Lodoz

Bisoprolol fumarate, hydrochlorothiazide.

Each film-coated tablet contains bisoprolol fumarate 2.5 or 5 and hydrochlorothiazide 6.25 mg.
Excipients/Inactive Ingredients: Tablet Core: Magnesium stearate, maize starch, microcrystalline cellulose, anhydrous calcium-hydrogen phosphate. Lodoz 2.5 mg/6.25 mg also contains crospovidone and pregelatinized maize starch. Lodoz 5 mg/6.25 mg also contain anhydrous colloidal silica.

Pharmacology: Pharmacodynamics: Clinical studies have shown that the antihypertensive effects of bisoprolol and hydrochlorothiazide are additive, and the efficacy of the lowest dose, 2.5 mg/6.25 mg, in the treatment of mild to moderate essential hypertension has been demonstrated.
The pharmacodynamic effects, including hypokalemia (hydrochlorothiazide) and bradycardia, asthenia and headache (bisoprolol) are dose-related.
Combining both drugs at ¼ and ½ the doses used in single-agent therapy (2.5 mg/6.25 mg) aims to reduce those effects.
Bisoprolol is a highly β₁-selective adrenoceptor-blocking agent with no intrinsic sympathomimetic activity and without significant membrane-stabilizing activity.
As with other β₁-receptor blocking drugs, the mechanism of bisoprolol's antihypertensive effect has not been completely established. However, it has been shown that Lodoz produces a marked decrease in plasma renin and a reduction in heart rate.
Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity. Its diuretic effect is due to inhibition of active Na⁺ transport from the renal tubules to the blood, affecting Na⁺ reabsorption.
Pharmacokinetics: Bisoprolol: Absorption: T_max varies from 1 to 4 hours.
Bioavailability is high (88%); hepatic first-pass extraction is very low; and absorption is not affected by the presence of food. Kinetics are linear for doses from 5 to 40 mg.
Distribution: Plasma protein-binding is 30%, and the volume of distribution is high (approximately 3 L/kg).
Biotransformation: 40% of the bisoprolol dose is metabolized in the liver. Bisoprolol metabolites are inactive.
Elimination: The plasma elimination half-life is 11 hrs.
Renal clearance and hepatic clearance are approximately comparable, and half a dose (unchanged) as well as the metabolites are excreted in urine. The total clearance is approximately 15 L/hour.
Hydrochlorothiazide: Absorption: The bioavailability of hydrochlorothiazide shows between-subject variability and ranges from 60 to 80%. T_max varies from 1.5 to 5 hours (mean approximately 4 hours).
Distribution: Plasma protein-binding is 40%.
Elimination: Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged drug, by glomerular filtration and active tubular secretion. The terminal half-life of hydrochlorothiazide is approximately 8 hours.
The renal clearance of hydrochlorothiazide is reduced and the elimination half-life prolonged in patients with renal and/or cardiac insufficiency. The same applies to elderly subjects, who also show an increase in C_max.
Hydrochlorothiazide crosses the placental barrier and is excreted in human milk.
Toxicology: Preclinical Safety Data: Bisoprolol or hydrochlorothiazide have not been found to be hazardous to humans according to the standard preclinical toxicity tests (long-term toxicity, mutagenicity, genotoxicity and carcinogenicity tests). Like other β-blockers, bisoprolol at high doses has been found in animal experiments to cause toxic effects to the mother (decreased food intake and body weight gain), and to the embryo/fetus (increased late resorptions, reduced birth weight of the offspring, retardation of the physical development up to the end of lactation). However, bisoprolol as well as hydrochlorothiazide were not teratogenic. There was no increase in toxicity when both components were given in combination.

Mild to moderate hypertension.

The initial dosage is 1 tab containing bisoprolol 2.5 mg plus hydrochlorothiazide 6.25 mg once daily.
If an inadequate response to treatment is obtained, the dosage should be increased to 1 tab containing bisoprolol 5 mg plus hydrochlorothiazide 6.25 mg in a once daily dose. If the latter proves to be insufficiently effective, the dosage may be increased to 1 tab containing bisoprolol 10 mg plus hydrochlorothiazide 6.25 mg once daily.
If discontinuation is necessary, gradual discontinuation of bisoprolol treatment is recommended since abrupt withdrawal of bisoprolol may lead to an acute deterioration of the patient's condition, particularly in patients with ischaemic heart disease.
No dosage adjustment is necessary in patients with mild to moderate hepatic or renal impairment [creatinine clearance (CrCl) >30 mL/min].
Elderly: No dose adjustment is normally required.
Administration: Lodoz must be taken in the morning and it may be taken with food. The film-coated tablets must be swallowed with a little liquid and must not be chewed.

