Bilocor Co Tablets

BILOCOR CO is indicated for the treatment of hypertension in patients who have been stabilised on the individual components given in the same proportions.

Adults
Antihypertensive therapy may be initiated with the lowest dose of BILOCOR CO, one 2,5/6,25 mg tablet once daily. Subsequent dose adjustment may be carried out with BILOCOR CO tablets up to the maximum recommended dose of one 10/6,25 mg tablet once daily as appropriate. Withdrawal of BILOCOR CO therapy should be achieved gradually over a period of about two weeks. Patients should be carefully monitored. A daily dose of 10 mg should not be exceeded in patients with mild to moderate renal or hepatic impairment.

Special populations
Elderly
Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction.
Paediatric population
Efficacy and safety in children less than 12 years have not been established (see section 4.4).

Method of administration
For oral administration. Missed dose: Doctors should advise patients who forget to take BILOCOR CO to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to bisoprolol or to any of the ingredients of BILOCOR CO
• 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 and lactation (see section 4.6)
• uncontrolled cardiac failure
• cardiogenic shock
• severe hypotension (systolic blood pressure of less than 100 mHg)
• 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
• addisonu2019s disease
• severe renal impairment (creatinine clearance < 30 ml/minute)
• severe hepatic impairment, in whom encephalopathy may be precipitated (see section 4.4)
• phaeochromocytoma
• sick sinus syndrome.

Peripheral vascular disease and Raynaud's phenomenon
The development of Raynaudu2019s phenomenon may occur with the use of BILOCOR CO due to unopposed arteriolar alpha-sympathomimetic activation. Peripheral gangrene may be precipitated (see section 4.3).

Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies. Photosensitising actions of HCTZ could act as a possible mechanism for NMSC. Patients taking BILOCOR CO should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. BILOCOR CO should not be used by patients who have had previous and/or current basal cell carcinoma and/or squamous cell carcinomas of the skin or lip (see section 4.3).

Quinidine
A potentially life threatening reaction may occur between BILOCOR CO and quinidine. The thiazide induced K + depletion worsens the quinidine-induced torsades des pointes and the bisoprolol aggravates these effects further.

Anaesthesia
If the decision is made to withdraw BILOCOR CO before anaesthesia, at least 48 hours should be allowed to elapse between the last dose and surgery. If BILOCOR CO is to be continued, care should be taken when using anaesthetics such as ether, cyclopropane and trichloroethylene. Atropine (1 u2013 2 mg I.V.) may be used to correct vagal dominance. The patient must be maintained on the usual dosage perioperatively to avoid aggravation of angina pectoris or hypertension.

Metabolic and endocrine effects
Diabetic patients
Particular caution should be taken in diabetes mellitus, as symptoms and signs of hypoglycaemia, such as tachycardia, may be masked by BILOCOR CO, and response to hypoglycaemia is diminished. BILOCOR CO may also delay recovery of insulin-induced hypoglycaemia. Hydrochlorothiazide diuretics as in BILOCOR CO may impair glucose tolerance. Dosage adjustment of antidiabetic medicines, including insulin, may be required.

Calcium levels
Decreased urinary calcium excretion caused by hydrochlorothiazides may result in intermittent and a slightly raised serum calcium concentration. Should marked hypercalcaemia occur, it may be evidence of underlying hyperparathyroidism. BILOCOR CO therapy should be discontinued before carrying out tests for parathyroid function (see section 4.3). Increased cholesterol and triglyceride levels may be a result of hydrochlorothiazide diuretic (contained in BILOCOR CO) therapy.

Uric acid
Hydrochlorothiazide diuretics may precipitate hyperuricaemia and/or gout in certain patients.

Sensitivity reactions
In patients receiving hydrochlorothiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of hydrochlorothiazides, as contained in BILOCOR CO.

Hypovolaemia/ blood loss
Tachycardiac responses, due to hypovolaemia or blood loss, may be obscured during or after surgery. Particular caution should be taken in this regard.

Renal insufficiency
Hydrochlorothiazideu2019s, such as in BILOCOR CO, should be used with caution in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency). The dosage of BILOCOR CO should be adjusted in patients with renal impairment (see section 4.2)

Hepatic disease
Caution should be exercised when hydrochlorothiazides, as in BILOCOR CO, are used in patients with hepatic impairment or progressive liver disease, as minor alterations of fluid and electrolyte balance may precipitate hepatic coma in these patients.

