Active ingredients: Diltiazem (Diltiazem hydrochloride)
TILDIEM 60 mg modified release tablets
Tildiem package inserts are available for pack sizes:- TILDIEM 60 mg modified release tablets
- TILDIEM 120 mg prolonged-release tablets
- TILDIEM 200 mg prolonged-release hard capsules, TILDIEM 300 mg prolonged-release hard capsules
Indications Why is Tildiem used? What is it for?
TILDIEM contains the active substance diltiazem hydrochloride which belongs to a group of medicines called calcium channel blockers (calcium channel blockers) used to treat high blood pressure.
TILDIEM is indicated for the treatment of:
- chest pain (angina pectoris) due to exertion, a heart attack or problems with the arteries that carry blood to the heart (Prinzmetal's angina);
- in cases of mild or moderate severity of high blood pressure.
Contraindications When Tildiem should not be used
Do not take TILDIEM
- if you are allergic to diltiazem or any of the other ingredients of this medicine (listed in section 6);
- if you have low blood pressure (maximum pressure below 90 mmHg);
- if you have an acute heart attack with lung problems;
- if you have an irregular heartbeat due to certain heart diseases (sinus node syndrome, atrioventricular block, sino-atrial block) and do not have a functioning pacemaker,
- if you have a very slow heartbeat (severe bradycardia, below 40 beats per minute);
- if you have severe heart problems, possibly with lung problems (left ventricular failure with pulmonary congestion and congestive heart failure);
- if you are using medicines such as dantrolene and amiodarone for infusion (see section "Other medicines and TILDIEM");
- if you are using a medicine containing ivabradine to treat certain heart diseases;
- if you are pregnant or suspect that you are pregnant, if you are breast-feeding or if you are a woman of childbearing potential and are not taking medicines to prevent pregnancy (contraceptives).
Precautions for use What you need to know before taking Tildiem
Talk to your doctor or pharmacist before taking TILDIEM.
Use this medicine with great caution and tell your doctor in the following cases:
- if you have heart problems such as decreased functioning of the left ventricle, slow heart beat (bradycardia) or other heart problems (first degree atrioventricular block);
- if you are elderly or if you have kidney or liver problems,
- if you are also taking other medicines that lower blood pressure, as your blood pressure may drop too much (see Other medicines and TILDIEM);
- if you are at risk of bowel obstruction as diltiazem affects bowel functioning;
- if you are going to have surgery, in this case please tell your anesthetist that you are taking this medicine.
In the cases mentioned, doses different from those normally used may be prescribed.
Your doctor will periodically check your heart, liver, kidney function (during and especially at the start of treatment) and blood sugar levels if you have diabetes mellitus, as there is a risk of increased blood sugar. .
Calcium channel blockers, such as diltiazem, can be associated with mood changes, including depression.
Children
This medicine is not recommended for children.
Interactions Which drugs or foods can modify the effect of Tildiem
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Do not use this medicine in combination with:
- dantrolene (infusion), a medicine used for muscle spasms and to treat a type of fever called malignant hyperthermia;
- amiodarone, a medicine used to treat some heart diseases.
Use particular caution and tell your doctor if you are taking any of the following medicines (in some cases your doctor may change the dose of diltiazem or the other medicines):
- Antihypertensives, medicines that lower blood pressure. If you are taking this medicine together with an antihypertensive, your doctor will closely monitor your blood pressure.
- nitro-derivatives, medicines that dilate blood vessels. If you are taking this medicine the nitro derivatives will be prescribed in gradually increasing doses;
- theophylline, a medicine used to treat asthma;
- beta-blockers, medicines used for high blood pressure and heart problems. In this case, the doctor will closely monitor the function of the heart, especially at the beginning of the treatment;
- medicines for the heart in general and in particular cardioactive glycosides (eg digoxin). Take special care especially if you are elderly or if you take high doses of diltiazem;
- medicines used for problems with the rhythm of the heart (antiarrhythmics). In this case, the doctor will closely monitor the function of your heart;
- carbamazepine and phenytoin, medicines used for epilepsy, in which case your doctor will monitor the carbamazepine and phenytoin levels in your blood.
