Bisoprolol Fumarate/ Perindopril Arginine

Registered South African indications:

• Substitution therapy for treatment of hypertension and/ or stable coronary artery disease (in patients with a history of myocardial infarction and/ or revascularisation) and/ or stable chronic heart failure with reduced systolic left ventricular function in adult patients adequately controlled with bisoprolol and perindopril given concurrently at the same dose level

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to any other angiotensin-converting enzyme inhibitors (ACE-inhibitors)
• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Porphyria
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney 
• Acute heart failure or during episodes of heart failure decompensation requiring IV inotropic therapy
• Cardiogenic shock
• Second or third-degree AV block (without pacemaker)
• Sick sinus syndrome
• Sinoatrial block
• Symptomatic bradycardia (<50bpm)
• Symptomatic hypotension
• Severe bronchial asthma or severe chronic obstructive pulmonary disease
• Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome
• Untreated phaeochromocytoma
• Metabolic acidosis
• A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs)
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Aortic stenosis
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces
• Coadministration with lithium
• Coadministration with potassium-sparing diuretics e.g. spironolactone, triamterene, amiloride
• Coadministration with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m²)
• Coadministration with sacubitril/valsartan (See additional prescribing points)
• Coadministration with fluoroquinolones in patients with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients

South African recommendations

• Mild to moderate renal impairment (CrCl≥30ml/min) 
• Severe hepatic impairment (for the indication of heart failure)
• Elderly
• Black patients
• Risk factors for hypotension
  - Volume-depletion e.g. diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting
  - Severe renin-dependent hypertension
  - Renovascular hypertension
  - Symptomatic heart failure with or without associated renal insufficiency
  - More severe degrees of heart failure
  - Congestive heart failure with normal or low blood pressure
• Ischaemic heart or cerebrovascular disease
• History of angioedema unrelated to ACE-inhibitor therapy
• Risk factors for hyperkalaemia
  - Renal insufficiency
  - Worsening renal function
  - Older age (>70 years)
  - Diabetes mellitus
  - Intercurrent events, in particular, dehydration, acute cardiac decompensation, metabolic acidosis and coadministration with potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride)
  - Potassium supplements or potassium-containing salt substitutes
  - Medicinal agents associated with increases in serum potassium (e.g. heparin, trimethoprim/sulfamethoxazole)
• Abrupt discontinuation
• First-degree AV block
• Mitral valve stenosis
• Obstruction in the outflow of the left ventricle
• Restrictive cardiomyopathy (for the indication of heart failure)
• Congenital heart disease (for the indication of heart failure)
• Haemodynamically significant organic valvular disease (for the indication of heart failure)
• Myocardial infarction within the last 3 months (for the indication of heart failure)
• Prinzmetal’s angina
• Low density lipoprotein-apheresis
• Desensitisation treatment (e.g. hymenoptera venom)
• Collagen vascular disease
• Bronchial asthma or other chronic obstructive lung diseases
• Diabetes mellitus
  - Insulin-dependent (for the indication of heart failure) 
  - With large fluctuations in blood glucose values
• Strict fasting
• Peripheral arterial occlusive disease
• Psoriasis or history of psoriasis
• Known or suspected phaeochromocytoma
• Hyperthyroidism
• Primary aldosteronism
• Immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these, especially with pre-existing impaired renal function
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Substitution therapy for treatment of hypertension and/ or stable coronary artery disease (in patients with a history of myocardial infarction and/ or revascularisation) and/ or stable chronic heart failure with reduced systolic left ventricular function in adult patients adequately controlled with bisoprolol and perindopril given concurrently at the same dose level

Bisoprolol/ Perindopril
5/5 (mg)
5/10 (mg)
10/5 (mg)
10/10 (mg)

• Oral (fct): 1 tab, dly in the morning before a meal

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Patients should be stabilised with bisoprolol and perindopril at the same dose level for at least 4 weeks. The fixed dose combination is not suitable for initial therapy

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For patients stabilised with bisoprolol 2.5mg and perindopril 2.5mg can use one half 5/5mg tablet once daily

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If a change of posology is required, titration should be done with the individual components

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• The use of bisoprolol/perindopril is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take bisoprolol/perindopril during pregnancy.  Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with bisoprolol/perindopril should be stopped immediately and alternative therapy should be started
• Bisoprolol/perindopril passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria (renal failure) in newborns, have been reported after administration of bisoprolol/perindopril during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Bisoprolol
  Bisoprolol should not be used in pregnancy. It has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn (reduce placental perfusion associated with growth retardation, intrauterine death, abortion or early labour and adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. The risk of hypoglycaemia and bradycardia is present for 3 days after the birth of the baby
• Perindopril
  Perindopril should not be used in pregnancy. Foetal exposure to ACE-inhibitors such as perindopril during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations

Breastfeeding

South African recommendations

• Contraindicated 
• Bisoprolol/perindopril should not be used by women breastfeeding their babies
• It is not known whether bisoprolol is excreted in human milk. Because no information is available regarding the use of perindopril during breastfeeding, alternative treatments with better established safety profiles during breastfeeding should be used

Fertility

South African recommendations

• There are no clinical data on fertility with the use of bisoprolol/perindopril

South African recommendations

5/5 (mg)

• Mild (CrCl≥60ml/min): Caution; no dose adjustment recommended 
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended 
• Severe (CrCl<30ml/min): Contraindicated 

CrCl (ml/min)	Recommended daily dose
≥60	1 tab, dly
30-60	1 half tab, dly
<30	Not suitable. Individual dose titration with the monocomponents is recommended

5/10 (mg)

• Mild (CrCl≥60ml/min): Caution; dose adjustment recommended 
• Moderate (CrCl 30-60ml/min): Caution; not recommended for use 
• Severe (CrCl<30ml/min): Contraindicated 

CrCl (ml/min)	Recommended daily dose
≥60	1 half tab, dly
30-60	Not suitable. Individual dose titration with the monocomponents is recommended
<30	Not suitable. Individual dose titration with the monocomponents is recommended

10/5 (mg)

• Mild (CrCl≥60ml/min): Caution; no dose adjustment recommended 
• Moderate (CrCl 30-60ml/min): Caution; not recommended for use 
• Severe (CrCl<30ml/min): Contraindicated 

CrCl (ml/min)	Recommended daily dose
≥60	1 tab, dly
30-60	Not suitable. Individual dose titration with the monocomponents is recommended
<30	Not suitable. Individual dose titration with the monocomponents is recommended

10/10 (mg)

• Caution; not recommended for use
  Individual dose titration with the monocomponents is recommended

South African recommendations

• Mild to moderate: No dose adjustment recommended  
• Severe: Caution; no dose adjustment recommended (for the indication of heart failure)
  There is no therapeutic experience with bisoprolol/perindopril containing bisoprolol in the treatment of heart failure in patients with severely impaired hepatic function 

South African recommendations

• Caution; dose adjustment recommended
  Administer according to renal function

Bisoprolol/ Perindopril

Central Nervous System Disorders

• Somnolence
• Syncope
• Malaise
• Fall

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Vasculitis
• Raynaud’s phenomenon
• Chest pain

Genitourinary Disorders

• Increased blood urea
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Hyperkalaemia
• Hyponatraemia

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Photosensitivity reactions
• Pemphigoid
• Aggravation of psoriasis 

Immune, Blood and Lymphatic System Disorders

• Eosinophilia
• Peripheral oedema
• Pyrexia

Bisoprolol

Central Nervous System Disorders

• Headache
• Dizziness
• Asthenia
• Sleep disorder
• Depression 
• Nightmares
• Hallucinations 
• Feeling of coldness or numbness in the extremities 

Cardiovascular Disorders

• Worsening of heart failure
• Hypotension and effects related to hypotension
• Bradycardia
• AV-conduction disturbances
• Orthostatic hypotension

Respiratory Disorders

• Rhinitis 
• Bronchospasm

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea 
• Constipation 

Hepatobiliary Disorders

• Hepatitis (cytolytic or cholestatic)
• Increased hepatic enzyme

Genitourinary Disorders

• Potency disorders

Endocrine and Metabolic Disorders

• Increased triglycerides 

Musculoskeletal Disorders

• Muscle cramps
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions
  - Itching
  - Flush
  - Rash
• Alopecia
• Psoriasis (worsened)
  - Psoriasis-like rash (induced)

Sensory Disorders

• Conjunctivitis
• Hearing disorders

Others

• Reduced tear flow (if patient uses lenses)

Perindopril

Central Nervous System Disorders

• Headache
• Dizziness
• Vertigo 
• Paraesthesia
• Asthenia
• Altered mood
• Sleep disorder
• Depression 
• Confusion 

Cardiovascular Disorders

• Dysrthymia
• Angina pectoris
• Myocardial infarction possibly secondary to excessive hypotension in high-risk patients
• Hypotension and effects related to hypotension
• Flushing
• Stroke possibly secondary to excessive hypotension in high-risk patients

Respiratory Disorders

• Cough
• Dyspnoea
• Rhinitis
• Bronchospasm
• Eosinophilic pneumonia

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain
• Diarrhoea 
• Constipation 
• Dyspepsia 
• Dry mouth 
• Intestinal angioedema
• Pancreatitis