Antidysrhythmic medicines
Care should be taken in prescribing BILOCOR CO together with Class 1 antidysrhythmic medicines such as disopyramide, myocardial depressants and inhibitors of AV conduction such as calcium antagonists. BILOCOR CO should be used with caution in combination with verapamil in patients with impaired ventricular function. This combination should not be given to patients with conduction abnormalities. Neither medicine should be administered within 48 hours of discontinuing the other. The intravenous administration of calcium antagonists and antidysrhythmic medicines should be avoided during therapy with BILOCOR CO.

Anaphylaxis
BILOCOR CO may increase sensitivity towards allergens and the incidence of anaphylactic reactions. Treatment of anaphylaxis with adrenaline (epinephrine) does not always have the expected effect.

Clonidine
Caution should be exercised when transferring a patient from clonidine, as the withdrawal of clonidine may result in the release of large amounts of catecholamines that may give rise to a hypertensive crisis. If BILOCOR CO is administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If BILOCOR CO and clonidine are given concurrently, the clonidine should not be discontinued until several days after the withdrawal of BILOCOR CO as severe rebound hypertension may occur.

Abrupt discontinuation of therapy
Abrupt discontinuation of therapy may cause exacerbation of angina pectoris in patients suffering from ischaemic heart disease. Discontinuation of therapy should be gradual (see section 4.2). Patients should be advised to limit the extent of their physical activity during the period that BILOCOR CO is being discontinued.

Psoriasis
Patients with psoriasis should be given BILOCOR CO with caution.

Long-term beta blocker therapy
Digitalisation of patients receiving long-term beta blocker therapy may be necessary if congestive cardiac failure is likely to develop. This combination can be considered despite the potentiation of the negative chronotropic effect of the two medicines. Careful control of dosages, and of the individual patient's response (and notably pulse rate), is essential in this situation (see section 4.5).

Contact lenses
BILOCOR CO may reduce tear flow causing irritation of the eye in contact lens wearers.

Ocular Effects:
Hydrochlorothiazide, such as in BILOCOR CO, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. The risk is greater in patients with a history of sulphonamide or penicillin allergy. Symptoms include active onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of therapy initiation. Primary treatment is discontinuation of BILOCOR CO as rapidly as possible. Untreated acute angle-closure glaucoma can lead to permanent vision loss. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Electrolyte imbalance
Hyponatraemia and hypochloraemia may occur. Hypochloraemic alkalosis and hypokalaemia may also occur, but its likelihood is reduced by the presence of bisoprolol in the combination with hydrochlorothiazide. All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy. Elderly patients are at higher risk of electrolyte imbalance.

Prinzmetal's angina
Cases of coronary vasospasm have been observed. Despite its high beta 1 -selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with Prinzmetal's angina.

Paediatric population
Safety and efficacy in children have not been established.

Combinations not recommended
u2022 calcium channel blockers, such as verapamil and diltiazem should not be given concomitantly with BILOCOR CO (see section 4.4)
u2022 BILOCOR CO, containing bisoprolol, may potentiate the effect of other concomitantly administered antihypertensives. Centrally acting antihypertensives, such as methyldopa, may worsen heart failure by a decrease in central sympathetic tone
u2022 concomitant use of BILOCOR CO with hypoglycaemic medicines, phenothiazines and various antidysrhythmic medicines can have life-threatening consequences for example:
o Profound hypoglycaemia with oral hypoglycaemic medicines and insulin
o Impaired myocardial function with antidysrhythmic medicines such as lidocaine, quinidine, disopyramide, flecainide and propafenone.