- acetylsalicylates (acetylsalicylic acid / lysine acetylsalicylate), medicines used to relieve pain, fever and inflammation: there may be an increased risk of bleeding;
- rifampicin, a medicine for bacterial infections (antibiotic);
- medicines used for stomach ulcers, called H2 blockers, such as cimetidine and ranitidine. If treatment with these medicines is started or stopped during treatment with TILDIEM your doctor may change the dose of diltiazem;
- cyclosporine, a medicine used against organ transplant rejection;
- medicines for depression (antidepressants) such as imipramine and tricyclic antidepressants;
- medicines used for mental disorders (antipsychotics) including lithium;
- medicines used for anesthesia (see section "Warnings and precautions");
- contrast media for X-ray examination, as they can increase the heart effects of diltiazem such as lowering blood pressure;
- benzodiazepines, medicines for depression, such as midazolam, triazolam as diltiazem increases the blood concentration of these drugs;
- corticosteroids, medicines used to treat inflammation. Your doctor will monitor you by adjusting the dose of corticosteroids if necessary;
- statins, medicines used to lower blood cholesterol, as there may be a risk of serious damage to the muscles (myopathy and rhabdomyolysis).
TILDIEM with drinks
Avoid taking this medicine together with grapefruit juice as this may increase its effect. If you are taking grapefruit juice, your doctor should check for possible side effects.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Do not take TILDIEM if you are pregnant, planning to become pregnant or if you are a woman of childbearing potential and are not taking medicines to prevent pregnancy (contraceptives).
Do not take this medicine if you are breast-feeding, as this medicine passes into breast milk.
If you have to take TILDIEM, stop breastfeeding.
Driving and using machines
This medicine may affect the ability to drive and use machines because it can cause side effects such as malaise and dizziness. If this happens to you, avoid driving or using machines.
TILDIEM contains castor oil
This medicine contains castor oil which can cause stomach upset and diarrhea.
TILDIEM contains lactose
This medicine contains a type of sugar called lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Tildiem: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Treatment of angina pectoris: the recommended dose is 1 tablet 3 times a day, at regular intervals. If necessary, your doctor may decide to increase the dose to 2 tablets 3 times a day depending on your condition.
Treatment of high blood pressure (hypertension): the recommended dose ranges from half to 1 tablet 3 times a day.
Use in children
The use of TILDIEM is not recommended in children.
Use in the elderly and with kidney or liver problems
If you are elderly or have liver or kidney problems or take other medicines for high blood pressure, the recommended starting dose is half a tablet 3 times a day.
If you forget to take TILDIEM
If you forget to take a tablet, do so as soon as you remember, unless it is almost time for your next dose. Do not take a double dose to make up for a forgotten dose.
If you stop taking TILDIEM
Do not stop treatment with this medicine abruptly as it may worsen heart problems such as angina. Talk to your doctor before stopping treatment. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Tildiem
Symptoms of overdose are: low blood pressure to collapse, slow heart rate (bradycardia) and other heart problems (atrioventricular conduction disturbances).
In case of accidental ingestion / intake of an excessive dose of TILDIEM, notify your doctor immediately or go to the nearest hospital emergency department.
Side Effects What are the side effects of Tildiem
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects may occur:
Very common (may affect more than 1 in 10 people)
- swelling due to fluid accumulation (peripheral edema).
Common (which may affect up to 1 in 10 people)
- headache (headache), dizziness;
- severe heart problems such as atrioventricular block, palpitations;
- hot flashes;
- constipation, digestive disorders, stomach pain, nausea;
- skin irritations such as redness (erythema);
- general malaise.
Uncommon (may affect up to 1 in 100 people)
- Nervousness, insomnia;
- slow heart rate (bradycardia);
- feeling of dizziness when standing up, due to a drop in blood pressure (orthostatic hypotension);
- vomiting, diarrhea;
- liver disorders with abnormal liver-related blood tests such as increased aspartate transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactic dehydrogenase (LDH).
