Zemtard 120 Xl
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zemtard 120 XL.
Angiozem 120 XL.
Uard 120 XL
2. Qualitative and Quantitative Composition
Diltiazem hydrochloride EP 120mg per capsule.
Excipients with known effect: each capsule contains not more than 65.0mg sucrose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard gelatin capsule containing prolonged release diltiazem hydrochloride beads.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of mild to moderate hypertension. Prophylaxis and treatment of angina pectoris.
4.2 Posology and method of administration
Capsules should be swallowed whole (not chewed) with half a glass of fluid.
Adults:
The recommended dose in adults is between 180 and 3 00mg given once daily. Doses of up to 360mg/day in hypertension and 480mg/day in angina may be of benefit in some patients.
Elderly and patients with impaired renal or hepatic function:
In the elderly or renally or hepatically impaired a starting dose of 120mg daily is recommended. The dose should not be increased if the heart rate falls below 50bpm.
Children: This product is not recommended for use in children.
4.3. Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Diltiazem depresses atrioventricular node conduction and is therefore contraindicated in patients with severe bradycardia (below 40 bpm): in sick sinus syndrome or in second- or third-degree AV block, except in the presence of a functioning ventricular pacemaker: in left ventricular failure with pulmonary congestion. Because of the risk of ventricular fibrillation, diltiazem should not be given concomitantly with dantrolene infusion (see section 4.5). Diltiazem is also contraindicated in combination with ivabradine (see section 4.5).
Diltiazem is contraindicated in pregnancy, in women of childbearing potential not using effective contraception and while breast-feeding (see section 4.6).
4.4. Special warnings and precautions for use
Close observation is necessary in patients with heart failure or reduced left ventricular function, bradycardia (risk of exacerbation), or with first-degree AV block detected on ECG (risk of exacerbation and rarely, of complete block). Patients with prolonged PR interval should also be observed closely.
Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem treatment. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers (see section 4.5).
Increase of plasma concentrations of diltiazem may be observed in the elderly and in patients with renal or hepatic insufficiency, therefore, treatment should commence with reduced doses in elderly patients and in patients with impaired liver or kidney function. The contraindications and precautions should be closely observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.
Sudden withdrawal of diltiazem might be associated with an exacerbation of angina.
Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression. Early recognition of relevant symptoms is important, especially in predisposed patients. In such cases, drug discontinuation should be considered.
Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility. Therefore, it should be used with caution in patients at risk to develop an intestinal obstruction.
This product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.5. Interaction with other medicinal products and other forms of interaction
Concomitant use contraindicated:
Dantrolene (infusion): Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and dantrolene are administered concomitantly. The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see section 4.3).
Ivabradine: Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of diltiazem to ivabradine (see section 4.3).
Concomitant use requiring caution:
Lithium: Risk of increase in lithium-induced neurotoxicity (without an increase in the plasma concentration of lithium).
Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects): In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.
Theophylline: Increase in circulating theophylline levels.
Alpha-antagonists: Increased antihypertensive effects: Concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha-antagonist should be considered only with strict monitoring of the blood pressure.
Amiodarone, digoxin: Caution is required when amiodarone or digoxin are combined with diltiazem, particularly in elderly subjects and when high doses are used. Increased risk of bradycardia: Increased risk of bradycardia, AV block and myocardial depression when diltiazem is given with amiodarone. The plasma concentration of digoxin may be increased by diltiazem. The pharmacodynamic effects on heart rhythm and AV conduction of digoxin and calcium-channel blockers may also be additive.
Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sinoatrial and atrioventricular conduction disturbances and heart failure (synergistic effect). Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.
Other antiarrhythmic agents: Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended (additive risk of increased cardiac adverse effects). This combination should only be used under close clinical and ECG monitoring.
Antiepileptics: The effect of carbamazepine is enhanced by diltiazem.
Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary. Diltiazem can increase the plasma concentration of phenytoin. The effect of diltiazem can be also reduced by phenytoin and probably by primidone.
Rifampicin: Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin: The patient should be carefully monitored when initiating or discontinuing rifampicin treatment.
Anti-H2 agents (cimetidine, ranitidine): Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. An adjustment in diltiazem daily dose may be necessary.
Immunosuppressants: Increase in circulating ciclosporin levels: It is recommended that the ciclosporin dose be reduced, renal function be monitored, circulating ciclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation. The plasma concentrations of sirolimus, tacrolimus and everolimus may be increased by diltiazem.
Antivirals: Plasma concentration of diltiazem increased by atazanavir (reduce dose of diltiazem); plasma concentration of calcium-channel blockers possibly increased by ritonavir.
Barbiturates: Effects of diltiazem probably reduced by barbiturates.
Cilostazol: Diltiazem increases the plasma concentration of cilostazol - avoid concomitant use.
