Lofamil Xl 300 Mg Prolonged-Release Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lofamil XL 300 mg Prolonged-release Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release hard capsule contains 300 mg Diltiazem Hydrochloride. For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release capsule, hard
Size “0” hard gelatin capsules having opaque green cap and opaque white body; each capsule contains white and whitish prolonged-release pellets
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Mild to moderate hypertension and angina pectoris
4.2 Posology and method of administration
Posology
Adults:
The usual starting dose is Lofamil XL 200 mg Prolonged-release Capsules once daily. This dose may be increased to Lofamil XL 300 mg Prolonged-release Capsules once daily, or 2 capsules of Lofamil XL 200 mg Prolonged-release Capsules daily (400 mg), if clinically indicated. A higher dose up to 500 mg daily may be required in certain cases.
Elderly and patients with impaired hepatic or renal function:
Heart rate should be monitored and if it falls below 50 beats per minute the dose should not be increased. Plasma levels of diltiazem can be increased in this group of patients.
Lofamil XL 300 mg Prolonged-release Capsules should be used with caution in patients with renal or hepatic impairment (see section 4.4)
Angina and hypertension: the initial dose should be one Lofamil XL 200 mg Prolonged-release capsule daily. This dose may be increased to one capsule of Lofamil XL 300 mg Prolonged-release Capsules daily if clinically indicated.
Paediatric population:
The safety and efficacy of diltiazem in children have not been established. Therefore diltiazem is not recommended for use in children.
Method of administration
Lofamil XL 200 mg Prolonged-release Capsules and Lofamil XL 300 mg Prolonged-release Capsules are prolonged release products for once daily dosing. The capsules should not be chewed but swallowed whole with water, ideally before or during a meal. The dosage requirements may differ in patients with angina or hypertension.
4.3 Contraindications
Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker. Severe bradycardia (less than 50 beats per minute).
Left ventricular failure with pulmonary stasis.
Concurrent use with dantrolene infusion, ivabradine (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Hypersensitivity to diltiazem or to any of the excipients.
4.4 Special warnings and precautions for use
Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk of exacerbation) or with a 1st degree AV block or prolonged PR interval detected on the electrocardiogram (risk of exacerbation and rarely, of complete block).
Increase of plasma concentrations of diltiazem may be observed in the elderly and patients with renal or hepatic insufficiency. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment.
In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.
Treatment with 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.
Diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk of developing an intestinal obstruction. Tablet residues from slow release formulations of the product may pass into the patient’s stools; however, this finding has no clinical relevance.
4.5 Interaction with other medicinal products and other forms of interaction
COMBINATIONS CONTRAINDICATED FOR SAFETY REASONS
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 Contraindications).
Ivabradine
Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect of diltiazem to ivabradine (see section 4.3 Contraindications).
Ergot derivatives (ergotamine, dihydroergotamine)
Diltiazem may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.
Cisapride
Increased risk of ventricular arrhythmia, notably torsades de pointes.
Sertindole
Increased risk of ventricular arrhythmia, notably torsades de pointes.
Pimozide
Increased risk of ventricular arrhythmia, notably torsades de pointes.
Nifedipine
The combination of diltiazem with nifedipine may lead to a substantial increase of nifedipine plasma concentrations, due to the inhibition of nifedipine metabolism by diltiazem.
COMBINATIONS REQUIRING CAUTION:
Alpha-antagonists
Increased anti-hypertensive 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 blood pressure.
Beta-blockers
Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect).
Such a combination must be used under close clinical and ECG monitoring, particularly at the beginning of treatment.
Amiodarone, Digoxin
Increased risk of bradycardia; caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used.
Antiarrhythmic agents
Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents (including dronedarone) is not recommended due to the risk of increased cardiac adverse effects due to an additive effect. This combination should only be used under close clinical and ECG monitoring.
Nitrate derivatives
Increased hypotensive effects and faintness (additive vasodilating effects).
In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.
Immunosuppressants (ciclosporine, tacrolimus, sirolimus)
Increase in circulating immunosuppressants levels. It is recommended that the immunosuppressants dose be reduced, renal function be monitored, circulating immunosuppressants levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation.
Carbamazepine
Increase in circulating carbamazepine levels. It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary.
Theophylline
Increase in circulating theophylline levels.
Anti-H2 agents (cimetidine and ranitidine)
Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H2 agents. Ad adjustment in diltiazem daily dose may be necessary.
Rifampicin
Risk of decrease of diltiazem plasma levels after intiating therapy with rifampicin. The patients should be carefully monitored when initiating or discontinuing rifampicin treatment.
Lithium
Risk of increase in lithium-induced neurotoxicity.
COMBINATIONS TO BE TAKEN INTO ACCOUNT:
Diltiazem is metabolised 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.
Statins
Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins. The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with statins metabolised by CYP3A4 (e.g. atorvastatin, fluvastatin and simvastatin). An adjustment of the dose of statin may be necessary (see also product information of the relevant statin). When possibile, it is recommended to use a statin not metabolised by CYP3A4 (e.g. pravastatin) with diltiazem.
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.