Symptoms: The most common signs expected with overdosage of a β-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is a wide interindividual variation in sensitivity to 1 single high dose of bisoprolol and patients with heart failure are probably very sensitive.
The clinical picture in acute or chronic overdosage of hydrochlorothiazide is characterised by the extent of fluid and electrolyte loss.
Most common signs are dizziness, nausea, somnolence, hypovolaemia, hypotension and hypokalaemia.
Treatment: In general, if overdosage occurs, discontinuation of Lodoz, and supportive and symptomatic treatment is recommended.
Bradycardia: Administer IV atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.
Hypotension: IV fluids and vasopressors should be administered.
Atrioventricular Block (2nd or 3rd Degree): Patients should be carefully monitored and treated with isoprenaline infusion or IV cardiac pacemaker insertion.
Acute Worsening of Heart Failure: Administer IV diuretics, inotropic agents and vasodilatating agents.
Bronchospasm: Administer bronchodilatator therapy eg, isoprenaline, β₂-sympathomimetic drugs and/or aminophylline.
Hypoglycaemia: Administer IV glucose.
Limited data suggest that bisoprolol is hardly dialyzable. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

Hypersensitivity to bisoprolol, hydrochlorothiazide, other thiazides, sulphonamides, or to any of the excipients of Lodoz.
Bisoprolol: Severe asthma or severe chronic obstructive pulmonary disease (COPD); heart failure not controlled by therapy; cardiogenic shock; sick-sinus syndrome (including SA block); 2nd or 3rd degree AV block (with no implanted pacemaker); symptomatic bradycardia; pheochromocytoma (except after prior α-receptor blocker therapy); severe forms of Raynaud's syndrome and severe peripheral arterial occlusive disease; metabolic acidosis; in combination with sultopride.
Hydrochlorothiazide: Severe renal impairment (CrCl ≤30 mL/min); severe hepatic impairment; refractory hypokalaemia.

Bisoprolol: Bisoprolol should not be stopped abruptly in patients with coronary artery disease [(CAD); angina pectoris]. Abrupt cessation of therapy may cause serious cardiac arrhythmias, myocardial infarction or sudden death.
Hydrochlorothiazide: Patients with liver disease, thiazide diuretics and related drugs may trigger hepatic encephalopathy. Should this happen, diuretic therapy must be stopped immediately.
Lodoz should not be taken in lactating women.