Rare (may affect up to 1 in 1000 people)
- Nosebleed (epistaxis)
- Memory problems (amnesia), depression, personality change, hallucinations, sleepiness;
- altered sensation in the limbs (paraesthesia), ringing in the ear (tinnitus), tremor;
- pain (angina), irregular heartbeats (arrhythmia) which can lead to loss of consciousness (syncope);
- dry mouth, taste disturbance, abdominal pain;
- abnormal blood tests such as increased creatine phosphokinase (CPK);
- lack of appetite (anorexia), weight gain;
- increased need to urinate (polyuria), including during night rest (nocturia);
- skin rashes such as hives, generalized redness (erythema) due to changes in blood vessels (leukocytoclastic vasculitis), small bleeding under the skin (petechiae), itching;
- pain in the bones and joints;
- changes in vision (amblyopia) and eye irritation;
- trouble breathing (dyspnoea);
- decreased sexual potency (impotence).
Very rare (may affect up to 1 in 10,000 people)
- kidney problems such as interstitial nephritis; - decrease in the number of white blood cells (leukopenia).
Frequency not known (the frequency of which cannot be estimated from the available data)
- decrease in some blood cells (platelets) and changes in blood clotting (lengthening of bleeding time).
- mood changes (including depression);
- appearance of abnormal movements that disturb the gait (extrapyramidal syndrome), dizziness;
- heart problems (sino-atrial block), severe decreased functioning of the heart (congestive heart failure), altered electrocardiogram results; temporary arrest of heart impulse formation at the sinus node (sinus arrest) and arrest of the heart due to the absence of the contraction phase (asystole);
- low blood pressure (hypotension), slow heart rate (bradycardia) and other heart problems (atrioventricular node block) if the medicine is given into a vein;
- fluid retention (edema) especially in the lower limbs;
- sweating;
- increase in the size of the gums (gingival hyperplasia);
- inflammation of the liver (hepatitis);
- increased blood sugar levels (hyperglycaemia);
- skin disorders from light sensitivity (including lichenoid keratosis in sun-exposed areas of skin);
- swelling of the skin and mucous membranes (angioneurotic edema);
- various skin diseases, with redness, blisters, peeling, pustules, sweating sometimes accompanied by fever (erythema multiforme, Steven-Johnson syndrome and toxic epidermal necrolysis, exfoliative dermatitis, acute generalized exanthematous pustular dermatitis, desquamative erythema with or without fever);
- breast growth in men (gynecomastia);
- decreased muscle strength (asthenia).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system www.agenziafarmaco.gov.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.
Do not use this medicine after the expiry date which is stated on the carton after "exp.". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
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 TILDIEM contains
- The active ingredient is diltiazem hydrochloride. One tablet contains 60 mg of diltiazem hydrochloride
- The other ingredients are: lactose, hydrogenated castor oil, macrogol 6000 and magnesium stearate.
Description of what TILDIEM looks like and contents of the pack
Carton containing 50 split-release modified-release tablets.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
TILDIEM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
TILDIEM 60 mg modified release tablets
Each tablet contains:
Active principle: diltiazem hydrochloride 60 mg.
Excipients: lactose 125.5 mg, hydrogenated castor oil 28 mg.
TILDIEM 120 mg prolonged-release tablets
Each tablet contains:
Active principle: diltiazem hydrochloride 120 mg.
Excipients:
Nucleus: sucrose 32 mg
Coating: sucrose 37.4 mg,
TILDIEM 200 mg prolonged-release hard capsules
Each capsule contains a blend of immediate-release and sustained-release microgranules.
Each capsule contains:
Active principle: diltiazem hydrochloride 200 mg.
TILDIEM 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.
TILDIEM 100 mg powder for solution for infusion
Each vial contains:
Active principle: diltiazem hydrochloride 100 mg.
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM -
Split-release modified-release tablets
Prolonged-release coated tablets
Prolonged-release hard capsules.
