesthetics can be potentiated by calcium channel blocking drugs. During anesthesia, in relation to the hypotensive effect of diltiazem, the simultaneous use of nitrates requires caution.
If halogenated anesthetics and diltiazem are used concurrently, the dose of diltiazem must be adapted to the haemodynamic response. In patients treated simultaneously with diltiazem and curare during anesthesia, a reduction in the rate of decurarization may be observed.
04.5 Interactions with other medicinal products and other forms of interaction
Contraindicated associations
For all formulations :
DANTROLENE (infusion)
When verapamil and dantrolene are administered intravenously simultaneously to the animal, lethal ventricular fibrillation is constantly observed.
The combination of a calcium channel blocker and dantrolene is therefore potentially dangerous (see section 4.3).
AMIODARONE
Diltiazem is contraindicated in patients receiving amiodarone (risk of bradycardia and atrioventricular block) (see section 4.3.).
IVABRADINA
Concomitant use with ivabradine is contraindicated due to the additional bradycardising effect of diltiazem over ivabradine (see section 4.3).
Associations requiring caution
For all formulations :
ANTI-HYPERTENSIVE: increased hypotensive effect, in particular of alpha-antagonists.
The combination of diltiazem with an alpha-antagonist requires close monitoring of blood pressure.
BETA-BLOCKERS: possibility of rhythm disturbances (severe bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances, cardiovascular decompensation (synergistic effect).
These combinations should not be used unless under close clinical and electrocardiographic surveillance, particularly at the start of treatment.
CARDIOACTIVE GLYCOSIDES: increase in the plasma concentration of digoxin; increased risk of bradycardia; Caution is required when combining with diltiazem, especially in elderly patients and if high doses are used.
The electrophysiological effects of diltiazem on the sinus node and the atrioventricular node potentiate those of digitalis preparations.
ANTIARRhythmics: Since diltiazem has antiarrhythmic properties, co-prescription with other antiarrhythmics is not recommended due to the increase in cardiac side effects due to additive effect.
This combination should not be used unless under close clinical and electrocardiographic surveillance.
NITRODERIVATES: increased hypotensive effect and lipotimie (additive vasodilator effects). In all patients treated with calcium channel blockers, the prescription of nitro-derivatives should be carried out at gradually increasing doses.
CYCLOSPORIN: increase in blood levels of free cyclosporine.
It is advisable to reduce the dose of cyclosporine, monitor renal function, measure the blood levels of cyclosporine and adjust the dosage both during the combination therapy and after its discontinuation.
CARBAMAZEPINE: increase in blood levels of free carbamazepine.
It is recommended to measure carbamazepine blood levels and adjust the dosage if necessary.
PHENYTOIN: diltiazem causes an increase in the plasma concentration of phenytoin; phenytoin reduces the effect of diltiazem.
ANTIDEPRESSANTS: increase in the plasma concentration of imipramine and, probably, also of the other tricyclics.
ANTIPSYCHOTICS: increased hypotensive effect.
THEOPHYLIN: increase in blood levels of free theophylline.
ANTI-H2 (cimetidine, ranitidine): increased blood levels of diltiazem.
Patients on diltiazem therapy should be closely monitored when starting or stopping treatment with H2 blockers. A modification of the daily dose of diltiazem may be required.
RIFAMPICIN: Risk of decreased plasma levels of diltiazem after initiation of rifampicin treatment. Patients should be closely monitored when initiating or stopping treatment with rifampicin.
LITHIUM: risk of increased neurotoxic effects of lithium.
ANESTHETICS: see section 4.4
Associations to consider carefully
For all formulations :
Due to the potential additive effects, caution and careful titration are required in patients receiving diltiazem together with other drugs that modify cardiac contractility or conduction.
Diltiazem is metabolised by CYP3A4. A moderate (less than 2-fold) increase in plasma concentrations of diltiazem has been documented when co-administered with a more potent CYP3A4 inhibitor. Diltiazem is also an inhibitor of the CYP3A4 isoform. Co-administration with other CYP3A4 substrates may result in increased plasma concentrations of either of the two co-administered drugs. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease in plasma concentrations of diltiazem.
BENZODIAZEPINES (midazolam, triazolam): Diltiazem significantly increases the plasma concentrations of midazolam and triazolam and increases their plasma half-life.
Particular caution is required when prescribing short-acting benzodiazepines metabolised by CYP3A4 in patients taking diltiazem.
