Beta-Adalat Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Beta-Adalat
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains 20 mg nifedipine and 50 mg atenolol.
For the full list of excipients, see Section 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard
Brown-reddish, opaque gelatin capsules overprinted with “BETA-ADALAT” and the Bayer cross.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Management of hypertension and of chronic stable angina pectoris where therapy with either a calcium channel blocker or a beta-blocker prove inadequate.
4.2 Posology and method of administration Adults:
Hypertension: One capsule daily swallowed with water. If necessary, the dosage may be increased to one capsule dosed every 12 hours. Patients can be transferred to the combination from other antihypertensive treatments with the exception of clonidine (see Section 4.4).
Angina: One capsule every 12 hours swallowed with water. 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.
The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.
Children:
There is no paediatric experience with Beta-Adalat and therefore this preparation should not be used in children.
General:
Patients with renal or hepatic insufficiency may require lower dosages of Beta-Adalat, (see Section 4.4).
Beta-Adalat should not be taken with grapefruit juice (see Section 4.5).
4.3 Contraindications
Beta-Adalat should not be administered to patients with known hypersensitivity to atenolol, nifedipine, or to any of the excipients (see Sections 4.4 and 6.1), or to other dihydropyridines because of the theoretical risk of cross-reactivity.
Beta-Adalat should not be administered to patients with a history of wheezing or asthma or a tendency to bronchospasm (obstructive respiratory disease/bronchial asthma). (Label warning: Do not use if you have a history of wheezing or asthma.)
Beta-Adalat must not be administered during pregnancy or to nursing mothers (see Section 4.6).
Beta-Adalat must not be used in the presence of second or third degree heart block, sick sinus syndrome, sino-atrial block, in patients with evidence of overt heart failure or inadequately treated heart failure or decompensated heart failure, NYHA grades III and IV.
Beta-Adalat should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina pectoris, or during or within one month of a myocardial infarction.
Beta-Adalat should not be used for the treatment of acute attacks of angina.
The safety of Beta-Adalat in malignant hypertension has not been established.
Beta-Adalat should not be used for secondary prevention of myocardial infarction.
Beta-Adalat must not be used in conjunction with other drugs with a cardio-depressant action, e.g. verapamil, as conduction disturbances may ensue.
Beta-Adalat should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see Section 4.5).
Beta-Adalat should not be used in bradycardia (resting heart rate before treatment less than 50 beats/min), hypotension, or in the late stages of circulatory disturbances in the hands and legs or in severe peripheral arterial circulatory disturbances.
Beta-Adalat should not be used in patients with a decline in the pH of the blood (metabolic acidosis).
In patients with phaeochromocytoma, Beta-Adalat must be administered only after prior therapy with alpha-blockers.
Beta-Adalat must not be given with simultaneous administration of monoamine oxidase inhibitors (MAO inhibitors).
Beta-Adalat must not be used in patients with severe impairment of renal function (GFR < 30 ml/min) (see Section 4.4).
Beta-Adalat must not be used in patients with severe hepatic insufficiency (see Section 4.4).
4.4 Special warnings and precautions for use Cardiac
Due to the negative effect on conduction time by atenolol, caution must be exercised if Beta-Adalat is given to patients with first degree heart block. However, the properties of the nifedipine component of Beta-Adalat will to some degree counteract the negative dromotropic effect from atenolol.
Therefore, particular care should be taken with patients with conduction defects or whose cardiac reserve is poor. However, in patients already treated with a beta-adrenoceptor antagonist, and/or where signs of cardiac failure have been controlled, Beta-Adalat may be substituted with care if necessary.
Beta-Adalat should only be used with caution in patients with controlled congestive heart failure. Evidence of this condition worsening should be regarded as an indication to discontinue therapy.
Beta-Adalat 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. Beta-Adalat will not prevent possible rebound effects after cessation of other antihypertensive therapy (see Section 4.5). Blood pressure should be monitored closely.
