- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
Route of administrationOral
PosologyDosage requirements may differ between patients with angina and patients with hypertension. In addition, individual patients' responses may vary necessitating careful titration. This range of capsule strengths facilitates titration to the optimal dose.The capsules should be swallowed whole and not chewed.
Adults:For patients new to diltiazem therapy the usual starting dose is one 240 mg capsule daily.Patients currently receiving a total daily dose of 180 mg diltiazem (as 90 mg b.d. or 60 mg t.i.d.) and transferring to ADIZEM-XL capsules should be given the 240 mg capsule (o.d.). A patient receiving 240 mg/day of diltiazem (as 120 mg b.d.) should commence treatment on the 240 mg capsule (o.d.), titrating to the 300 mg capsule (o.d.) if required.
Elderly and patients with impaired hepatic and renal function:For patients new to diltiazem therapy, the usual starting dose is one 120 mg capsule daily. If necessary the dose may be gradually increased but careful monitoring of this group of patients is advised. Elderly patients transferring to ADIZEM-XL capsules should receive the same total daily dose of diltiazem, titrating upwards as required.
Children:ADIZEM-XL capsules are not recommended for children. Safety and efficacy in children have not been established.In order to avoid confusion, it is suggested that patients, once titrated to an effective dose using ADIZEM-XL capsules, should remain on this treatment and should not be changed between different presentations.ADIZEM-XL capsules should not be taken at the same time as an alcoholic beverage (refer to Section 4.5, Interactions 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).
Concomitant use requiring caution:Lithium: Risk of increase in lithium-induced neurotoxicity.Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects): In all the 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 the strict monitoring of the blood pressure.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. Diltiazem hydrochloride may cause small increases in plasma levels of digoxin, requiring careful monitoring of AV conduction.Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Patients with pre-existing conduction defects should not receive the combination of diltiazem and beta-blockers. Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.Other antihypertensive drugs: Enhanced antihypertensive effect may occur with concomitant use of other antihypertensive drugs (e.g. beta-blockers, diuretics, ACE-inhibitors) or drugs that cause hypotension such as aldesleukin and antipsychotics.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.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.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.Protease inhibitors (atazanavir, ritonavir): Increase in plasma diltiazem concentrations.Ciclosporin: Increase in circulating cyclosporin levels:It is recommended that the cyclosporin dose be reduced, renal function be monitored, circulating cyclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation.
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.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 (e.g. cilostazol, ivabradine, sirolimus, tacrolimus). Care should be exercised in patients taking these drugs. Concomitant use of diltiazem with cilostazol and ivabradine should be avoided.Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.Barbiturates (phenobarbital, primidone): serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers. Phenytoin: serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers.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 metabolized by the CYP3A4 pathway in patients using diltiazem.Diltiazem may increase bioavailability of tricyclic antidepressants.Corticosteroids (methylprednisolone): 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.Statins (simvastatin, atorvastatin, lovastatin): Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of some statins. 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.ADIZEM-XL capsules should not be taken at the same time as alcohol, as it may increase the rate of release of diltiazem from the prolonged release preparation. In addition the combination of alcohol and diltiazem may have an additive vasodilatory effect.
|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), hypotension|
|Gastrointestinal disorders||Constipation, dyspepsia, gastric pain, nausea||Vomiting, diarrhoea||Dry mouth||Gingival hyperplasia, gastrointestinal disorder|
|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), hyperhidrosis, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever, allergic dermatitis|
|Reproductive system and breast disorders||Gynecomastia|
|General disorders and administration site conditions||Peripheral oedema||Malaise, fatigue|
Capsule ContentsMicrocrystalline Cellulose Ethylcellulose N10 Colloidal Anhydrous Silica Polysorbate 80 Dibutyl Sebacate Magnesium Stearate
Capsule shellsIron oxide (E172) Titanium dioxide (E171) Sodium laurilsulfate Gelatin Erythrosine (E127) (not present in the 200 mg capsule) Indigo carmine (E132) (not present in the 200 mg capsule) Patent blue V (E131) (300 mg capsule only)
Printing inkShellac SimeticonePropylene glycol Titanium dioxide (E171)
Napp Pharmaceuticals Limited
Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire, CB4 0GW
+44 (0)1223 424 444