Powder for solution for infusion.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
TILDIEM 60 mg modified-release tablets, TILDIEM 120 mg prolonged-release tablets, TILDIEM 200 mg prolonged-release hard capsules, TILDIEM 300 mg prolonged-release hard capsules :
• Treatment of exertional, post-infarct and vasospastic angina pectoris (Prinzmetal's angina).
• Treatment of mild and moderate arterial hypertension.
TILDIEM 100 mg powder for solution for infusion :
Protection of the myocardium in acute ischemia from coronary artery spasm or from non-functional coronary occlusion.
04.2 Posology and method of administration -
TILDIEM 60 mg modified release 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.
TILDIEM 120 mg prolonged-release tablets :
Angina pectoris and hypertension :
One tablet every twelve hours.
TILDIEM 200 mg prolonged-release hard capsules, TILDIEM 300 mg prolonged-release hard capsules :
Angina pectoris and hypertension :
The recommended starting dose is one capsule of 200 mg prolonged-release hard capsules per day.
This dose may be increased to one capsule of 300 mg prolonged-release hard capsules per day, depending on the therapeutic response and tolerability.
In elderly patients and those with renal or hepatic insufficiency or who require two anti-hypertensive drugs, the starting dose will be one capsule of 200 mg prolonged-release hard capsules per day.
The time of intake during the day is indifferent, but must remain constant for the same patient; ideal is the intake before or during a meal.
The capsules and tablets should not be chewed, but swallowed whole with some liquid.
TILDIEM 120 mg prolonged-release tablets, TILDIEM 200 mg prolonged-release hard capsules, TILDIEM 300 mg prolonged-release hard capsules are pharmaceutical forms indicated for maintenance therapy.
TILDIEM 100 mg powder for solution for infusion :
The maximum dosage for continuous intravenous infusion administration at a constant rate should 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.
For the continuation of therapy it is recommended to use the oral form.
Pediatric population
The safe use and efficacy in children have not been established. The use of diltiazem is not recommended in children.
04.3 Contraindications -
For oral formulations :
• Hypersensitivity to the active substance 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 atrioventricular 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).
• Combination with ivabradine (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).
For injectable formulation :
• Hypersensitivity to the active substance 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).
• Combination with ivabradine (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).
• Diltiazem e.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 -
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.
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.
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.
Careful monitoring is necessary in patients with latent or overt diabetes mellitus due to the risk of increased blood glucose.
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.
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 the 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 TILDIEM 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.
TILDIEM 60 mg modified release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
TILDIEM 60 mg modified-release tablets contain hydrogenated castor oil, which can cause stomach upset and diarrhea.
TILDIEM 120 mg prolonged-release tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take this medicine.
For injectable formulation :
TILDIEM 100 mg powder for solution for infusion it is reserved exclusively for perfusion use, therefore it must be compulsorily administered in a hospital setting.
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.
Close monitoring is required in patients with latent or overt diabetes mellitus due to the risk of increased blood glucose.
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 another calcium channel blocker (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 an additive heart rate lowering effect of diltiazem in addition to that of 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 an additive effect.
This combination should not be used unless under close clinical and electrocardiographic surveillance.
NITRODERIVATES: increase of the 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. Monitoring the plasma concentration of phenytoin is recommended.
ACETYLSALICYLATES [Acetylsalicylic acid / Lysine acetylsalicylate]: Due to the risk of bleeding due to the potential additive effect on platelet aggregation, concomitant administration of diltiazem with acetylsalicylates [Acetylsalicylic acid / Lysine acetylsalicylate] should be undertaken with caution.
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.
X-RAY CONTRAST MEDIUM: Possible enhancement of the cardiovascular effects of an intravenous bolus of an ionic X-ray contrast agent, such as hypotension. Concomitant administration of diltiazem and X-ray contrast agents requires special caution.
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.
Grapefruit juice may increase diltiazem exposure (1.2-fold). Patients consuming grapefruit juice should be monitored for increased side effects of diltiazem. Grapefruit juice should be avoided if an interaction is suspected. .
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 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; It has been observed to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis following statins metabolised by CYP3A4 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:
Diltiazem is excreted in breast milk in low concentrations. Breastfeeding should be avoided while taking this drug. Breastfeeding patients must decide whether to give up breastfeeding and start treatment or, conversely, continue breastfeeding without administering the drug.