Although contraindicated in severe peripheral arterial circulatory disturbances (see Section 4.3), Beta-Adalat may also aggravate less severe peripheral arterial circulatory disturbances.
In patients with peripheral circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), beta-blockers should be used with caution as aggravation of these disorders may occur.
Care should be taken in prescribing a beta-adrenoceptor blocking drug with Class I anti-dysrhythmic agents such as disopyramide.
One of the pharmacological actions of beta-adrenoceptor blocking drugs is to reduce heart rate. Atenolol will reduce heart rate. This effect is however opposed by the properties of the nifedipine component of Beta-Adalat. In the rare instances where symptoms may be attributable to the slow heart rate at a dose of one capsule daily, the drug should be discontinued.
Ischaemic pain has been reported in a small proportion of patients within one to four hours of the introduction of nifedipine therapy. Although a "steal" effect has not been demonstrated, patients experiencing this effect should discontinue Beta-Adalat.
In patients with ischaemic heart disease, cessation of therapy with a beta-adrenoceptor blocking drug such as Beta-Adalat should be gradual, and not abrupt, if necessary initiating replacement therapy at the same time, to prevent exacerbation of angina pectoris.
Caution should be exercised when transferring patients from clonidine to beta-adrenoceptor blocking drugs. If beta-adrenoceptor blocking drugs are given concurrently, clonidine should not be discontinued until several days after withdrawal of the beta-adrenoceptor blocking drug.
Caution should be exercised in patients with severe hypotension (systolic pressure <90 mm Hg).
Caution should be exercised in cases of first degree heart block or mild heart failure, NYHA grade II.
Beta-blockers may increase the number and duration of anginal attacks in patients with Prinzmetal’s angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. Therefore, betai selective blockers such as atenolol should be used with care.
Obstructive airways disease
Although cardioselective (beta1) beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should not be administered to patients with reversible obstructive airways disease.
Patients with bronchospastic disease should, in general, not receive beta-blockers due to an increase in airways resistance. Atenolol is a beta1-selective beta-blocker, however this selectivity is not absolute. Therefore the lowest possible dose of Beta-Adalat should be used and utmost caution must be exercised. If increased airways resistance does occur, Beta-Adalat should be discontinued and bronchodilator therapy administered if necessary.
Renal impairment
Dosage should not exceed one capsule daily in patients with renal dysfunction. The use of the combination is contra-indicated in patients with severe renal impairment (see Section 4.3).
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
Since Beta-Adalat is contraindicated for severe hepatic insufficiency (see Section 4.3), care should be taken in patients with marked hepatic impairment. Although no dosage adjustment is suggested from the systemic availability of the monocomponents in patients with cirrhosis, hypertensive patients with clinically significant liver disease have not been studied. Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored.
Anaesthesia
It is not advisable to withdraw beta-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using Beta-Adalat with anaesthetic agents such as ether, cyclopropane and trichloroethylene. 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. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg intravenously).
Diabetes
The use of nifedipine in diabetic patients may require adjustment of their control.
The nifedipine component has no diabetogenic effect. Transient increases in blood glucose levels have been observed in rare cases in acute studies with nifedipine.
Atenolol should be used with caution in diabetics subject to frequent episodes of hypoglycaemia. Symptoms of hypoglycaemia may be masked.
Beta-Adalat may modify the tachycardia of hypoglycaemia and, therefore, may mask the signs of thyrotoxicosis.
General
The benefits and risks must be carefully considered before drugs containing beta-receptor blockers (such as Beta-Adalat) are used in patients with a history or family history of psoriasis, patients with a history of severe hypersensitivity reactions and patients on desensitisation therapy (decreased adrenergic counter-regulation).
Beta-Adalat 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 used to treat the allergic reactions.
Whilst nifedipine is contra-indicated in pregnancy, particular care must be exercised when administering nifedipine in combination with i.v. magnesium sulphate to pregnant women.
In patients with treated phaeochromocytoma Beta-Adalat must be administered only after alpha-receptor blockade.