Hepatobiliary Disorders

• Cholestatic jaundice
• Fulminant hepatic necrosis (including death)
• Hepatitis (cytolytic or cholestatic)
• Increased hepatic enzyme 
• Increased blood bilirubin

Genitourinary Disorders

• Acute renal failure
• Renal insufficiency
• Anuria/oliguria
• Erectile dysfunction

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Musculoskeletal Disorders

• Muscle cramps 

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritis 
• Urticaria
• Hyperhidrosis
• Erythema multiforme
• Angioedema
  - Face
  - Extremities
  - Lips
  - Mucous membranes
  - Tongue
  - Glottis and/or larynx

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Pancytopenia
• Leukopenia
• Anaemia
• Haemolytic anaemia in patients with a congenital deficiency of G-6PDH
• Decreased haemoglobin
• Decreased haematocrit

Sensory Disorders

• Visual impairment 
• Tinnitus
• Dysgeusia

Bisoprolol/ Perindopril

• Aliskiren
• Potassium salts
• Potassium-sparing diuretics
• Triamterene
• Amiloride
• Spironolactone
• Eplerenone
• Non-potassium-sparing diuretics
• Angiotensin-converting enzyme inhibitors (ACE-inhibitors)
• Angiotensin-II receptors antagonists (ARBs)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Acetylsalicylic acid
• COX-2 inhibitors
• Heparins
• Immunosuppressant agents
• Ciclosporin
• Tacrolimus
• Trimethoprim
• Fluoroquinolones
• Sacubitril/valsartan
• Insulins
• Oral hypoglycaemic agents
• Vasodilators
• Nitroglycerin
• Nitrates
• Agents that have blood-pressure-reducing potential
• Tricyclic antidepressants
• Barbiturates
• Phenothiazines
• Antipsychotics
• Anaesthetic agents
• Sympathomimetics
• Beta-sympathomimetics
• Isoprenaline
• Dobutamine

Bisoprolol

• Centrally acting antihypertensives
• Clonidine
• Methyldopa
• Moxonidine
• Rilmenidine
• Class I antidysrhythmic agents
• Quinidine
• Disopyramide
• Lidocaine
• Phenytoin
• Flecainide
• Propafenone
• Calcium antagonists
• Verapamil
• Diltiazem
• Felodipine
• Amlodipine
• Alpha- and beta-adrenoceptor sympathomimetics
• Norepinephrine
• Epinephrine
• Parasympathomimetics
• Topical beta-blockers
• Digoxin
• Mefloquine
• Monoamine oxidase inhibitors (except MAO-B inhibitors)
• Class-III antidysrhythmic medicines
• Amiodarone

Perindopril

• Estramustine
• Trimethoprim/sulfamethoxazole
• Lithium
• Baclofen
• Racecadotril
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus
• Gliptins
• Linagliptin
• Saxagliptin
• Sitagliptin
• Vildagliptin

Other interactions

• Extracorporeal treatments
  - Dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes)
  - Low density lipoprotein apheresis with dextran sulphate
• Gold
• Sodium aurothiomalate

None routine. Specific cases may require

• Electrolytes
• Renal function
• Blood pressure
• White blood cell count

Race

• ACE-inhibitors, including perindopril, cause a higher rate of angioedema in black patients than in non-black patients
• ACE-inhibitors, including perindopril, may be less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population

Stopping treatment

• Abrupt cessation of therapy with a beta-blocker such as bisoprolol contained in this combination product should be avoided, especially in patients with ischaemic heart disease, because this may lead to transitional worsening of heart condition. The posology should be decreased gradually, using the individual components, ideally over a period of two weeks while at the same time starting the replacement therapy if necessary

Sacubitril/valsartan

• The combination of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema
• Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy
• If treatment with sacubitril/valsartan is stopped, perindopril therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan

Bisoprolol
Bisoprolol is a beta₁-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows low affinity to the beta₂-receptor of the smooth muscles of bronchi and vessels as well as to the beta₂-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta₂-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range. 

Perindopril
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE). The converting enzyme, or kininase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE-inhibitors and is partially responsible for certain of their side effects (e.g. cough). Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.

COMBINATION PREPARATIONS

Bisoprolol/ Perindopril
Film coated tablet 5mg/5mg

• Cosyrel (Servier Laboratories) originator

Film coated tablet 5mg/10mg

• Cosyrel (Servier Laboratories) originator

Film coated tablet 10mg/5mg

• Cosyrel (Servier Laboratories) originator

Film coated tablet 10mg/10mg

• Cosyrel (Servier Laboratories) originator