CORTICOSTEROIDS (methylprednisolone): Inhibition of the metabolism of methylprednisolone (CYP3A4) and inhibition of P-glycoprotein. Patients should be monitored when initiating methylprednisolone treatment. The methylprednisolone dose may need to be adjusted.
STATINS: Diltiazem is a CYP3A4 inhibitor and has been shown to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis following CYP3A4 metabolised statins may be increased by concomitant use of diltiazem. If possible, a statin not metabolised by CYP3A4 should be used with diltiazem, otherwise close monitoring for signs and symptoms of potential statin toxicity is required.
04.6 Pregnancy and breastfeeding
Pregnancy
The use of diltiazem is contraindicated in pregnancy.
Diltiazem has shown reproductive toxicity in some animal species (rat, mouse, rabbit). To date, very limited data are available in humans on the use of diltiazem in pregnancy.
In women of childbearing age, any pregnancy must always be excluded before the start of treatment and effective contraceptive coverage must be ensured during treatment.
Feeding time
Since diltiazem is excreted in breast milk, breastfeeding while taking this medicinal product should be avoided.
If the use of Altiazem is considered clinically essential, an alternative method of feeding the baby should be used.
04.7 Effects on ability to drive and use machines
Based on reported side effects, such as sleepiness, dizziness and feeling sick, the ability to drive and use machines may be impaired. In this case, avoid driving vehicles or using machines. However, no studies were carried out.
04.8 Undesirable effects
The frequency of adverse reactions described below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to
04.9 Overdose
Clinical effects of acute overdose may include severe hypotension up to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances.
The treatment to be undertaken in the hospital will consist of gastric lavage and osmotic diuresis.
The automaticity and conduction disturbances can be resolved with a temporary electrosystolic induction. The recommended pharmacological treatments are: atropine, vasopressor agents such as adrenaline, inotropic agents, glucagon and calcium gluconate for infusion.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blockers with direct cardiac effect, benzothiazepine derivatives.
ATC code: C08DB01.
Diltiazem is a calcium channel blocker that selectively reduces the entry of calcium into the slow calcium channel of vascular smooth muscle and myocardial muscle fibers in a voltage-dependent manner. By this mechanism, diltiazem reduces the intracellular concentration of calcium in the vicinity of the contractile proteins.
Diltiazem is recognized by the WHO as a reference product for class III of calcium channel blockers.
Studies in animals
Anti-anginal properties: diltiazem increases coronary blood flow without inducing coronary steal phenomena. It acts on the small arteries and on the collateral branches of the large arteries. This vasodilating effect, which is moderate in the peripheral arterial system, occurs at doses with no negative inotropic effect and is associated with an increase in cardiac resistance to exertion and prevention of coronary spasm, with consequent reduction in the frequency of angina attacks. .
At the myocardial level, diltiazem has a direct effect on energy metabolism; it also reduces coronary resistance and oxygen consumption in the heart muscle.
The two main circulating metabolites, ie deacetyldiltiazem and N-monodemetildiltiazem, induce coronary vasodilation equal to 10 and 20%, respectively, of that of the active ingredient.
Antihypertensive properties: diltiazem decreases the tone of arterial smooth muscle by reducing the entry of calcium into vascular smooth muscle cells and causes vasodilation, which, in turn, causes a decrease in total peripheral resistance. Diltiazem lowers blood pressure without causing reflex tachycardia. different models of hypertension in animals, particularly in the genetically hypertensive rat.
It does not modify cardiac output and renal blood flow.
It also preferentially inhibits the vasoconstrictive effects of noradrenaline and angiotensin II. Diltiazem increases diuresis without changing the urinary sodium / potassium ratio and reduces cardiac hypertrophy in the genetically hypertensive rat.
High doses of diltiazem reduce the development of arterial calcinosis in rats treated with high doses of vitamin. D3 or dihydrotachisterol.
The two main circulating metabolites (deacetyldiltiazem and N-monodemetildiltiazem) have a pharmacological activity equal to about 50% of that of the active ingredient.
Studies in man
For oral formulations :
Anti-anginal properties: diltiazem increases coronary blood flow by reducing coronary resistance.
Thanks to its moderate bradycarding effect and the reduction of systemic arterial resistance, diltiazem reduces cardiac work.
From an electrophysiological point of view, diltiazem causes moderate bradycardia in normal subjects, marginally prolongs intranodal conduction, and has no effect on conduction in the His bundle and infrahissian structures.