Combinations to be used with caution
u2022 strong inducers of the hepatic cytochrome P450 isoenzymes, CYP3A4 and CYP2D6, such as rifampicin and the barbiturates, may shorten the half-life of bisoprolol. An increase in the dose of BILOCOR CO however, is generally unnecessary with rifampicin
u2022 strong inhibitors of the hepatic cytochrome P450 isoenzymes CYP3A4 and CYP2D6, such as cimetidine, erythromycin, fluoxetine and hydralazine may increase the half-life of bisoprolol. The pharmacokinetics of bisoprolol are not significantly influenced by cimetidine
u2022 topical beta blocker eye drops may add to the systemic side effects of BILOCOR CO
u2022 beta-adrenoceptor stimulating medicines (such as dopamine, dobutamine and isoprenaline) may antagonise the effects of BILOCOR CO
u2022 alpha-adrenoceptor stimulants, such as pseudoephedrine and phenylephrine, as well as adrenergic neurone blocking medicines such as reserpine may lead to life-threatening vasoconstriction in combination with BILOCOR CO
u2022 BILOCOR CO and digoxin may be used concomitantly for patients with congestive heart failure provided that the pulse rate and patient response is monitored (see section 4.4)
u2022 BILOCOR CO, containing thiazides, may increase the responsiveness to neuromuscular blockers such as atracurium and other competitive muscle relaxants
u2022 potentiation of orthostatic hypotension caused by thiazides may occur with concurrent use of BILOCOR CO with alcohol, barbiturates or narcotics
u2022 concomitant use of a thiazide diuretic with corticosteroids or ACTH, may intensify electrolyte depletion and hypokalaemia
u2022 thiazide diuretics may decrease response to pressor amines e.g. adrenaline (epinephrine). This decrease in response is not sufficient to preclude the use of pressor amines
u2022 NSAIDs such as indomethacin may reduce the antihypertensive effects of beta-adrenergic blocking medicines, such as BILOCOR CO, possibly by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention
u2022 severe hyponatraemia has occurred in patients taking trimethoprim or carbamazepine with BILOCOR CO.

Do not use BILOCOR CO during pregnancy and lactation (see section 4.3)
Pregnancy
Administration of BILOCOR CO to pregnant mothers shortly before birth or during labour may result in hypotonia, bradycardia, collapse or hypoglycaemia in the newborn (see section 4.3)
Hydrochlorothiazides cross the placental barrier and appear in cord blood. Hazards include foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occur in the adult.

Breastfeeding
Hydrochlorothiazides appear in human milk. If BILOCOR CO is deemed essential, the patient should stop breastfeeding.

BILOCOR CO has a moderate influence on the ability to drive and use machines. Patients should be advised not to drive or use machinery if dizziness or drowsiness is experienced.

Summary of the safety profile
Adverse reactions are more common in patients with renal decompensation.

