Nifetex TR

Nifetex TR should not be used in patients with any of the following conditions:

-

- other dihydropyridines because of the theoretical risk of cross-reactivity

- bradycardia

- cardiogenic shock

- hypotension

- metabolic acidosis

- severe peripheral arterial circulatory disturbances

- second or third degree heart block

- sick sinus syndrome

- untreated phaeochromocytoma

- uncontrolled heart failure

- women capable of childbearing or during pregnancy or during lactation

- patients with clinically significant aortic stenosis

- patients with marked renal impairment (i.e. creatinine clearance below 15 ml/min/1.73 m²; serum creatinine greater than 600 micromol/litre; GFR less than 30 ml/min)

- patients receiving calcium channel blockers with negative inotropic effects e.g. verapamil and diltiazem

- within one month of acute coronary syndromes (ST- or non-ST-elevation myocardial infarction and unstable angina pectoris)

- during or within one month of a myocardial infarction

- severe hepatic insufficiency.

Nifetex TR should not be used for the treatment of acute attacks of angina.

The safety of Nifetex TR in malignant hypertension has not been established.

Nifetex TR should not be used for secondary prevention of myocardial infarction.

Due to the nifedipine component, Nifetex TR should not be administered in combination with rifampicin because plasma levels of nifedipine, predictive of efficacy, may not be attained due to enzyme induction.

Due to its beta-blocker component, Nifetex TR:

- Although contraindicated in uncontrolled heart failure , may be substituted with care in patients already treated with a beta-blocking drug, and/or whose signs of heart failure have been controlled. Caution must be exercised in patients with conduction defects or whose cardiac reserve is poor, especially as nifedipine also has negative inotropic effects. However, in patients already treated with a beta-blocker and/or where signs of cardiac failure have been controlled, Nifetex TR may be substituted with care if necessary.

- May increase the number and duration of angina attacks in patients with Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Atenolol is a beta₁-selective beta-blocking drug; consequently, the use of Nifetex TR may be considered although utmost caution must be exercised.

- Although contra-indicated in severe peripheral arterial circulatory disturbances , Nifetex TR may also aggravate less severe peripheral arterial circulatory disturbances.

Due to its negative effect on conduction time by atenolol, caution must be exercised if Nifetex TR is given to patients with first-degree heart block. However, the properties of the nifedipine component of Nifetex TR will to some degree counteract the negative dromotropic effect from atenolol.

- Atenolol should be used with caution in diabetics subject to frequent episodes of hypoglycaemia. Symptoms of hypoglycaemia may be masked (may modify the tachycardia of hypoglycaemia.)

- May mask the signs of thyrotoxicosis.

- Will reduce heart rate, as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms, which may be attributable to a slow heart rate, the dose may be reduced. This effect is however opposed by the properties of the nifedipine component of Nifetex TR.

- Should not be discontinued abruptly in patients suffering from ischaemic heart disease.

- In patients with treated phaeochromocytoma Nifetex TR must be administered only after alfa-receptor blockade. Blood pressure should be monitored closely.

- May cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline (epinephrine) used to treat the allergic reactions.

- May cause a hypersensitivity reaction including angioedema and urticaria.

- Caution must be exercised when using anaesthetic agents with Nifetex TR. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-blockers with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.

- Administration of Nifetex TR may lead to positive result in doping tests.

- Patients with hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Nifetex TR.

Obstructive airways disease

Patients with bronchospastic disease should, in general, not receive beta-blockers due to increasing in airways resistance.

Nifetex TR contains the cardioselective beta-blocking drug atenolol. Although cardioselective (beta₁) beta-blocking drugs may have less effect on lung function than non-selective beta-blocking drugs, however this selectivity is not absolute. As with all beta-blocking drugs, these should be avoided in patients with reversible obstructive airways disease, unless there are compelling clinical reasons for their use. Where such reasons exist, the lowest possible dose of Nifetex TR should be used and utmost caution should be exercised. Occasionally, some increase in airways resistance may occur in asthmatic patients, Nifetex TR should be discontinued, and this may usually be reversed by commonly used dosage of bronchodilators such as salbutamol or isoprenaline.

The label and patient information leaflet for this product state the following warning: “If you have ever had asthma or wheezing, you should not take this medicine unless you have discussed these symptoms with the prescribing doctor”.

Due to its nifedipine component it should be noted that:

- The nifedipine component has no diabetogenic effect. In rare cases, a transient increase in blood glucose has been observed with nifedipine in acute studies. This should be considered in patients suffering from diabetes mellitus.

- Ischaemic pain occurs in a small proportion of patients following introduction of nifedipine monotherapy. Although a “steal” effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine therapy.

Hypertensive or anginal patients with clinically significant liver disease have not been studied and no dosage adjustment is suggested from the systemic availability of the monocomponents in patients with cirrhosis. However nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored. As a precaution, it is recommended that the dose should not exceed one capsule daily.

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Nifetex TR has no or negligible influence on the ability to drive and use machines. However, it should be taken into account that occasionally dizziness or fatigue may occur.

Tabulated list of adverse reactions

The following undesired events, listed by body system, have been reported with the following frequencies: 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) and not known (cannot be estimated from the available data).

* Frequency reported for the mono component atenolol

** Frequency reported for the mono component nifedipine

As with other sustained release dihydropyridines, exacerbation of angina pectoris may occur rarely at the start of treatment with sustained release formulations of nifedipine. 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.

Discontinuance of Nifetex TR should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions.

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: Website: www.mhra.gov.uk/yellowcard

Toxicity

The toxicity of both components is potentiated by the other.