Administration of Beta-Adalat may lead to positive results in doping tests.
Since this medicinal product contains lactose, patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Beta-Adalat.
4.5 Interaction with other medicinal products and other forms of interaction
Known Interactions
Concomitant use of prostaglandin synthetase inhibiting drugs (e.g. ibuprofen, indomethacin) may decrease the hypotensive effects of beta-blockers. When Beta-Adalat is administered simultaneously with reserpine, alpha-methyldopa, clonidine, guanethidine, guanfacine, or cardiac glycosides, the heart rate may decline more markedly, and stimulus conduction may be delayed.
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 (e.g., disopyramide) and amiodarone may have potentiating effects on atrial-conduction time and induce negative inotropic effects.
Concomitant use of sympathomimetic agents (e.g., adrenaline) may counteract the effect of beta-blockers.
Beta-Adalat should be used with great caution in patients who are receiving concomitant myocardial depressants such as chloroform, lignocaine, procainamide, beta-adrenoceptor stimulants such as isoprenaline, or alpha-adrenoceptor stimulants such as noradrenaline.
If Beta-Adalat is administered simultaneously with another beta-blocker, in addition to a more marked decrease in the blood pressure, heart failure may develop. Simultaneous administration of intravenous beta-receptor blockers must therefore be avoided.
In patients with a hypoglycaemic metabolic disorder simultaneously treated with Beta-Adalat and insulin or oral antidiabetics, normalisation of the condition may be delayed, and the symptom of hypoglycaemia, tachycardia, be masked. Regular monitoring of the blood glucose is therefore necessary.
When Beta-Adalat is administered simultaneously with calcium channel blockers with negative inotropic effects (e.g., verapamil or diltiazem) or antiarrhythmics, this may result in severe hypotension, bradycardia, cardiac failure and disturbances of heart rhythm. Patients at particular risk are those with impaired ventricular function and/or sino atrial or atrio ventricular conduction abnormalities. Careful monitoring of the blood pressure and ECG is therefore necessary. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
Simultaneous therapy with noradrenaline or adrenaline can lead to an excessive increase in blood pressure.
Simultaneous therapy with MAO-inhibitors can cause an increase of the pharmacodynamic effects and an excessive increase in blood pressure up to hypertensive crises.
Since simultaneous therapy with narcotics or antiarrhythmics adversely affects cardiac output, the anaesthetist should be informed that the patient is being treated with Beta-Adalat. If possible, Beta-Adalat should not be discontinued before the operation. However, it must be borne in mind that in the course of interaction of atenolol with narcotics or antiarrhythmics, cardiac output may be reduced more markedly, since the cardiac depressant effects (negative inotropism) of atenolol with narcotics or antiarrhythmics may be additive.
The action of non-depolarising muscle relaxant drugs may be potentiated by Beta-Adalat.
Baclofen: Concurrent use of baclofen may increase the antihypertensive effect of Beta-Adalat.
Drugs that affect nifedipine
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 (see Section 4.4).
The extent as well as the duration of interactions should be taken into account when administering Beta-Adalat together with the following drugs:
Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon coadministration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of Beta-Adalat in combination with rifampicin is therefore contraindicated (see Section 4.3).
Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.
Drugs increasing nifedipine exposure:
• macrolide antibiotics (e.g., erythromycin)
• anti-HIV protease inhibitors (e.g., ritonavir)
• azole anti-mycotics (e.g., ketoconazole)
• fluoxetine
• nefazodone
• quinupristin/dalfopristin
• cisapride
• valproic acid
• cimetidine (which may potentiate the antihypertensive effect of Beta-Adalat)
• diltiazem
Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in the nifedipine dose considered. If the dose of nifedipine is increased during coadministration of both drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.
Drugs decreasing nifedipine exposure:
• rifampicin (see above)
• phenytoin
• carbamazepine
• phenobarbital
Effects of Beta-Adalat on other drugs
Potentiation of the blood pressure-lowering action and heart rate modulating effect must be anticipated when Beta-Adalat is used in combination with other antihypertensives, or with diuretics, vasodilators, nitrates, narcotics, tricyclic antidepressants, barbiturates or phenothiazines (see Section 4.4).