General information to be taken into account:
Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction eg. other calcium channel blockers and other anti-hypertensive drugs. Plasma concentrations of both drugs may increase when diltiazem is given with nifedipine.
Diltiazem is metabolized by CYP3A4. A moderate (less than 2-fold) increase of diltiazem plasma concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other CYP3A4 substrates may result in an increase in plasma concentration of either co-administered drug. Coadministration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
Benzodiazepines (midazolam, triazolam): Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short-acting benzodiazepines metabolised by the CYP3A4 pathway in patients using diltiazem.
Anxiolytics and hypnotics: Enhanced hypotensive effect when calcium-channel blockers are given with anxiolytics and hypnotics.
Corticosteroids: Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein: The patient should be monitored when initiating methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be necessary. The hypotensive effect of calcium-channel blockers may be antagonised by concurrent administration with corticosteroids.
Statins: Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins (atorvastatin, simvastatin and lovastatin). The risk of myopathy and rhabdomyolysis due to statins metabolised by CYP3A4 may be increased with concomitant use of diltiazem. When possible, a non CYP3A4-metabolised statin should be used together with diltiazem, otherwise close monitoring for signs and symptoms of a potential statin toxicity is required.
Other interactions:
Anaesthetics, General: Enhanced hypotensive effect when calcium-channel blockers are given with general anaesthetics (see section 4.4).
Antidepressants: Diltiazem may increase the plasma concentration of imipramine and possibly other tricyclics, possibly accompanied by undesirable ECG changes. Enhanced hypotensive effect when calcium-channel blockers are given with MAOIs.
Anti-fungals: Negative inotropic effect possibly increased when calcium-channel blockers are given with itraconazole.
Antimalarials: Possible increased risk of bradycardia when calcium-channel blockers are given with mefloquine.
Fertility, pregnancy and lactation
4.6.
Pregnancy:
There are very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity in certain animal species (rat, mice, rabbit). In the absence of adequate evidence of safety in human pregnancy, diltiazem should not be used in pregnancy or in women of childbearing potential not using effective contraception (see section 4.3).
Breastfeeding:
Breastfeeding while taking this drug should be avoided (see section 4.3). If use of the drug is considered essential in nursing mothers, an alternative method of feeding should be instituted, since diltiazem is excreted in breast milk at low concentrations.
4.7. Effects on ability to drive and use machines
On the basis of reported adverse drug reactions ie. dizziness (common), malaise (common) and hypotension (uncommon), the ability to drive and use machines could be altered. However, no studies have been performed.
Patients should be warned not to drive or operate machinery until the effect of diltiazem has been established.
4.8. Undesirable effects
The following CIOMS frequency rating is used, when applicable: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
|
Very common |
Common |
Uncommon |
Rare |
Not known | |
|
Blood and lymphatic system disorders |
Thrombocytopenia | ||||
|
Psychiatric disorders |
Nervousness, insomnia |
Mood changes (including depression) | |||
|
Nervous system disorders |
Headache, dizziness |
Extrapyramidal syndrome | |||
|
Cardiac disorders |
Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations |
Bradycardia |
Sinoatrial block, congestive heart failure | ||
|
Vascular disorders |
Flushing |
Orthostatic hypotension |
Vasculitis (including leukocytoclastic vasculitis) |
|
Very common |
Common |
Uncommon |
Rare |
Not known | |
|
Gastrointestina l disorders |
Constipation, dyspepsia, gastric pain, nausea |
Anorexia, vomiting, diarrhoea, taste disturbance, weight gain |
Dry mouth |
Gingival hyperplasia | |
|
Hepatobiliary disorders |
Hepatic enzymes increase (AST, ALT, LDH, ALP increase) |
Hepatitis | |||
|
Skin and subcutaneous tissue disorders |
Erythema |
Urticaria |
Photosensitivity (including lichenoid keratosis at sun exposed skin areas), photodistributed hyperpigmentation, angioneurotic oedema, rash, erythema multiforme (including Steven-Johnson's syndrome and toxic epidermal necrolysis), sweating, exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP), occasionally desquamative erythema with or without fever | ||
|
Reproductive system and breast disorders |
Gynecomastia | ||||
|
General disorders and administration site conditions |
Peripheral oedema |
Malaise |
Asthenia/fatigue |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9. Overdose
The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse, sinus bradycardia which may be accompanied by isorhythmic dissociation, and atrioventricular conduction disturbances.
Treatment, in a hospital setting, will include gastric lavage and/or osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing. Observation in a coronary care unit is advisable. Proposed corrective treatments: atropine, vasopressors such as adrenaline may be given in those with severe hypotension, inotropic agents, glucagon and calcium gluconate infusion may help reverse the effects of calcium entry blockade.