Tabulated summary of adverse reactions

Side effects for bisoprolol
System Organ Class
Frequency
Side effects
Blood and lymphatic system disorders
Frequent
Less frequent
Thrombocytopenia
Leukopenia
Immune system disorders
Less frequent
Hypersensitivity (allergic) reactions
Endocrine disorders
Frequency unknown
Hypoglycaemia
Metabolism and nutrition disorders
Frequency unknown
Metabolic disturbances increase in uric acid levels, hypercholesterolaemia
Psychiatric disorders
Less frequent
Frequency unknown
Anxiety, nervousness, mental depression, nightmares and vivid dreams
Psychosis, hallucinations
Nervous system disorders
Frequent
Less frequent
Frequency unknown
Drowsiness, unusual tiredness or weakness, sleep disorders or trouble sleeping
Dizziness, mild headache, restlessness, syncope
Lassitude, paraesthesia
Eye disorders
Less frequent
Frequency unknown
Dry, sore eyes, reduced tear flow, conjunctivitis
Disturbances of vision
Ear and labyrinth disorders
Frequency unknown
Transient hearing loss
Cardiac disorders
Less frequent
Bradycardia and congestive heart failure, heart block, dysrhythmias
Vascular disorders
Less frequent
Frequency unknown
Fluid retention, reduced peripheral circulation, orthostatic hypotension
Exacerbation of peripheral vascular disease or the development of Raynaudu2019s phenomenon. Peripheral gangrene may be precipitated, paradoxical hypertension
Respiratory, thoracic and mediastinal disorders
Less frequent
Allergic rhinitis, nasal congestion, bronchoconstriction or bronchospasm may occur in in patients suffering from asthma, bronchitis and other chronic pulmonary diseases
Gastrointestinal disorders
Less frequent
Frequency unknown
Nausea, vomiting, diarrhoea, constipation
Mass gain, stomatitis
Hepatobiliary disorders
Less frequent
Frequency unknown
Hepatotoxicity
Raised liver enzymes
Skin and subcutaneous tissue disorders
Less frequent
Frequency unknown
Skin rash, psoriasiform eruption
Perspiration, alopecia
Musculoskeletal, connective tissue and bone disorders
Less frequent
Frequency unknown
Back pain or joint pain, chest pain
Muscle cramps, myopathy, skeletal muscle weakness
Reproductive system and breast disorders
Frequent
Decreased sexual ability
General disorders and administrative site conditions
Less frequent
Asthenia
Side effects for hydrochlorothiazide
System Organ Class
Frequency
Side effects
Neoplasms benign and malignant (including cysts and polyps)
Frequency unknown
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)
Blood and lymphatic system disorders
Less frequent
Frequency unknown
Hyperuricaemia, thrombocytopenia, blood dyscrasias
Leucopenia, aplastic anaemia, haemolytic anaemia, agranulocytosis, hyperglycaemia, glycosuria, neutropenia, bone marrow depression
Immune system disorders
Less frequent
Anaphylactic reactions
Endocrine disorders
Less frequent
Frequency unknown
Pancreatitis
Sialadenitis
Metabolism and nutrition disorders
Frequent
Less frequent
Electrolyte imbalance including hyponatraemia, hypochloraemic alkalosis, hypokalaemia
Anorexia, metabolic disturbances, hyperglycaemia, hyperuricaemia precipitating attacks of gout, hypomagnesaemia
Psychiatric disorders
Frequent
Less frequent
Restlessness
Depression, sleep disturbances
Nervous system disorders
Frequent
Less frequent
Frequency unknown
Vertigo, fever, restlessness, seizures
Headache, dizziness, paraesthesia
Light-headedness
Eye disorders
Frequency unknown
Xanthopsia, transient blurred vision, choroidal effusion
Cardiac disorders
Frequency unknown
Cardiac dysrhythmias
Vascular disorders
Less frequent
Frequency unknown
Postural hypotension
Necrotising vasculitis (cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders
Frequency unknown
Respiratory distress including pneumonitis and pulmonary oedema
Gastrointestinal disorders
Frequent
Less frequent
Gastrointestinal disturbances, dry Mouth
Gastric irritation, nausea, vomiting, constipation, diarrhoea, intestinal ulceration (in tablets containing thiazides with an enteric-coated core of potassium chloride), cramping
Hepatobiliary disorders
Less frequent
Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders
Less frequent
Frequency unknown
Photosensitivity
Purpura, urticaria, activation of worsening psoriasis or inducing a psoriasis-like rash, erythema multiforme including Stevens-Johnson Syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia, cutaneous lupus erythematosus- like reactions, reactivation of cutaneous lupus erythematosus, urticaria
Musculoskeletal, connective tissue and bone disorders
Frequent
Less frequent
Muscle pain and cramps
Muscle spasm
Renal and urinary disorders
Frequent
Less frequent
Frequency unknown
Oliguria
Glycosuria, urinary excretion of calcium is reduced
Renal failure, renal dysfunction and interstitial nephritis
Reproductive system and breast disorders
Less frequent
Impotence
General disorders and administrative site conditions
Frequent
Frequency unknown
Thirst, weakness
Fever
Investigations
Less frequent
Frequency unknown
Adverse changes in plasma lipids have been noted but their clinical significance is unclear
Increases in cholesterol and triglycerides
Eye disorders: Cases of choroidal effusion with visual field defect have been reported after the use of thiazide and thiazide-like diuretics.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8 or http://www.sahpra.org.za/document/adverse-drug-reactions-and-quality-problemreporting-form/. An email can be sent directly to the company, [email protected] to ensure safety of the product.

Signs and symptoms:
Bisoprolol
Overdosage may produce bradycardia, severe hypotension and/or third degree AV block. Bronchospasm and heart failure may be produced. Cases of overdose should be observed for at least 4 hours, as apnoea and cardiovascular collapse may appear suddenly.
Hydrochlorothiazide
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has been used concomitantly, hypokalaemia may accentuate cardiac dysrhythmias.

Management of overdose:
Bisoprolol
Repeated activated charcoal may be necessary in overdose, intravenous atropine may be used to treat severe bradycardia. If the response is inadequate, glucagon may be given intravenously. Alternatively, dobutamine may be required to reverse beta-blockade. Cardiac pacing may be required for severe bradycardia. Bronchospasm should be treated with intravenous aminophylline or inhaled or intravenous beta 2 adrenergic agonist e.g. salbutamol.
Hydrochlorothiazide
In massive overdosage, treatment is symptomatic and supportive. Recommended treatment for overdose includes supportive, symptomatic treatment; monitoring of serum electrolyte concentrations and renal function and immediate institution of appropriate treatment for hypokalaemia. Correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures. If required, give oxygen or artificial respiration for respiratory impairment. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.