Digoxin: The simultaneous administration of Beta-Adalat and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced.
Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels regardless of dosage of quinidine, and, after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when Beta-Adalat is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.
Theophylline: Beta-Adalat can increase the plasma levels of theophylline. Monitoring is therefore recommended, and in some cases a reduction of the dose may be necessary.
Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
Drug food interactions
Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of Beta-Adalat 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 of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking Beta-Adalat (see Section 4.2).
Other forms of interaction
Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.
4.6 Fertility, pregnancy and lactation
Beta-Adalat is contraindicated in women who are, or plan to become, pregnant (see Section 4.3).
The safety of nifedipine for use in human pregnancy has not been established. Evaluation of experimental animal studies has shown reproductive toxicity consisting of embryotoxicity and teratogenic effects at maternally toxic doses.
Beta-Adalat is contra-indicated in nursing mothers, as nifedipine and atenolol may be present in breast milk.
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.
Theoretically, beta-blockers such as atenolol cause a decrease in placental blood flow, which can result in intrauterine foetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in foetus and neonates. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.
4.7 Effects on ability to drive and use machines
Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery. Although this is unlikely, it applies particularly at the start of treatment, on changing the medication, and in combination with alcohol. It should also be taken into account that occasionally dizziness or fatigue may occur.
4.8 Undesirable effects
Beta-Adalat is well tolerated. Side effects occur predominantly at the beginning of treatment or at high doses, and are generally mild and transient. In clinical studies, the undesired events reported are usually attributed to the pharmacological actions of its components.
For nifedipine monotherapy, most side-effects are consequences of the vasodilatory effects of nifedipine and usually regress on withdrawal of therapy. Side-effects of nifedipine such as flushing and headache may occur at the beginning of the treatment. They are, however, mostly slight and diminish with continuous use.
As with other sustained release dihydropyridines, exacerbation of angina pectoris may occur rarely (with unknown frequency) 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.
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).
|
Body System |
Frequency |
Undesirable event |
|
Blood and lymphatic |
Rare |
Thrombocytopenia* |
|
system disorders |
Unknown |
Agranulocytosis**, Leucopenia**, Purpura |
|
Immune system |
Uncommon |
Allergic reaction**, Allergic oedema (including |
|
disorders |
larynx oedema)** | |
|
Unknown |
Anaphylactic/anaphylactoid reaction** | |
|
Metabolism and nutrition disorders |
Unknown |
Hyperglycaemia* * |
|
Psychiatric disorders |
Uncommon |
Sleep disturbances of the type noted with other beta-blockers*, Anxiety reactions**, Sleep disorders** |
|
Rare |
Mood changes (including depression)*, Nightmares*, Confusion*, Psychoses and hallucinations* | |
|
Nervous system |
Common |
Headache** |
|
disorders |
Uncommon |
Vertigo**, Migraine**, Dizziness**, Tremor**, Syncope** |
|
Rare |
Dizziness*, Headache*, Paraesthesia*, Par-/dysaesthesia** | |
|
Unknown |
Hypoaesthesia**, Somnolence**, Dizziness, Headache | |
|
Eye disorders |
Uncommon |
Visual disturbances** |
|
Rare |
Dry eyes*, Visual disturbances* | |
|
Unknown |
Eye pain** | |
|
Cardiac disorders |
Common |
Bradycardia* |
|
Uncommon |
Tachycardia**, Palpitations** | |
|
Rare |
Heart failure deterioration*, Precipitation of heart block* | |
|
Unknown |
Chest pain (angina pectoris)**, Flushing, Oedema | |
|
Vascular disorders |
Common |
Cold extremities*, Vasodilation** |
|
Uncommon |
Hypotension** | |
|
Rare |
