Tensipine MR 10

1. Name Of The Medicinal Product

Tensipine MR 10

2. Qualitative And Quantitative Composition

Tensipine MR 10 tablets: Pink-grey lacquered modified release tablets each containing 10mg nifedipine, one side marked TMR and the reverse side marked 10.

3. Pharmaceutical Form

Modified release tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prophylaxis of chronic stable angina pectoris and the treatment of hypertension.

4.2 Posology And Method Of Administration

Adults

The recommended starting dose of Tensipine MR is 10mg every 12 hours swallowed with water with subsequent titration of dosage according to response. The dose may be adjusted to 40mg every 12 hours.

Tensipine MR 10 permits titration of initial dosage. The recommended dose is one Tensipine MR 10 tablet (10mg) every 12 hours.

Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored.

Patients with renal impairment should not require adjustment of dosage.

Elderly patients

The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Children

Nifedipine is not recommended for use in children.

Treatment may be continued indefinitely.

4.3 Contraindications

Tensipine MR should not be administered to patients with known hypersensitivity to nifedipine or other dihydropyridines because of the theoretical risk of cross-reaction, to women capable of child-bearing or to nursing mothers.

Tensipine MR should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.

Tensipine MR should not be used for the treatment of acute attacks of angina.

The safety of Tensipine MR in malignant hypertension has not been established.

Tensipine MR should not be used for secondary prevention of myocardial infarction.

Tensipine MR should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.

4.4 Special Warnings And Precautions For Use

Tensipine MR is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker preferably over 8 - 10 days.

Tensipine MR may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Tensipine MR will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Tensipine MR should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

Caution should be exercised in patients with severe hypotension.

Diabetic patients taking Tensipine MR may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

Patients with rare heriditary problems of fructose intolerances, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The antihypertensive effect of Tensipine MR may be potentiated by simultaneous administration of cimetidine.

When used in combination with nifedipine, serum quinidine levels have been shown to be suppressed regardless of dosage of quinidine.

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in the plasma digoxin level. Plasma digoxin levels should be monitored and, if necessary, the digoxin dose reduced.

Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Therefore, caution should be taken when both drugs are used in combination and a reduction of the nifedipine dose may be necessary.

Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.

Rifampicin interacts with nifedipine (see Contra-indications).

As with other dihydropyridines, nifedipine should not be taken with grapefruit juice because bioavailability is increased.

4.6 Pregnancy And Lactation

Tensipine MR is contra-indicated in women capable of child-bearing and nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Ischaemic pain has been reported in a small proportion of patients within one to four hours of the introduction of Tensipine MR therapy. Although a "steal" effect has not been demonstrated, patients experiencing this effect should discontinue Tensipine MR.

Most side-effects are consequences of the vasodilatory effects of nifedipine. Headache, flushing, tachycardia and palpitations may occur, most commonly in the early stages of treatment with nifedipine. Gravitational oedema not associated with heart failure or weight gain may also occur.

Paraesthesia, dizziness, lethargy and gastro-intestinal symptoms such as nausea and altered bowel habit occur occasionally.

There are reports of skin reactions such as rash, pruritus and urticaria.

Other less frequently reported side-effects include myalgia, tremor and visual disturbances.

Impotence may occur rarely.

Increased frequency of micturition may occur.

There are reports of gingival hyperplasia and, in older men on long-term therapy, gynaecomastia, which usually regress upon withdrawal of therapy.

Mood changes may occur rarely.

Side-effects which may occur in isolated cases are photosensitivity, exfoliative dermatitis, systemic allergic reactions and purpura. Usually, these regress after discontinuation of the drug.

Rare cases of hypersensitivity-type jaundice have been reported. In addition, disturbances of liver function such as intra-hepatic cholestasis may occur. These regress after discontinuation of therapy.

