Bisoprolol/ Hydrochlorothiazide

Registered South African indications:

• Hypertension

Contraindications

South African recommendations

• Hypersensitivity to bisoprolol or any of the ingredients of bisoprolol/hydrochlorothiazide
• Hypersensitivity to hydrochlorothiazide or other sulphonamide derived medicines
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinoma of the skin and lip
• Second and third-degree heart block and bradycardia (less than 50 beats per minute)
• Pregnancy
• Lactation
• Uncontrolled cardiac failure
• Cardiogenic shock
• Severe hypotension (systolic blood pressure of less than 100mmHg)
• Metabolic acidosis
• Sinus bradycardia (less than 50 beats per minute)
• Hyperthyroidism, as clinical manifestations may be masked
• Bronchospasm or asthma, or patients with a history of bronchitis or chronic respiratory diseases
• Late stage peripheral vascular diseases and Raynaud's phenomenon
• Addison’s disease
• Severe renal impairment (CrCl<30ml/minute)
• Severe hepatic impairment, in whom encephalopathy may be precipitated
• Porphyria
• Phaeochromocytoma
• Sick sinus syndrome

Cautions

South African recommendations

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Potential development of Raynaud's phenomenon and peripheral gangrene
• Increased risk of non-melanoma skin cancer with cumulative hydrochlorothiazide exposure (photosensitivity)
• Exposure to sunlight and UV rays
• Previous and/or current basal cell carcinoma and/or squamous cell carcinomas of the skin or lip
• Progressive liver disease
• Use of anaesthetics such as ether, cyclopropane and trichloroethylene
• Diabetic patients (potential masking of hypoglycaemia symptoms)
• Risk of disturbed calcium levels (increased serum calcium concentration)
• Hyperuricaemia or gout
• Sensitivity reactions, including allergy or bronchial asthma
• Systemic lupus erythematosus
• During or after surgery
• Clonidine transfer
• Abrupt discontinuation
• Physical activity during the discontinuation period
• Patients with psoriasis
• Long-term beta-blocker therapy
• Contact lens wearers
• History of sulphonamide or penicillin allergy
• Risk of acute transient myopia and acute angle-closure glaucoma
• Signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy
• Prinzmetal's angina
• Coadministration with verapamil in patients with impaired ventricular function and within 48 hours of discontinuing either one
• Coadministration with class 1 antidysrhythmic medicines like disopyramide and myocardial depressants and inhibitors of AV conduction such as calcium antagonists
• Coadministration with quinidine
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Hypertension
- In patients who have been stabilised on the individual components given in the same proportions

Bisoprolol / Hydrochlorothiazide
2.5/6.25 (mg)
5/6.25 (mg)
10/6.25 (mg)

• Oral (fct, tab): Initial: 2.5/6.25 (mg), dly; Titrate as appropriate to 10/6.25 (mg), dly; Max: 10/6.25 (mg)/24hrs

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Antihypertensive therapy may be initiated with the lowest dose of bisoprolol/hydrochlorothiazide

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If discontinuation of bisoprolol/hydrochlorothiazide becomes necessary, it should be done gradually over a period of about two weeks while closely monitoring patients

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In case of a missed dose, patients should take a dose as soon as possible and then continue with the normal dose. They should not take a double dose to compensate for the missed dose

Not established for use in children

Pregnancy

• Contraindicated
• Bisoprolol/hydrochlorothiazide is not to be used during pregnancy
• Administration of bisoprolol/hydrochlorothiazide to pregnant mothers shortly before birth or during labour may result in hypotonia, bradycardia, collapse or hypoglycaemia in the newborn
• Hydrochlorothiazide, crosses the placental barrier and appears in cord blood. Potential hazards include foetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which occur in the adult

Breastfeeding

• Contraindicated
• Hydrochlorothiazides appear in human milk. If bisoprolol/hydrochlorothiazide is deemed essential, the patient should stop breastfeeding

Renal Impairment

• Mild to moderate: Caution; dose adjustment recommended
  A daily dose of 10mg should not be exceeded in patients with mild to moderate renal impairment
• Severe: Contraindicated

Hepatic Impairment

• Mild to moderate: Caution; dose adjustment recommended
  A daily dose of 10mg should not be exceeded in patients with mild to moderate hepatic impairment
• Severe: Contraindicated

Elderly

• Caution; no dose adjustments recommended
  Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction

Porphyria Information

• Contraindicated

Drugs in Sport

• Prohibited - At all times

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Bisoprolol
Central Nervous System Disorders