Postural hypotension which may be associated with syncope*, Intermittent claudication may be increased if already present in susceptible patients to Raynaud’s phenomenon* |
|
Respiratory, thoracic |
Uncommon |
Nosebleed**, Nasal congestion** |
|
and mediastinal | ||
|
disorders |
Rare |
Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints* |
|
Unknown |
Dyspnoea** | |
|
Gastrointestinal |
Common |
Gastrointestinal disturbances*, Constipation** |
|
disorders | ||
|
Uncommon |
Gastrointestinal and abdominal pain**, Nausea**, Dyspepsia**, Flatulence**, Dry mouth** | |
|
Rare |
Gingival hyperplasia**, Dry mouth*, | |
|
Unknown |
Vomiting**, Gastrointestinal sphincter insufficiency**, Constipation*, Gastrointestinal disturbance | |
|
Hepatobiliary disorders |
Rare |
Hepatic toxicity including hepatitis and intrahepatic cholestasis* |
|
Uncommon |
Transient increases in liver enzymes** | |
|
Unknown |
Jaundice** | |
|
Skin and subcutaneous |
Uncommon |
Angioedema**, Erythema** |
|
disorders | ||
|
Rare |
Alopecia*, Psoriasiform skin reaction*, Exacerbation of psoriasis, Skin rashes*, Pruritus**, Urticaria**, Rash** | |
|
Unknown |
Toxic epidermal necrosis**, Photosensitivity allergic reaction**, Palpable purpura**, Exfoliative dermatitis** | |
|
Musculoskeletal and |
Uncommon |
Muscle cramps**, Joint swelling** |
|
connective tissue | ||
|
disorder |
Unknown |
Arthralgia**, Myalgia** |
|
Renal disorders |
Uncommon |
Polyuria**, Dysuria** |
|
Reproductive system |
Uncommon |
Erectile dysfunction** |
|
and breast disorders | ||
|
Rare |
Impotence* | |
|
Unknown |
Impotence | |
|
General disorders and |
Common |
Fatigue*, Feeling unwell**, Oedema** |
|
administration site | ||
|
conditions |
Uncommon |
Unspecific pains**, Chills** |
Very rare An increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear*
* Frequency reported for the mono component atenolol ** Frequency reported for the mono component nifedipine
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 at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
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, whilst 500 mg, in a 15 year old, resulted in moderate to severe intoxication.
Clinical effects
As far as treatment is concerned, elimination of active substances and the restoration of stable cardiovascular conditions have priority.
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:
acute 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, hypoglycaemia, hypocalcaemia, impaired renal function, rhabdomyolysis, nausea and emesis.
General symptomatic treatment should involve close supervision and monitoring of the patient’s condition and should include:
treatment in an intensive care ward; monitoring of the cardiac rhythm; the use of gastric lavage, which can also be justified late after intake (if clumping of modified release tablets occurs consider gastroscopy); atropine should be given prior to lavage to counteract the risks from potential vagal stimulation; activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract; the use of plasma and plasma substitutes to treat hypotension and shock; correction of acid, base and electrolyte imbalances.
Bradyarrhythmias can be treated with atropine (repeated doses may become necessary).
A pacemaker should be employed early in cases with more severe bradyarrhythmias. Excessive bradycardia can be countered with atropine 1-2 mg intravenously. Cases with circulatory failure should have their haemodynamics monitored to guide therapy and fluid substitution. Vasoconstricting therapy may commence with noradrenaline or phenylephrine. Intravenous calcium gluconate combined with metaraminol and given as repeated injections or by infusion may be beneficial for hypotension induced by nifedipine. If necessary, in cases not responding to the above measures, 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/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a phosphodiesterase inhibitor (milrinone or amrinone) may be given, or a beta-adrenoceptor stimulant such as dobutamine 2.5 - 10 microgram/kg/minute by intravenous infusion may be given. Dobutamine, due to its positive inotropic effects 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. Insulin-glucose infusion can also be used. It can be expected that dose escalation of sympathomimetic drugs will be necessary to overcome the beta-blocking effects.
