Bisoprolol Fumarate/ Amlodipine

Registered South African indications:

• Treatment of hypertension as substitution therapy in patients adequately controlled with the individual products given concurrently at the same dose level as in the combination, but as separate tablets
• Treatment of hypertension in patients whose blood pressure cannot be controlled by either bisoprolol or amlodipine monotherapy

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to dihydropyridine derivatives 
• Acute heart failure or during episodes of heart failure decompensation requiring intravenous inotropic therapy
• Obstruction of the outflow tract of the left ventricle (e.g. high-grade aortic stenosis)
• Cardiogenic shock
• Second- or third-degree AV block (without a pacemaker)
• Sick sinus syndrome
• Sinoatrial block
• Symptomatic bradycardia
• Symptomatic hypotension
• Severe bronchial asthma
• Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome
• Untreated phaeochromocytoma
• Metabolic acidosis

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Hepatic impairment
• Elderly

Hepatic impairment

• Caution is advised when bisoprolol fumarate/amlodipine is administered in patients with impaired hepatic function, since the half-life of amlodipine is prolonged

Use in elderly

• In elderly patients, the dosage increase should be done with care

Heart failure

• Patients with heart failure should be treated with caution. An increased risk of a further deterioration of the ventricular pump function cannot be excluded
• Especially in patients with ischaemic heart disease, the cessation of therapy with bisoprolol fumarate/amlodipine must not be done abruptly unless clearly indicated, as this may lead to transitional worsening of heart condition

Diabetes and related conditions

• Bisoprolol fumarate/amlodipine must be used with caution in diabetes mellitus showing large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked
• Bisoprolol fumarate/amlodipine should be used with caution in patients with strict fasting or ongoing desensitisation therapy, as bisoprolol may increase both the sensitivity to allergens and the severity of anaphylactic reactions. Epinephrine (adrenaline) treatment may not always yield the expected therapeutic effect

Cardiovascular conditions

• Bisoprolol fumarate/amlodipine should be used with caution in patients with first-degree AV block or Prinzmetal's angina. Cases of coronary vasospasm have been observed, and despite its high beta1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with Prinzmetal's angina. Utmost caution must be exercised
• Bisoprolol fumarate/amlodipine should be used cautiously in patients with peripheral arterial occlusive disease as symptoms may be aggravated, especially when starting therapy

Psoriasis

• Patients with psoriasis or a history of psoriasis should only be given bisoprolol after carefully balancing the benefits against risks

Thyrotoxicosis

• Under treatment with bisoprolol fumarate/amlodipine, the symptoms of thyrotoxicosis may be masked

Phaeochromocytoma

• In patients with phaeochromocytoma, bisoprolol must not be administered until after alpha receptor blockade

General anaesthesia

• In patients undergoing general anaesthesia, beta-blockade reduces the incidence of dysrhythmias and myocardial ischemia during induction of anaesthesia and intubation, and in the post-operative period. It is currently recommended that maintenance beta-blockade be continued perioperatively. The anaesthetist must be aware of beta-blockade because of potential interactions with other medicines, which may result in bradydysrhythmias, attenuation of reflex tachycardia, and decreased reflex ability to compensate for blood loss
• If beta-blocker therapy is thought necessary to be withdrawn before surgery, this should be done gradually and completed about 48 hours before anaesthesia

Obstructive airway diseases

• Although cardioselective (beta1) beta-blockers may have less effect on lung function than non-selective beta-blockers, they should be avoided in patients with obstructive airway diseases unless there are compelling clinical reasons for their use. Where such reasons exist, bisoprolol fumarate/amlodipine may be used with caution
• In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended
• Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of β2-stimulants may have to be increased

Use in children

• Safety and efficacy have not been established in children

Effects on ability to drive and use machinery

• Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions, or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur. Patients should not drive until they know how treatment with bisoprolol fumarate/amlodipine affects them

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Treatment of hypertension as substitution therapy in patients adequately controlled with the individual products given concurrently at the same dose level as in the combination, but as separate tablets
Treatment of hypertension in patients whose blood pressure cannot be controlled by either bisoprolol or amlodipine monotherapy

Bisoprolol Fumarate/ Amlodipine
5/5 (mg)
5/10 (mg)
10/5 (mg)
10/10 (mg)

• Oral (tab): Initial (lowest dose): 1 tab of 5/5mg, dly for the first 6 weeks; Increase to 1 tab of 5/10mg or 10/5mg, dly according to tolerability for a further 6 weeks; Then: Dosage may be increased for patients with uncontrolled blood pressure to 1 tab of 10/10mg, dly

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For patients who are not tolerating their increased dose, their dose should be down titrated to their prior dose

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The recommended daily dose is one tablet of the given strength