Corticosteroids (methylprednisolone)
Diltiazem can increase methylprednisolone levels (through inhibition of CYP3A4 and possible inhibition of P-glycoprotein). The patient should be monitored when initiating methylprednisolone treatment. An adjustment to the dose of methylprednisolone may be necessary.
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.
4.6 Fertility, pregnancy and lactation
Pregnancy: There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity (see section 5.3) in certain animal species (rat, mice, rabbit). Diltiazem is therefore not recommended during pregnancy, as well as in women of child-bearing potential not using effective contraception.
Use during breastfeeding: Diltiazem is excreted in breast milk at low concentrations. Breast feeding while taking this drug should be avoided. If use of diltiazem is considered medically essential, an alternative method of infant feeding should be instituted.
Fertility: Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by channel blockers.
4.7 Effects on ability to drive and use machines
On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the ability to drive and use machines could be altered. However, no studies have been performed.
4.8 Undesirable effects
The following MedDRA 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) | ||
|
Gastrointestinal disorders |
Constipation, dyspepsia, gastric pain, nausea |
Vomiting, diarrhea |
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), angioneurotic oedema, rash, erythema multiforme (including Steven- Johnson's syndrome and toxic epidermal necrolysis), sweating, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever | ||
|
Reproductive system and breast disorders |
Gynecomastia | ||||
|
General disorders and administration site conditions |
Peripheral oedema |
Malaise |
4.9 Overdose
The clinical effects of acute overdose can involve pronounced hypotension leading to collapse, sinus bradycardia with or without isorhythmic dissociation and atrioventricular conduction disturbances.
Treatment, under hospital supervision, will include gastric lavage, osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing.
Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calcium channel blocker, ATC-code: C08DB01
Calcium antagonist, antihypertensive agent.
Diltiazem restricts calcium entry into the slow calcium channel of vascular smooth muscle and myocardial muscle fibres in a voltage-dependent manner. By this mechanism, diltiazem reduces the concentration of intracellular calcium in contractile protein.
In animals: diltiazem increases coronary blood flow without inducing any coronary steal phenomena. It acts both on small, large and collateral arteries. This vasodilator effect, which is moderate on peripheral systemic arterial territories, can be seen at doses that are not negatively inotropic.
The two major active circulating metabolites, i.e. desacetyl diltiazem and N-monodesmethyl diltiazem, possess pharmacological activity in angina corresponding to 10 and 20% respectively of that of the parent compound.
In humans: diltiazem increases coronary blood flow by reducing coronary resistance.
Due to its moderate bradycardia-inducing activity and the reduction in systemic arterial resistance, diltiazem reduces cardiac workload.
Lofamil XL 200 mg Prolonged-release Capsules and Lofamil XL 300 mg Prolonged-release Capsules does not have a significant myocardial depressant action in man.
5.2 Pharmacokinetic properties
Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.
The sustained release capsule provides prolonged absorption of the active constituent, producing steady state plasma concentrations between 2 and 14 hours post-dose, during which time peak plasma levels occur.
Bioavailability of Prolonged Release Diltiazem formulation relative to the immediate release formulation is approximately 80%. The mean apparant plasma half-life is 8 hours.
Diltiazem in plasma is 80 to 85% protein bound and is poorly dialysed. It is extensively metabolised by the liver.
The major circulating metabolite, N-monodesmethyl diltiazem accounts for approximately 35% of the circulating diltiazem.
Less than 5% of diltiazem is excreted unchanged in the urine.
Twenty four hours after intake, plasma concentrations remain, even after the 200 mg dose administration, at the level of 50 ng/ml, in patients. During long term administration in any one patient, plasma concentrations of diltiazem remained constant.
Mean plasma concentrations in the elderly and patients with renal and hepatic insufficiency are higher than in young subjects.
Food intake does not significantly affect the kinetics of Diltiazem Prolonged Release formulation, however, when administered with food, absorption was observed to be higher in the first few hours post-dose.
Diltiazem and its metabolites are poorly dialysed.
Once daily formulations of diltiazem have been shown to have different pharmacokinetic profiles and therefore it is not advised to substitute different brands for one another.
5.3 Preclinical safety data
Pregnancy: Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4 to 6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg q.d. or 8 mg/kg q.d. for a 60 Kg patient) resulted in embryo and fetal lethality. These studies revealed, in one species or another, a propensity to cause fetal abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights, pup survival, as well as prolonged delivery times and an increased incidence of stillbirths.
6 PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Excipients in pellets
Povidone
Talc
Ethylcellulose Stearic Acid
Excipients in the capsule shell: Gelatin
Titanium dioxide (E171) Indigo Carmine (E132) Quinoline Yellow (E104)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store in the original packaging.
6.5 Nature and contents of container
28, 30, 56, 60, 84, 90, 98, 100, 50x1 prolonged-release capsules, in a transparent PVC/PVDC-Alu-foil blister pack
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road,
Hampden Park,
Eastbourne,
East Sussex BN22 9AG,
UNITED KINGDOM
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MARKETING AUTHORISATION NUMBER(S)
PL 00289/1649
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
05/10/2012
DATE OF REVISION OF THE TEXT
12/11/2015