Bronchospasm can usually be reversed by inhalation of beta2-stimulants such as salbutamol (2 puffs), or orciprenaline sulphate (0.5-1.0 mg) slowly iv. For generalised convulsions, administration of diazepam slowly intravenously is recommended.
Other possible treatments in cases of life-threatening intoxication are: pacemaker therapy, artificial/mechanical ventilation and haemodialysis (atenolol and nifedipine) or plasma separation (nifedipine).
Seizures can be treated with benzodiazepines.
Protracted resuscitation - over several hours - can be justified.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC codes:
C08CA55
Selective calcium channel blocker (dihydropyridine derivative) with mainly vascular effects.
Nifedipine, combinations.
C07F B03
Beta blocking agents, selective, and other antihypertensives. Atenolol with other antihypertensives.
Atenolol is classified as a beta1-selective (cardioselective) beta-adrenoceptor antagonist with no membrane-stabilising activity and no partial agonist activity. It is clearly the most hydrophilic of the currently available beta-blockers, and thus demonstrates poor penetration of cell membrane lipids. Atenolol has marked negative inotropic and chronotropic effects, thereby reducing cardiac output, myocardial oxygen demand, and blood pressure, particularly during exercise.
Nifedipine is a calcium antagonist of the 1,4-dihydropyridine type. Calcium antagonists reduce the transmembrane influx of calcium ions through the L-type calcium channels into the cell. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels.
The fixed combination of nifedipine 20 mg and atenolol 50 mg is designed for the antihypertensive treatment of patients whose blood pressure is inadequately controlled on monotherapy. This combination of a cardioselective, hydrophilic beta1-adrenoceptor antagonist (atenolol), and a potent, specific calcium antagonist (nifedipine) lowers blood pressure to a greater extent than either of its individual components.
Nifedipine’s tendency to increase heart rate and plasma renin activity is counteracted by beta-adrenoceptor blockade, while the tendency of atenolol to increase peripheral resistance is counterbalanced by the vasodilatation and reflex increase in sympathetic tone induced by the calcium antagonist.
There is no evidence of clinically significant negative inotropic, dromotropic or chronotropic effects with the combined use of nifedipine and atenolol in man compared with treatment with atenolol alone. Similarly, the chronic renal pharmacodynamic effects of the fixed combination are not dissimilar to the use of atenolol alone; the acute natriuretic, uricosuric and diuretic effects of nifedipine alone are not seen following chronic use of the fixed combination in man.
5.2 Pharmacokinetic properties
The fixed combination of nifedipine 20 mg (slow release) and atenolol 50 mg is bioequivalent to its individual drug components, and there is no evidence of pharmacokinetic interaction between the two drugs.
In the elderly, the half life of nifedipine alone is increased from approximately 5 V hours to 9 hours, but peak plasma levels are unchanged.
The pharmacokinetics of atenolol 50 mg when dosed in free combination with nifedipine 20 mg (slow release) in the elderly were consistent with the published atenolol experience in demonstrating an approximately 45% increase in systemic bioavailability, with increased blood levels 24 hours after dosing in the elderly.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber which are additional to those already included in other sections of the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Nifedipine tablets: microcrystalline cellulose, maize starch, lactose, polysorbate 80, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide (E171) and red iron oxide (E172).
Atenolol granules: heavy magnesium carbonate, maize starch, sodium lauryl sulphate, gelatin, magnesium stearate.
Capsule shell: red iron oxide (E172), titanium dioxide (E171) and gelatin.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Blister packs composed of PP foil backed with aluminium foil: 48 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister packs composed of PP foil, backed with aluminium foil, each containing 28 capsules.
6.6 Special precautions for disposal
No additional information
7 MARKETING AUTHORISATION HOLDER
Bayer plc Bayer House Strawberry Hill Newbury Berkshire RG14 1JA United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00010/0155
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 25 July 1988
Date of last renewal: 19 September 2001
10 DATE OF REVISION OF THE TEXT
09/06/2015