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Treatment must not be stopped abruptly since the abrupt withdrawal of bisoprolol may lead to a transitory worsening of clinical condition. Especially in case of patients with ischaemic heart disease treatment must not be discontinued suddenly. Gradual reduction of the daily dose is recommended, and patients should be advised to limit the extent of their physical activity during the period that bisoprolol fumarate/ amlodipine is being discontinued

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Method of administration
Tablets are taken in the morning with or without food. They are swallowed with some liquid and not to be chewed

Not established for use in children

Pregnancy

South African recommendations

• Caution; not recommended
• Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, spontaneous abortion and early labour
• Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant
• The safety of amlodipine in human pregnancy has not been established
• In animal studies, reproductive toxicity was observed at high doses. Bisoprolol fumarate/amlodipine is not recommended during pregnancy unless clearly necessary. If treatment is considered necessary, the uteroplacental blood flow and the foetal growth should be closely monitored
• In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days

Breastfeeding

South African recommendations

• Caution; not recommended
• It is not known whether bisoprolol is excreted in human milk. Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%
• The effect of amlodipine on infants is unknown. Therefore, administration of bisoprolol fumarate/amlodipine is not recommended during breastfeeding

Fertility

South African recommendations

• No human data on fertility are known for the combination product. Reversible biochemical changes in spermatozoa have been reported in some patients treated by calcium channel blockers, however clinical data are insufficient regarding the potential effect of amlodipine on fertility
• Bisoprolol had no influence on fertility or on general reproduction performance in animal studies, while amlodipine showed in a published investigation, adverse effects on male fertility parameters

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe (CrCl<30ml/min): Caution; no dose adjustment recommended
  The daily dose of the bisoprolol component must not exceed 10mg

South African recommendations

• Caution; no dose adjustment recommended
  In case of severe hepatic impairment, the daily dose of the bisoprolol component in bisoprolol fumarate/amlodipine must not exceed 10mg
  Due to the amlodipine component in case of hepatic impairment special caution must be taken when bisoprolol fumarate/amlodipine is administered

South African recommendations

• Caution; no dose adjustment recommended
  No dosage adjustment is required however, caution is advised when the dose is increased

Bisoprolol

Metabolism and Nutrition Disorders

Rare

• Elevated triglyceride level

Psychiatric Disorders

Uncommon

• Depression
• Sleep disorder

Rare

• Nightmare
• Hallucination

Nervous System Disorders

Common

• Dizziness**
• Headache**

Rare

• Syncope

Eye Disorders

Rare

• Decreased tear secretion (consideration for contact lens wearers)

Very rare

• Conjunctivitis

Ear and Labyrinth Disorders

Rare

• Hearing impairments

Cardiac Disorders

Uncommon

• AV-conduction disorders
• Deterioration of pre-existing heart failure
• Bradycardia

Vascular Disorders

Common

• Feeling of coldness and numbness in the extremities

Uncommon

• Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Bronchospasm in patients with bronchial asthma or history of obstructive pulmonary disease

Rare

• Allergic rhinitis

Gastrointestinal Disorders

Common

• Nausea
• Vomiting
• Diarrhoea
• Constipation

Hepatobiliary Disorders

Rare

• Hepatitis

Skin and Subcutaneous Tissue Disorders

Rare

• Hypersensitivity reactions such as pruritus, flush, rash

Very rare

• Alopecia
• Psoriasis or cause psoriasis-like skin disorder
  - Beta-blockers can provoke or aggravate these disorders

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Muscle weakness
• Muscle cramps

Reproductive System and Breast Disorders

Rare

• Erectile dysfunction

General Disorders and Administration Site Conditions

Common

• Fatigue**

Uncommon

• Asthenia**

Investigations

Rare

• Increased liver enzymes (ALAT, ASAT)

Amlodipine

Blood and Lymphatic System Disorders

Very rare

• Leukopenia
• Thrombocytopenia

Immune System Disorders

Very rare

• Allergic reactions, mainly affecting the skin
• Angioedema

Metabolism and Nutrition Disorders

Very rare

• Hyperglycaemia

Psychiatric Disorders

Uncommon

• Depression
• Mood changes (including anxiety)
• Insomnia

Rare

• Confusion

Nervous System Disorders

Common

• Somnolence
• Dizziness
• Headache (especially at the beginning of the treatment) 

Uncommon

• Tremor
• Dysgeusia
• Syncope
• Hypoesthesia
• Paraesthesia

Very rare

• Hypertonia
• Peripheral neuropathy

Eye Disorders

Common

• Visual disturbances (including diplopia)

Ear and Labyrinth Disorders

Uncommon

• Tinnitus

Cardiac Disorders

Common

• Palpitations
• Bradycardia

Uncommon

• Dysrhythmia (including ventricular tachycardia and atrial fibrillation)