Antihypertensive properties: at the vascular level, the calcium-antagonist effect of diltiazem produces a moderate arterial vasodilation and improves the compliance of the great arteries. This well-balanced vasodilation leads to a reduction in blood pressure in hypertensive subjects, thanks to the decrease in peripheral resistance, without determining Reflex tachycardia In fact, a slight slowing of the heart rate is observed The extent of visceral blood flows, in particular renal and coronary blood flows, are unchanged or increased.
A moderate natriuretic effect is observed after acute administration. Diltiazem does not stimulate the renin-angiotensin-aldosterone system during long-term therapy and does not cause water and sodium retention, as evidenced by the absence of changes in body weight and in the water and electrolyte balance of plasma.
Diltiazem acts as a coronary dilator towards the heart, reducing left ventricular hypertrophy in hypertensive individuals. It has only a slight effect on cardiac output.
Diltiazem reduces cardiac work through its moderate bradycardic effect associated with the reduction of systemic arterial resistance.
No negative inotropic effects were observed in healthy myocardium. Diltiazem moderately decreases heart rate and can cause sinus node activity depression if it is disturbed. It slows atrioventricular conduction and there is therefore a risk of AV block.
Diltiazem does not modify conduction in the His bundle or at the infrahissian level.
Diltiazem does not affect glycoregulation and has no negative effects on plasma lipoproteins and lipid metabolism.
For injectable formulation :
Studies conducted with diltiazem in the injectable form have shown the following properties:
• antiarrhythmic activity at the junctional level
• beneficial activity in myocardial ischemia; reduction in oxygen consumption, increase in coronary blood flow, correction of coronary spasm, protection of the myocardium during extracorporeal cardiac surgery
• no effect on intraventricular conduction and no direct effect on the antegrade or retrograde conduction of the alternative routes.
05.2 Pharmacokinetic properties
ALTIAZEM 60 mg tablets :
After oral administration in healthy volunteers, diltiazem is extensively absorbed (90%). The peak plasma concentration is observed 3-4 hours after dosing and the mean apparent plasma half-life is 4-8 hours.
The kinetics of diltiazem are linear and not subject to saturation. During long-term administration, the plasma concentration of diltiazem in each patient remains constant.
Due to the first pass effect, the bioavailability of the 60 mg tablets is approximately 40% and is dose dependent.
Diltiazem is 80-85% bound to plasma proteins. It is extensively metabolised by the liver. The major circulating metabolite N-monodemetildiltiazem accounts for approximately 35% of circulating diltiazem.
A percentage of diltiazem between 0.7% and 5% is excreted unchanged in the urine.
Mean plasma concentrations are higher in patients with renal and hepatic insufficiency than in healthy subjects.
Diltiazem and its metabolites are poorly dialyzable.
ALTIAZEM 120 mg prolonged-release tablets :
After oral administration in healthy volunteers, diltiazem is extensively absorbed (90%); due to the first pass effect, the bioavailability is about 40%.
The bioavailability of this controlled-release formulation of diltiazem is approximately 90% of that of traditional tablets. The mean apparent plasma half-life is 7-8 hours and effective plasma levels are maintained for at least 12 hours.
After repeated administration, a 30% increase in the following parameters is obtained: Cmax, AUC, Cmin; this increase is due to the partial saturation of the hepatic first pass metabolism.
Diltiazem is 80-85% bound to plasma proteins. It is extensively metabolised by the liver. The major circulating metabolite N-monodemetildiltiazem accounts for approximately 35% of circulating diltiazem.
A percentage of diltiazem between 0.7% and 5% is excreted unchanged in the urine.
Mean plasma concentrations are higher in patients with renal and hepatic insufficiency.
Diltiazem and its metabolites are poorly dialyzable.
ALTIAZEM 300 mg prolonged-release hard capsules :
The kinetics of diltiazem are linear and not subject to saturation.
After oral administration in healthy volunteers, diltiazem is extensively absorbed (90%).
The bioavailability of this controlled-release formulation of diltiazem is approximately 80% of that of ALTIAZEM 60 mg tablets. The mean apparent plasma half-life is 8 hours.
Twenty-four hours after dosing, plasma concentrations in patients remain at the level of 50 ng / ml. During long-term administration, the plasma concentration of diltiazem in each patient remains constant.
Diltiazem is 80-85% bound to plasma proteins. It is extensively metabolised by the liver. The major circulating metabolite N-monodemetildiltiazem accounts for approximately 35% of circulating diltiazem.
A percentage of diltiazem between 0.7% and 5% is excreted unchanged in the urine.
Mean plasma concentrations are higher in patients with renal and hepatic insufficiency.