• Sleep disorders
• Depression
• Nightmares
• Hallucinations
• Dizziness
• Headache
• Syncope
• Fatigue

Cardiovascular Disorders

• Chest pain
• Bradycardia
• Worsening of pre-existing heart failure
• Atrioventriular conduction disturbances
• Feeling of coldness or numbness in the extremities
• Hypotension
• Orthostatic hypotension

Respiratory Disorders

• Bronchospasm
• Allergic rhinitis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation

Hepatobiliary Disorders

• Hepatitis
• Increased liver enzymes

Genitourinary Disorders

• Potency disorders

Endocrine and Metabolic Disorders

• Increased triglycerides

Musculoskeletal Disorders

• Muscle weakness
• Muscle cramps

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions
• Worsening psoriasis 
• Psoriasis-like rash
• Alopecia

Sensory Disorders

• Reduced tear flow 
• Conjunctivitis
• Hearing disorders

Hydrochlorothiazide
Central Nervous System Disorders

• Weakness
• Lethargy
• Drowsiness
• Restlessness
• Seizures
• Headache
• Paraesthesia
• Dizziness

Cardiovascular Disorders

• Postural hypotension

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Intestinal ulceration

Hepatobiliary Disorders

• Cholestatic jaundice
• Pancreatitis

Genitourinary Disorders

• Oliguria
• Impotence

Endocrine and Metabolic Disorders

• Hypochloraemic alkalosis
• Hyponatremia
• Hypokalaemia
• Hyperglycaemia
• Hyperuricaemia
• Gout
• Hypomagnesaemia
• Anorexia

Musculoskeletal Disorders

• Muscle pain
• Cramps

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions

Immune, Blood and Lymphatic System Disorders

• Thrombocytopaenia
• Granulocytopaenia
• Leucopenia
• Aplastic anaemia
• Haemolytic anaemia

Sensory Disorders

• Dry mouth
• Thirst
• Yellow vision

• Calcium channel blockers
• Verapamil
• Diltiazem
• Antihypertensives
• Centrally acting antihypertensives
• Methyldopa
• Hypoglycaemic medicines
• Phenothiazines
• Oral hypoglycaemic medicines
• Insulin
• Antidysrhythmic medicines
• Lidocaine
• Quinidine
• Disopyramide
• Flecainide
• Propafenone
• Strong inducers of the hepatic cytochrome P450 isoenzymes (CYP3A4 and CYP2D6)
• Rifampicin
• Barbiturates
• Strong inhibitors of the hepatic cytochrome P450 isoenzymes (CYP3A4 and CYP2D6)
• Cimetidine
• Erythromycin
• Fluoxetine
• Hydralazine
• Topical beta-blocker eye drops
• Beta-adrenoceptor stimulating medicines
• Dopamine
• Dobutamine
• Isoprenaline
• Alpha-adrenoceptor stimulants
• Pseudoephedrine
• Phenylephrine
• Adrenergic neurone blocking medicines
• Reserpine
• Digoxin
• Neuromuscular blockers
• Atracurium
• Competitive muscle relaxants
• Substances that can potentiate orthostatic hypotension
• Alcohol
• Narcotics
• Corticosteroids or ACTH
• Pressor amines
• Adrenaline (epinephrine)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Indomethacin
• Medicines associated with hyponatraemia
• Trimethoprim
• Carbamazepine

• ECG
• Heart rate

Specific cases may require

• Serum potassium
• Renal function
• Blood glucose

Bisoprolol
Bisoprolol is a beta-blocker which acts preferentially on beta1-adrenergic receptors in the heart. It has negative inotropic effects resulting in reduction in heart rate, myocardial contractility, impulse conduction rate and adrenergic-induced renin release. As with other beta-blockers, the mode of action of bisprolol in the treatment of hypertension is unclear. 

Hydrochlorothiazide
Hydrochlorothiazide acts primarily in the distal convoluted tubule where it inhibits sodium chloride transport. It competes for the chloride site and affects the electrolyte reabsorption by increasing sodium and chloride excretion. This reduces plasma volume indirectly and increases plasma renin activity, aldosterone secretion and urinary potassium loss. 

COMBINATION PREPARATIONS

Bisoprolol/ Hydrochlorothiazide

Tablet 2.5mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisozyd Co (Zydus)
• Tevacard Co (Teva)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)

Tablet 5mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisoprolol Co Unicorn (Unicorn)
• Bisozyd Co (Zydus)
• Tevacard Co (Teva)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)

Tablet 10mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisoprolol Co Unicorn (Unicorn)
• Bisozyd Co (Zydus)
• Tevacard Co (Teva)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)