5.1 Pharmacodynamic properties
The cardiovascular activity of diltiazem is based upon its ability to inhibit the entry of calcium from extra-cellular fluid into the muscle cells and the release of intracellular calcium stores inhibiting the contractile mechanism. In vascular tissues diltiazem relaxes arterial smooth muscle, reducing peripheral resistance in both systemic and coronary circulation. The reduction in blood pressure that accompanies vasodilation with diltiazem is usually accomplished without reflex tachycardia - probably because it suppresses sinoatrial node stimulation, In cardiac muscle, diltiazem reduces contractility and has a mild negative inotropic effect, although in vivo its potent vasodilatory activity leads to decreases in peripheral resistance and blood pressure, with a resultant increase in cardiac output due to decreased afterload. In angina, diltiazem reduces O2 consumption by decreasing afterload and decreasing heart rate. It also increases O2 supply to coronary arteries and improves O2 utilisation. Diltiazem neither reduces renal blood flow nor alters glomerular filtration rate.
Haemodynamic effects are related to dose and to plasma levels, although the relationship between these is not simple. A minimum plasma level of 40-50ng/ml has been reported as being required for haemodynamic effects and several authors quote this value when examining plasma levels in pharmacokinetic studies of sustained release preparations. However, more recently the minimally effective concentration is being given as 100ng/ml and typical plasma levels of diltiazem observed in patients are described as between 50 and 300ng/ml. There is no consistent correlation between plasma levels of diltiazem and the magnitude of haemodynamic effects, although some studies have shown a correlation between antianginal effects and plasma levels. Standard texts do not quote an effective plasma concentration range. It should be noted that oral doses can produce a wide scatter of plasma concentrations.
The accepted effective dose ranges vary from country to country, with Japan and Asia using lower doses. For France and West Germany, oral dosages of 180-360mg/day are used in hypertension while l20-360mg/day is used in the United States. In angina the dose ranges from 120-180mg/day in France and from 120-360mg/day in the United States.
5.2 Pharmacokinetic properties
A number of studies of the pharmacokinetics of diltiazem have been published and the work has been extensively reviewed. Studies have included both healthy subjects and patients with angina or hypertension.
5.2.1 Absorption
Oral doses of diltiazem are well absorbed (about 90% of dose) but the compound undergoes considerable first-pass metabolism.
Absorption is rapid after the conventional formulation with half-lives of around 0.25-0.5 hours being reported.
5.2.2 Distribution
In single and multiple dose studies in normal subjects and in those with coronary artery disease, diltiazem is about 78-87% bound to plasma protein. The percentage of unbound drug is independent of the concentration of diltiazem over the range tested (3-500p,g/l) and the percentage is not influenced by the metabolite desacetyldiltiazem. The mean volume of distribution is between 4 and 7 l/kg, and this relatively large volume is considered probably to result from its high lipid solubility.
5.2.3 Metabolism
Diltiazem is mainly metabolised in the liver and less than 5% of parent drug appears in the urine. It is metabolised to form at least eight metabolites via pathways that include O-deacetylation, N-demethylation and O-demethylation with oxidative deamination identified as a major route. The main metabolites are desmethyl- and desacetyl-diltiazem and these have about 20% and 50%, respectively, of the activity of the parent compound. However, the concentration in plasma is not usually more than 30-50% of the parent for desmethyldiltiazem and 10-30% for desacetyldiltiazem, and most activity is due to diltiazem itself.
5.2.4 Excretion
Only 0.2% to 4% of a single orally administered dose (60-210mg) and 1-3% of a dose following repeat oral administration (120-180mg/day for 7-15 days) is excreted unchanged in urine.
Hoglund and Nilsson studied oral labelled diltiazem and found between 7073% of label in urine with the rest of the label appearing in faeces.
5.3 Preclinical safety data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sugar spheres (sucrose and starch) Ammoniomethacrylate Copolymer A Ammoniomethacrylate Copolymer B Paraffin Talc
Capsule Components
Red Iron Oxide E172 Yellow Iron Oxide E172 Erythrosine E127 Indigotine E132 Titanium Dioxide E171 Gelatin
Overprint Ink Constitiuents
Shellac
Propylene glycol Black iron oxide (E172)
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in a dry place below 25°C; protect from light.
Nature and contents of container
6.5
Blister packs composed of PVC/PVDC sealed to aluminium-PVDC containing 28, 30, 56, 60 or 100 Size 2 capsules with a brownish-red cap and orange body. Capsules are marked DIL 120.
6.6 Special precautions for disposal
None stated.
7 MARKETING AUTHORISATION HOLDER
Galen Limited
Seagoe Industrial Estate
Craigavon
BT63 5UA
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 27827/0033
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/03/1996 / 03/05/2001
10 DATE OF REVISION OF THE TEXT
29/09/2016