04.7 Effects on ability to drive and use machines -
Based on reported side effects, such as 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
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 -
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 substance.
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 its 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 -
TILDIEM 60 mg modified release 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.
TILDIEM 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.
TILDIEM 200 mg prolonged-release hard capsules, TILDIEM 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 TILDIEM 60 mg modified release tablets. The mean apparent plasma half-life is 8 hours.
Twenty-four hours after dosing, even with the dose of 200 mg prolonged-release hard capsules, 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.
After the administration of TILDIEM 20 mg prolonged-release hard capsules mean plasma concentrations are higher in elderly than in young subjects; however the plasma levels of diltiazem are lower than those found in young subjects after administration of TILDIEM 300 mg prolonged-release hard capsules.
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.
TILDIEM 100 mg powder for solution for infusion :
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 -
TILDIEM 60 mg modified release tablets :
Lactose, macrogol 6000, hydrogenated castor oil, magnesium stearate.
TILDIEM 120 mg prolonged-release tablets :
Nucleus: monobasic sodium citrate, sucrose, povidone, macrogol 6000, magnesium stearate;
Coating: sucrose, modified PVC, acetyltributyl citrate, sodium bicarbonate, ethylvanillin, titanium dioxide (E171).
TILDIEM 200 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), iron oxides (E172).
TILDIEM 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), iron oxides (E172).
TILDIEM 100 mg powder for solution for intravenous infusion :
Nobody.
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
TILDIEM 60 mg modified release tablets : 3 years
TILDIEM 120 mg prolonged-release tablets : 3 years
TILDIEM 200 mg prolonged-release hard capsules and TILDIEM 300 mg prolonged-release hard capsules : 3 years
TILDIEM 100 mg powder for solution for infusion : 3 years
06.4 Special precautions for storage -
TILDIEM 60 mg modified release tablets
This medicine does not require any special storage conditions.
TILDIEM 120 mg prolonged-release tablets
This medicine does not require any special storage conditions
TILDIEM 200 mg prolonged-release hard capsules
TILDIEM 300 mg prolonged-release hard capsules
Store at a temperature not exceeding 30 ° C.
TILDIEM 100 mg powder for solution for infusion
This medicine does not require any special storage conditions.
After reconstitution: From a microbiological point of view the product should be used immediately. Otherwise, storage conditions after reconstitution are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C to 8 ° C, unless reconstitution has taken place under controlled and validated aseptic conditions.
06.5 Nature of the immediate packaging and contents of the package -
TILDIEM 60 mg modified release tablets :
Box of 50 tablets contained in PVC / alu blisters.
TILDIEM 120 mg prolonged-release tablets :
Box of 24 tablets contained in Aluminum / (oPA / Aluminum / PVC) blisters.
TILDIEM 200 mg prolonged-release hard capsules :
Box of 36 controlled release capsules contained in PVC / alu blisters.
TILDIEM 300 mg prolonged-release hard capsules :
Box of 14 controlled release capsules contained in PVC / alu blisters.
TILDIEM 100 mg powder for solution for infusion :
Carton containing 5 glass vials for intravenous use.
06.6 Instructions for use and handling -
For oral formulations :
No special instructions.
For injectable formulation :
The product must be diluted with 5% physiological or glucose solution.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Sanofi S.p.A. & ndashi; Viale L. Bodio, 37 / B & ndashi; Milan
08.0 MARKETING AUTHORIZATION NUMBER -
TILDIEM 60 mg modified release tablets: A.I.C. n. 025278019
TILDIEM 120 mg prolonged-release tablets : A.I.C. n. 025278058
TILDIEM 200 mg prolonged-release hard capsules : A.I.C. n. 025278072
TILDIEM 300 mg prolonged-release hard capsules : A.I.C. n. 025278060
TILDIEM 100 mg powder for solution for infusion: A.I.C. n. 025278045
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Renewal of the authorization: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT -
January 2016