Food intake does not significantly affect the kinetics of this controlled-release formulation of diltiazem; however, when diltiazem is taken with food, increased absorption is observed in the first few hours after intake.
Diltiazem and its metabolites are poorly dialyzable.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection :
After intravenous administration in humans, the distribution half-life of diltiazem is between 25 and 30 minutes.
Diltiazem is 80-85% bound to plasma proteins. It is extensively metabolised by the liver. The major active metabolite is desacetyldiltiazem. The plasma elimination half-life is approximately 3 hours. Only 3% of the administered dose, on average, is excreted unchanged in the urine.
05.3 Preclinical safety data
Acute and subacute toxicity studies in animals confirmed the good tolerability of the drug at the therapeutic doses used in humans.
Studies of teratogenesis and peri- and postnatal toxicity in various animal species have led to the contraindication of the drug in the case of confirmed or presumed pregnancy.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
ALTIAZEM 60 mg tablets :
lactose, hydrogenated castor oil, macrogol 6000, magnesium stearate.
ALTIAZEM 120 mg prolonged-release tablets :
Nucleus: monosodium citrate, sucrose, povidone, magnesium stearate, macrogol 6000;
Coating: sucrose, coating polymer, acetyltributyl citrate, polymerized castor oil, sodium bicarbonate, ethylvanillin, titanium dioxide (E171).
ALTIAZEM 300 mg prolonged-release hard capsules :
microcrystalline cellulose, carmellose sodium, acrylic copolymer and methacrylic esters, ethylcellulose, diacetylated monoglycerides, magnesium stearate.
Composition of the capsule: gelatin, titanium dioxide (E171), yellow iron oxide (E172).
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use :
mannite.
The solvent vial contains: water for injections.
06.2 Incompatibility
For oral formulations : none.
For injectable formulation : do not dilute the drug with an alkaline pH solution.
06.3 Period of validity
ALTIAZEM 60 mg tablets : 3 years.
ALTIAZEM 120 mg prolonged-release tablets : 2 years.
ALTIAZEM 300 mg prolonged-release hard capsules : 3 years.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use : 3 years.
06.4 Special precautions for storage
ALTIAZEM 60 mg tablets :
This medicinal product does not require any special storage conditions
ALTIAZEM 120 mg prolonged-release tablets :
Store at a temperature not exceeding 25 ° C.
ALTIAZEM 300 mg prolonged-release hard capsules :
Store at a temperature not exceeding 30 ° C.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use :
After dissolving the lyophilized powder, the contents of the bottle should be used within 24 hours.
06.5 Nature of the immediate packaging and contents of the package
ALTIAZEM 60 mg tablets :
Box of 50 divisible tablets contained in PVC / alu blisters.
ALTIAZEM 120 mg prolonged-release tablets :
Box of 24 tablets contained in PVC / alu blisters.
ALTIAZEM 300 mg prolonged-release hard capsules :
Box of 14 controlled release capsules contained in PVC / alu blisters.
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use :
Carton containing 5 glass bottles and 5 vials of 5 ml solvent.
06.6 Instructions for use and handling
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use :
The product must be reconstituted with the vial included in the package.
07.0 MARKETING AUTHORIZATION HOLDER
LUSOFARMACO
Luso Farmaco Institute of Italy S.p.A.
Milanofiori - Street 6 - Building L - Rozzano (MI)
ALTIAZEM 120 mg prolonged-release tablets and ALTIAZEM 300 mg prolonged-release hard capsules licensed by Tanabe Seiyaku Co. Ltd - Osaka - Japan
08.0 MARKETING AUTHORIZATION NUMBER
ALTIAZEM 60 mg tablets: A.I.C. n. 025271014
ALTIAZEM 120 mg prolonged-release tablets : A.I.C. n. 025271038
ALTIAZEM 300 mg prolonged-release hard capsules: A.I.C. n. 025271040
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use: A.I.C. n. 025271026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
ALTIAZEM 60 mg tablets :
Date of first authorization: 17.03.84
Authorization renewal date: 01.06.10
ALTIAZEM 120 mg prolonged-release tablets :
Date of first authorization: 27.04.91
Authorization renewal date: 01.06.10
ALTIAZEM 300 mg prolonged-release hard capsules :
Date of first authorization: 31.10.94
Authorization renewal date: 01.06.10
ALTIAZEM 50 mg / 5 ml powder and solvent for solution for injection for intravenous use :
Date of first authorization: 07.10.85
Authorization renewal date: 01.06.10
10.0 DATE OF REVISION OF THE TEXT
December 2015