Very rare

• Myocardial infarction

Vascular Disorders

Common

• Flushing

Uncommon

• Hypotension

Very rare

• Vasculitis

Respiratory, Thoracic and Mediastinal Disorders

Common

• Dyspnoea

Uncommon

• Cough
• Rhinitis

Gastrointestinal Disorders

Common

• Abdominal pain
• Nausea
• Dyspepsia
• Altered bowel habits (including diarrhoea and constipation)

Uncommon

• Vomiting
• Dry mouth

Very rare

• Pancreatitis
• Gastritis
• Gingival hyperplasia

Hepatobiliary Disorders

Very rare

• Hepatitis
• Jaundice
• Hepatic enzyme increased (in most cases with cholestasis)

Skin and Subcutaneous Tissue Disorders

Uncommon

• Alopecia
• Purpura
• Skin discolouration
• Hyperhidrosis
• Pruritus
• Rash
• Exanthema
• Urticaria

Very rare

• Angioedema
• Erythema multiforme
• Exfoliative dermatitis
• Stevens-Johnson syndrome
• Quincke oedema
• Photosensitivity

Not known

• Toxic epidermal necrolysis

Musculoskeletal and Connective Tissue Disorders

Common

• Ankle swelling
• Muscle cramps

Uncommon

• Arthralgia
• Myalgia
• Back pain

Renal and Urinary Disorders

Uncommon

• Micturition disorder
• Nycturia
• Increased urinary frequency

Reproductive System and Breast Disorders

Uncommon

• Erectile dysfunction
• Gynecomastia

General Disorders and Administration Site Conditions

Very common

• Oedema

Common

• Fatigue
• Asthenia

Uncommon

• Chest pain
• Pain
• Malaise

Investigations

Uncommon

• Weight increase
• Weight decrease

Exceptional cases of extrapyramidal syndrome have been reported

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**These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1-2 weeks

Bisoprolol

• Verapamil
• Diltiazem
• Clonidine
• Methyldopa
• Moxonidine
• Rilmenidine
• Hypoglycaemic medicines
• Insulin
• Oral antidiabetics
• Phenothiazines
• Class I antidysrhythmic medicines
• Disopyramide
• Quinidine
• Lidocaine
• Phenytoin
• Flecainide
• Propafenone 
• Class III antidysrhythmic medicines
• Amiodarone 
• Dantrolene (infusion) 
• Parasympathomimetics
• Topical beta-blockers
• Glaucoma eye drops
• Anaesthetic medicines
• Digitalis glycosides
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Beta-sympathomimetic medicines
• Isoprenaline
• Dobutamine
• Norepinephrine (noradrenaline)
• Epinephrine (adrenaline)
• Tricyclic antidepressants
• Barbiturates
• Mefloquine
• Monoamine oxidase inhibitors (excluding MAO-B inhibitors)
• Ergotamine derivatives

Amlodipine

• Verapamil
• Diltiazem
• Strong or moderate inhibitors of CYP3A4
• Protease inhibitors
• Azole antifungals
• Macrolide antibiotics
• Erythromycin
• Clarithromycin
• Rifampicin
• Simvastatin
• Tacrolimus
• Ciclosporin

Other interactions

• St. John's Wort (Hypericum perforatum)
• Grapefruit or grapefruit juice

Specific cases may require

• Blood pressure
• Uteroplacental blood flow
• Tacrolimus blood levels
• Ciclosporin blood levels

Additional observations

• Foetal growth

Bisoprolol/ Amlodipine

This combination allows to increase the antihypertensive and anti-anginal efficacy by complementary mechanism of actions of the two active compounds: vasoselective effect of the calcium channel blocker amlodipine (decrease of peripheral resistance) and cardioselective beta blocker bisoprolol (decrease of cardiac output).

Bisoprolol fumarate

Bisoprolol is a β1-selective-adrenoreceptor antagonist lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows low affinity to the β2-receptor of the smooth muscles of bronchi and vessels as well as to the β2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and β2 mediated metabolic effects. Its β1-selectivity extends beyond the therapeutic dose range. Bisoprolol has no pronounced negative inotropic effect. Bisoprolol reaches its maximal effect 3-4 hours after oral administration. The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage. The maximal antihypertensive effect of bisoprolol treatment is generally reached after 2 weeks. In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases. Among others, the depression of plasma rennin activity is discussed as a mechanism of action underlying the antihypertensive effect of beta-blockers.

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker. Amlodipine inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle (slow channel blocker or calcium ion antagonist). The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle causing reduction in peripheral vascular resistance. The precise mechanism by which it relieves angina has not been fully determined, it may have the following two actions:

• It dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload). Since it does not cause reflex tachycardia, myocardial energy consumption and oxygen requirement will be reduced.
• By means of dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions it improves oxygen supply. By the above mechanism it increases myocardial oxygen delivery even in case of coronary artery spasm (Prinzmetal’s or variant angina).