The toxicity of nifedipine varies between individuals. The risk for severe effects in the presence of simultaneous beta-blocker overdosing should be noted, though. Atenolol has in doses of 300 - 350 mg been associated with mild intoxication in adults, while 500 mg, in a 15 year old, resulted in moderate to severe intoxication.

Symptoms

Due to the properties of being a modified release formulation with long effect duration, the symptoms from nifedipine-atenolol intoxication may emerge 12 - 18 hours after intake and severe effects can appear after several days.

Circulatory effects are the main risks from:

heart failure including pulmonary oedema and shock, brady- as well as tachyarrhythmias (including both asystole and ventricular fibrillation), cardiac conduction disturbances such as AV-dissociations and AV-blocks, low blood pressure.

Neurologic effects:

Depressed consciousness, Seizures, Coma, Headache, Flush with hypothermia.

Metabolic and respiratory effects have been observed:

Bronchospasm, Dyspnoea with non-cardiac pulmonary oedema, ARDS, acidosis, hypokalaemia, hyperglycaemia, hypocalcaemia, impaired renal function, rhabdomyolysis, nausea and emesis.

The symptoms of overdosage may also include hypotension and acute cardiac insufficiency.

Treatment

General treatment should include: close supervision, treatment in an intensive care ward.

Gastric lavage which can be justified also late after intake (clumping of modified release tablets occur: consider gastroscopy). Activated charcoal can be considered and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock. Atropine should be given prior to lavage to counteract the risks from potential vagal stimulation. The possible use of haemodialysis, haemoperfusion and plasmapheresis (nifedipine) may be considered.

The patient's condition, including cardiac rhythm, should be monitored. Mechanical ventilation should be considered on wide indications.

Acid base and electrolyte imbalances are to be corrected.

Bradyarrhythmias can be treated with atropine 1 to 2 mg intravenously (repeated doses may become necessary). Pacemaker should be employed early in cases with more severe bradyarrhythmias. Cases with circulatory failure should have their haemodynamics monitored to guide therapy and fluid substitution. Vasoconstricting therapy may commence with noradrenaline or phenylephrine. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1 to 10 mg/hour depending on response. Intravenous calcium gluconate combined with metaraminol may be beneficial for hypotension induced by nifedipine and can be given as repeated injections or infusion. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion may be given or glucagon can be potentially followed by a phosphodiesterase inhibitor (milrinone or amrinone). Dobutamine, because of its positive inotropic effect could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta-blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient. In severe cases of hypotension cardiac pacing with appropriate cardiorespiratory support may be necessary.

Insulin-glucose infusion can also be used. It can be expected that dose escalation of sympathomimetic drugs will be necessary to overcome the β blocking effects.

Bronchospasm can usually be reversed by bronchodilators.

Protracted - over several hours - resuscitation can be justified.

Seizures can be treated with benzodiazepines.

Symptomatic treatment.

Pharmacotherapeutic group: Beta-blocking agents, selective and other antihypertensives, ATC code: CO7 FB

Atenolol is a beta-blocking drug which is beta₁selective (i.e. acts preferentially on beta₁-adrenergic receptors in the heart). Selectivity decreases with increasing dose.

Atenolol is without intrinsic sympathomimetic and membrane stabilising activities and as with other beta-blocking drugs, atenolol has negative inotropic effects (and is therefore contraindicated in uncontrolled heart failure).

As with other beta-blocking drugs, its mode of action in the treatment of hypertension is unclear.

It is probably the action of atenolol in reducing cardiac rate and contractility which makes it effective in eliminating or reducing the symptoms of patients with angina.

Atenolol is effective and well-tolerated in most ethnic populations although the response may be less in black patients.

It is unlikely that any additional ancillary properties possessed by S (-) atenolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.

Nifedipine is a calcium channel blocker. It is a powerful coronary and peripheral vasodilator which increases myocardial oxygen supply and reduces blood pressure (afterload) and peripheral resistance. Concomitant use of atenolol, therefore, ameliorates the reflex sympathetic response to nifedipine monotherapy by blocking the rise in heart rate, while the tendency of atenolol to increase peripheral resistance is balanced by the vasodilation and increased sympathetic tone induced by the calcium antagonist.

Consequently, greater antihypertensive or antianginal efficacy is achieved by the concomitant use of nifedipine and atenolol than either drug alone. This beneficial pharmacodynamic interaction also results in fewer side effects when lower dosages of the two drugs are used in combination.

Absorption of atenolol following oral dosing is consistent but incomplete (approximately 40 to 50%) with peak plasma concentrations occurring 2 to 4 hours after dosing. The atenolol blood levels are consistent and subject to little variability. There is no significant hepatic metabolism of atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. The plasma half-life is about 6 hours but this may rise in severe renal impairment since the kidney is the major route of elimination. Atenolol penetrates tissues poorly due to its low lipid solubility and its concentration in brain tissue is low. Plasma protein binding is low (approximately 3%). Absorption of nifedipine following oral dosing is complete with peak plasma concentrations occurring about 3 hours after dosing. Nifedipine is >90% plasma protein bound. There is significant hepatic metabolism of nifedipine. The plasma half-life is between 6 and 11 hours for the sustained formulation of nifedipine.

Co-administration of atenolol and nifedipine has little effect on the pharmacokinetics of either. In the elderly, the systemic bioavailability and elimination half-life of both components are increased.

Nifetex TR is effective when given either once or twice daily. This simplicity of dosing facilitates compliance by its acceptability to patients.

Atenolol and nifedipine are drugs on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Prescribing Information.

Not applicable

No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.