AstraZeneca Pharmaceuticals (Ireland) Ltd

'-NIF-TEN^® 50mg / 20mg Capsules

Each capsule contains 50 mg atenolol and 20 mg nifedipine.

For a full list of excipients, see section 6.1.

Capsules, hard.

Reddish-brown capsules containing atenolol and a slow-release formulation of nifedipine.

i) Management of Hypertension

ii) Management of Angina pectoris

NIF-TEN should not be taken with grapefruit juice (see section 4.5).

Adults

Hypertension:

One capsule daily. NIF-TEN is recommended for use in hypertensive patients where monotherapy may prove inadequate. If necessary, the dosage may be increased to one capsule twice daily.

Angina

One capsule twice daily. NIF-TEN is recommended for use in angina patients where monotherapy may prove inadequate. Where additional efficacy is necessary, prophylactic nitrate therapy or additional nifedipine may be of benefit.

Elderly

Dosage should not exceed one capsule daily in hypertension, or one capsule twice daily in angina.

Children

There is no paediatric experience with NIF-TEN and for this reason it is not recommended for use in children.

Renal Impairment

NIF-TEN should not be used in patients with marked renal impairment (see section 4.3).

NIF-TEN should not be used in patients with any of the following:

- Known hypersensitivity to either active component or any of the excipients.

- 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 severe 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) .

- Patients receiving calcium channel blockers with negative inotropic effects e.g. verapamil and diltiazem (see section 4.5).

Due to the nifedipine content, NIF-TEN must not be used in combination with rifampicin because plasma levels of nifedipine, predictive of efficacy, may not be attained due to enzyme induction (See section 4.5).

Due to its beta-blocker component, NIF-TEN:

- Although contraindicated in uncontrolled heart failure (see section 4.3), may be substituted with care in patients already treated with a beta-blocker, and/or where 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.

- 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-blocker; consequently the use of NIF-TEN may be considered although utmost caution must be exercised.

- Although contraindicated in severe peripheral arterial circulatory disturbances (see section 4.3), may also aggravate less severe peripheral arterial circulatory disturbances.

- Due to its negative effect on conduction time, caution must be exercised if given to patients with first-degree heart block.

- 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.

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

- 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 an increase in airways resistance in asthmatic patients. Atenolol is a beta₁-selective beta-blocker; consequently the use of NIF-TEN may be considered if there is no alternative to the use of a beta-blocker although utmost caution must be exercised. If increased airways resistance does occur, NIF-TEN should be discontinued and bronchodilator therapy (e.g. salbutamol) administered if necessary.

Due to its nifedipine component it should be noted that:

- 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. Nifedipine has no diabetogenic effect.

- 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.

- In single cases of in vitro fertilisation, calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

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, such patients should be carefully monitored and, as a precaution, it is recommended that the dose should not exceed one capsule daily.

NIF-TEN must not be used in conjunction with calcium channel blockers with negative inotropic effects e.g. verapamil, or diltiazem, since this can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or sinoatrial or atrioventricular conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure (see section 4.3).

Concomitant therapy with additional dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

NIF-TEN should not be taken with grapefruit juice because its metabolism may be inhibited.

Atenolol monotherapy

Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time.

Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.

Class I anti-arrhythmic drugs (eg, disopyramide) and amiodarone may have a potentiating effect on atrial-conduction time and induce negative inotropic effect.

Concomitant use of sympathomimetic agents, e.g. adrenaline (epinephrine), may counteract the effect of beta-blockers.

Concomitant use of prostaglandin synthetase-inhibiting drugs (e.g. ibuprofen, indometacin) , may decrease the hypotensive effects of beta-blockers.

Caution must be exercised when using anaesthetic agents with NIF-TEN. The anaesthetist should be informed and the choice of anaesthetic should be an 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.

Nifedipine monotherapy:

The antihypertensive effect of nifedipine can be potentiated by simultaneous administration of cimetidine.

The simultaneous administration of nifedipine and quinidine may lead to serum quinidine levels being 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. Patients' plasma digoxin levels should be monitored and, if necessary the digoxin dose reduced.

Due to enzyme induction, rifampicin has been shown to decrease the nifedipine AUC and C_max by 95% (288 ng.L/ml to 8 ng.L/ml and 154 ng/ml to 7.5 ng/ml respectively. This may result in reduced efficacy, therefore co-administration of nifedipine with rifampicin is contraindicated (see section 4.3).

Concomitant intake of grapefruit juice with nifedipine inhibits the oxidative metabolism of nifedipine, resulting in increased AUC and C_max by 103% (SD 73, Range 48 to 265%) and 94% (SD 83, Range 23 to 259%) respectively. This may result in increased reduction in blood pressure.

Other forms of interaction: Nifedipine may cause falsely increased spectrophotometric values of urinary vanillylmandellic acid. However, measurement with HPLC is unaffected.

NIF-TEN is contraindicated in women capable of childbearing or during pregnancy or during lactation (see section 4.3).

Use is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.

NIF-TEN is well-tolerated. In clinical studies, the undesired events reported are usually attributed to the pharmacological actions of its components.

The following undesired events, listed by body system, have been reported:

NIF-TEN

Atenolol monotherapy

Nifedipine monotherapy:

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

Symptoms

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

Treatment

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal as 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. The possible use of haemodialysis or haemoperfusion may be considered.

Excessive bradycardia can be countered with atropine 1–2 mg intravenously. 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 1–10 mg/hr depending on response. Intravenous calcium gluconate combined with metaraminol may be beneficial for hypotension induced by nifedipine. 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, or isoprenaline 10 to 25 micrograms given as an infusion at a rate not exceeding 5 micrograms/minute may be given, although larger doses may be required. 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 patients. In severe cases of hypotension, cardiac pacing with appropriate cardiac respiratory support may be necessary. Bronchospasm can usually be reversed by bronchodilators.

Beta-blocking agents and other antihypertensives

C07 FB

Atenolol is a beta-blocker which is beta₁-selective (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-blockers, atenolol has negative inotropic effects (and is therefore contraindicated in uncontrolled heart failure).

As with other beta-blockers, 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 atenolol's tendency 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 40-50%) with peak plasma concentrations occurring 2-4 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 every 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.

NIF-TEN 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 Summary of Product Characteristics.

Granule

Maize starch

Heavy magnesium carbonate

Sodium laurilsulfate

Gelatin

Magnesium stearate

Tablet core

Microcrystalline cellulose

Maize starch

Lactose monohydrate

Polysorbate 80

Magnesium stearate

Tablet coating

Hypromellose

Macrogol 4000

Titanium dioxide (E171)

Iron oxide red (E172)

Capsule shell

Iron oxide red (E172)

Titanium dioxide (E171)

Gelatin

Printing ink

Shellac

Soya lecithin

Titanium dioxide (E171)

2-ethoxyethanol

Dimethylpolysiloxane

Not applicable.

4 years.

Do not store above 30°C. Protect from light and moisture.

Store in the original package. Keep the container in the outer carton.

PVC/PVDC/AL blister strips (box of 28 capsules).

No special requirements.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PA 970/14/1

1st September 2000/29^th September 2003/31 July 2009

31^st July 2009