As with other sustained release dihydropyridines, exacerbation of angina pectoris may occur rarely at the start of treatment. The occurrence of myocardial infarction has been described although it is not possible to distinguish such an event from the natural course of ischaemic heart disease.

4.9 Overdose

Clinical effects

Reports of nifedipine overdosage are limited and symptoms are not necessarily dose-related. Severe hypotension due to vasodilatation, and tachycardia or bradycardia are the most likely manifestations of overdose.

Metabolic disturbances include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia.

Cardiac effects may include heart block, AV dissociation and asystole, and cardiogenic shock with pulmonary oedema.

Other toxic effects include nausea, vomiting, drowsiness, dizziness, confusion, lethargy, flushing, hypoxia and unconsciousness to the point of coma.

Treatment

As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority.

After oral ingestion, gastric lavage is indicated, if necessary in combination with irrigation of the small intestine. Ipecacuanha should be given to children.

Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance. Activated charcoal should be given in 4-hourly doses of 25g for adults, 10g for children.

Blood pressure, ECG, central arterial pressure, pulmonary wedge pressure, urea and electrolytes should be monitored.

Hypotension as a result of cardiogenic shock and arterial vasodilatation should be treated with elevation of the feet and plasma expanders. If these measures are ineffective, hypotension may be treated with 10% calcium gluconate 10 - 20ml intravenously over 5 - 10 minutes. If the effects are inadequate, the treatment can be continued, with ECG monitoring. In addition, beta-sympathomimetics may be given, e.g. isoprenaline 0.2mg slowly i.v. or as a continuous infusion of 5μg/min. If an insufficient increase in blood pressure is achieved with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.

Bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required.

Additional fluids should be administered with caution to avoid cardiac overload.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Mode of action

Nifedipine is a specific and potent calcium antagonist. In hypertension, the main action of Tensipine MR is to cause peripheral vasodilatation and thus reduce peripheral resistance.

In angina, Tensipine MR reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load.

Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.

Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.

Tensipine MR administered twice-daily provides 24-hour control of raised blood pressure. Tensipine MR causes reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Tensipine MR has little or no effect on blood pressure.

5.2 Pharmacokinetic Properties

Nifedipine is absorbed almost completely from the gastro-intestinal tract regardless of the oral formulation used and undergoes extensive metabolism in the liver to inactive metabolites, with less than 1% of the parent drug appearing unchanged in the urine. The rate of absorption determines the drug's apparent elimination. The terminal elimination half-life of the modified release formulation is 6 - 11 hours.

After enteral or intravenous doses, 70 - 80% of activity is eliminated (primarily as metabolites) via the urine. Remaining excretion is via the faeces.

After 24 hours, 90% of the administered dose is eliminated.

Protein binding of nifedipine exceeds 90% in human serum.

5.3 Preclinical Safety Data

Reproduction toxicology

Nifedipine administration has been associated with a variety of embryotoxic, placentotoxic and fetotoxic effects in rats, mice and rabbits. All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tensipine MR tablets contain the following excipients:

Microcrystalline cellulose, maize starch, lactose, polysorbate 80, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol 4000, iron oxide red and titanium dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

PVC blister strips: 48 months

PP blister strips: 30 months

6.4 Special Precautions For Storage

The tablets should be protected from strong light and stored in the manufacturer's original container.

6.5 Nature And Contents Of Container

Tensipine MR 10 tablets: blister strips of 14 tablets in a cardboard outer container, packs of 56 tablets.

Blister strips are composed of red polypropylene foil (0.3mm) with aluminium backing foil (0.02mm) or red PVC foil (0.3mm) with aluminium backing foil (0.02mm).

6.6 Special Precautions For Disposal And Other Handling

No additional information.

7. Marketing Authorisation Holder

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury, Berkshire

RG14 1JN

8. Marketing Authorisation Number(S)

PL 06831/0048

9. Date Of First Authorisation/Renewal Of The Authorisation

22 April 1996

10. Date Of Revision Of The Text

5 September 2011