Tenif

Tenif 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.

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

The safety of Tenif in malignant hypertension has not been established.

Tenif should not be used for secondary prevention of myocardial infarction.

Due to the nifedipine component, Tenif 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, Tenif:

- 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, Tenif 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 Tenif may be considered although utmost caution must be exercised.

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

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

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

- In patients with treated phaeochromocytoma Tenif 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 Tenif. 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 Tenif may lead to positive result in doping tests.

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

Obstructive airways disease

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

Tenif 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 Tenif should be used and utmost caution should be exercised. Occasionally, some increase in airways resistance may occur in asthmatic patients, Tenif 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.

Tenif must not be used in conjunction with calcium channel blockers with negative inotropic effects e.g. verapamil, diltiazem since this can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or sino-atrial or atrioventricular conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

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.

Atenolol monotherapy:

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

Beta-blocking drugs may exacerbate the rebound hypertension, which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocking drug therapy, the introduction of beta-blocking drugs 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-blocking drugs.

Concomitant use with insulin and oral antidiabetic drugs may lead to the intensification of the blood sugar-lowering effects of these drugs.

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

Baclofen

Concurrent use of baclofen may increase the antihypertensive effect of Tenif.

MAO inhibitors

Combination with a beta-blocker can cause an increase of the pharmacodynamic effects and an increase in blood pressure up to hypertension crises.

Nifedipine monotherapy:

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine. The extent as well as the duration of interactions should be taken into account when administering Tenif together with the following drugs.

Rifampicin

Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of Tenif in combination with rifampicin is therefore contraindicated.

Upon co-administration of the following weak to moderate inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, a reduction in the dose considered.

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 is contraindicated.

Macrolide antibiotics (e.g., erythromycin)

No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of macrolide antibiotics and Tenif cannot be excluded Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP3A4 inhibition.

Anti-HIV protease inhibitors (e.g., ritonavir)

A clinical study investigating the potential of a drug interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with Tenif, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded.

Azole anti-mycotics (e.g., ketoconazole)

A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with Tenif, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded.

Fluoxetine

A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of fluoxetine and Tenif cannot be excluded.

Nefazodone

A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase of nifedipine plasma concentrations upon co-administration of nefazodone and Tenif cannot be excluded.

Quinupristin / Dalfopristin

Simultaneous administration of quinupristin / dalfopristin and Tenif may lead to increased plasma concentrations of nifedipine.

Valproic acid

No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded upon co-administration of valproic acid and Tenif.

Cimetidine

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect of Tenif.

Further studies:

Cisapride

Simultaneous administration of cisapride and Tenif may lead to increased plasma concentrations of nifedipine.

Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbitone.

Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When phenytoin and Tenif are concomitantly administered, the clinical response to Tenif should be monitored and, if necessary, an increase of the Tenif dose considered. If the dose of Tenif is increased during co-administration of both drugs, a reduction of the Tenif dose should be considered when the treatment with phenytoin is discontinued.

No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy is possible following co-administration of carbamazepine or Phenobarbital with Tenif.

Effects of Tenif on other drugs:

Blood pressure lowering drugs

Tenif may increase the blood pressure lowering and heart rate modulating effects of concomitant applied antihypertensives, such as:

- diuretics,

- beta-blockers,

- ACE-inhibitors,

- Angiotensin 1 (AT1) receptor- antagonists,

- other calcium antagonists,

- α-adrenergic blocking agents,

- PDE5 inhibitors,

- anti-sympathomimetics

Quinidine

The simultaneous administration of nifedipine and quinidine may lead to serum quinidine levels being suppressed regardless of dosage of quinidine, lowered quinidine or, after discontinuation of nifedipine, distinct increase in plasma concentrations of quinidine have been observed in individual cases. For this reason, when Tenif is either additionally administered or discontinued, monitoring of the quinidine plasma concentration and, if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon co-administration of nifedipine and quinidine, while others did not observe an alteration in the pharmacokinetics of nifedipine. Therefore, the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with Tenif if necessary, the dose of Tenif should be decreased.

Digoxin

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in the plasma concentrations of digoxin. The patients' plasma digoxin levels should be monitored and checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin.

Tacrolimus

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of tacrolimus and Tenif, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Drug-food interactions:

Grapefruit juice

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

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of Tenif together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect may be increased. After regular intake of grapefruit juice this effect may last for at least 3 days after the last ingestion of grapefruit juice.

Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking Tenif.

Other forms of interactions:

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

Pregnancy and breast-feeding

Tenif is contraindicated in women capable of childbearing or during pregnancy or during lactation.

Fertility

In-vitro fertilisation:

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 fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Tenif 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 Tenif 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.

Tenif 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.

Maize starch

Heavy magnesium carbonate

Gelatin

Sodium lauryl sulphate

Magnesium stearate

Tablet core

Microcrystalline cellulose

Lactose

Magnesium stearate

Maize starch

Polysorbate 80

Tablet coating

Iron oxide red (E172)

Hypromellose

Macrogol 4000

Titanium dioxide (E171)

Capsule shell

Iron oxide red (E172)

Titanium dioxide (E171)

Gelatin

Printing ink

Ink 1

Titanium dioxide (E171)

Shellac

Ink 2

Titanium dioxide (E171)

Shellac

Povidone

Not applicable

48 months

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

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

PVC/PVDC/AL Blister strips of 28 capsules.

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

AstraZeneca UK Limited,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0047

Date of first authorisation: 1^st June 2000

Date of latest renewal: 7^th December 2004

12^th January 2017