Bisoprolol: Asthma and Chronic Obstructive Pulmonary Disease: β-blockers may be used only in mild forms of asthma or COPD, using a β₁-selective adrenoceptor blocking agent and a low starting dose. Pulmonary function testing is recommended before the start of therapy. Concomitant bronchodilating therapy is recommended in symptomatic patients. An occasional increase of airway resistance may occur in patients with asthma or COPD, therefore the dose of β₂-stimulants may have to be increased.
Cardiac Failure: Patients with compensated cardiac failure who require β-blocker therapy may be administered with bisoprolol using a very low starting dose, to be increased gradually with close medical monitoring.
First-Degree Atrioventricular (AV) Block: Having negative dromotropic activity, β-blockers should be used cautiously in patients with 1st-degree AV block.
Prinzmetal's Angina: β-blockers may increase the frequency and length of vasospastic episodes in patients with Prinzmetal's angina. A β₁-selective blocker may be used in minor or mixed clinical presentations of Prinzmetal's angina if a vasodilator is used concurrently.
Peripheral Arterial Occlusive Disease: β-blockers may aggravate the symptoms of peripheral arterial occlusive disease (PAOD) or Raynaud's syndrome. Such patients should preferably be prescribed a β₁-selective β-blocker.
Pheochromocytoma: In patients with pheochromocytoma, Lodoz must not be administered until after α-receptor blockade. Blood pressure response should be closely monitored.
Diabetics: Diabetic patients should be aware of the risk of hypoglycemic episodes and of the increased need for careful home glucose monitoring in the initial phase of therapy. The warning signs of hypoglycemia, particularly tachycardia, palpitations and sweating, may be masked.
Psoriasis: There have been reports of β-blockers being associated with worsening of psoriasis; thus, patients with psoriasis should receive bisoprolol only if clearly needed.
Hypersensitivity Reactions: In patients at risk of severe anaphylactic reaction to whatever allergen, particularly when using iodine-containing contrast materials or during specific immunotherapy (desensitisation), β-blockers may aggravate the anaphylactic reaction and cause unresponsiveness to the usual doses of epinephrine used to treat hypersensitivity reactions.
General Anesthesia: In patients undergoing general anaesthesia, β-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the postoperative period. It is currently recommended that maintenance β-blockade be continued perioperatively.
The anaesthetist must be aware of β-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss.
If it is thought necessary to withdraw β-blocker therapy before surgery, this should be done gradually and completed about 48 hrs before anaesthesia.
Thyrotoxicosis: β-blockers may mask the cardiovascular signs of hyperthyroidism.
Competitive Athletes: Competitive athletes should be aware that Lodoz contains an agent that may give a positive reaction in doping tests.
Interactions with Other Medicinal Products and Other Forms of Interaction: Interaction Related to Bisoprolol: Contraindication: Sultropide: Increased risk of ventricular arrhythmias, notably Torsades de pointes.
Not Recommended Combinations: Verapamil, Diltiazem: Risk of bradycardia, as well as negative effects on heart contractility and auriclo-ventricular conduction. Such a combination requires a close clinical and ECG monitoring, notably in the elderly and at the beginning of the treatment.
Beripidil: Risk of bradycardia, as well as negative effects on heart contractility and auriclo-ventricular conduction. Additionally, increased risk of ventricular arrhythmias, notably Torsades de pointes. Such a combination requires a close clinical and electrocardiogram (ECG) monitoring, notably in the elderly and at the beginning of the treatment. Combinations requiring a caution for use.
Centrally-Acting Antihypertensive Drugs (eg, Clonidine, Methyldopa, Moxonidine, Rilmenidine): Concomitant use of centrally acting antihypertensive drugs with bisoprolol may further decrease the central sympathetic and may thus lead to an additive reduction in heart rate and cardiac output and to vasodilation/hypotension.
Abrupt withdrawal, particularly if prior to β-blocker discontinuation, may increase the risk of rebound hypertension. Avoid any sudden interruption of the centrally acting antihypertensive agent.
Propafenone, Cibenzoline and Flecainide: Risk of bradycardia, as well as negative effects on heart contractility and auriculo-ventricular conduction. Clinical monitoring and ECG, if appropiate, are required.
Lidocaine: Increased lidocaine plasma levels increasing the likelihood of neurologic and cardiac side effects, due to reduced hepatic blood flow by the βblocking agent and subsequent reduced clearance of lidocaine. Clinical and biological monitoring and ECG, if appropiate, are required, with dosage adjustment of lidocaine if necessary.
Antidiabetics (Insulin, Sulphonylureas, Glinides): All β-blockers may mask warning signs of hypoglycemia, notably palpitations and tachycardia. Diabetic patients should be aware of the risk of hypoglycemic episodes and of that increased need for careful home glucose monitoring, especially in the initial phase of therapy.
Other Bradycardia-Inducing Drugs (Anticholinesterase, Digitalis Glycosides, Mefloquine): Increased risk of bradycardia. A regular clinical monitoring should be made.
Calcium-Channel Blocker of the Dihydropyridine Type (eg, Nifedipine, Amlodipine): Concomitant use may increase the risk of hypotension and further risk of deterioration of the ventricular pump function in patient with heart failure cannot be executed.
Topical β-blockers (eg, Eye Drops for Glaucoma Treatment): They may add their effect to systemic one or bisoprolol.
Interactions Related to Hydrochlorothiazide: Not Recommended Combinations: Lithium: Increased lithium plasma levels with signs of overdosage, as occur on a low-sodium diet, due to reduced urinary lithium excretion. If this combination cannot be avoided, provide close lithium plasma level monitoring and adjust dosage as necessary.
Combinations Requiring A Caution for Use: Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) Systemic, Acetylsalicylic Acid (ASA) and Anti-Inflammatory Regimen: Acute renal failure in dehydrated patients (NSAIDs reduce glomerular blood flow by inhibiting vasodilatory prostaglandins). Patients should be rehydrated and the kidney function monitored at the start of the therapy.
Potassium-Sparing Diuretics (Alone or Combined): Such a combination, possibly useful, does not preclude hypo- or hyperkalemia, the latter being more frequent in case of diabetes or renal impairment. Kalemia should be monitored, and if appropiate, ECG. Treatment may possibly have to be reconsidered.
Hypokalemic drugs (IV Amphotericin, Systemic Corticosteroids, Tetracosactide, Stimulating Laxatives): Increased risk of hypokalemia. Monitor and, if appropiate, correct plasma potassium. This is notably of importance with the concomitant use of digitalis glycosides. Rather use non-stimulating laxatives.
Angiotensin Converting Enzyme Inhibitors (ACEi), Angiotensin II Receptors Antagonists (AIIA): Risk of significant blood pressure and/or acute renal failure during initiation if ACEi therapy in patients with preexisting sodium depletion (particularly in patients with renal artery stenosis). If prior diuretic therapy may have produced sodium depletion, either stop the diuretic 3 days before starting ACEi or AIIA therapy and re-introduce the diuretic later if necessary, or start patient on a reduced ACEi or AIIA dose to be gradually increased thereafter.
Carbamazepine: Risk of symptomatic hyponatremia. Clinical and biological monitoring is required. Another class of diuretics should be eventually used.
Iodinated Contrast Media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.
Resin's Reduction of the Absorption of Hydrochlorothiazide: A time interval of atleast 2 hrs should separate the resin intake from Lodoz administration.
Uric Acid Lowering Agents: Their effect may be attenuated with the concomitant administration of hydrochlorothiazide.
Calcium Salts: Risk of hypercalcemia due to reduced urinary excretion.
Cyclosporine: Risk of increased creatininemia without change of cyclosporine levels, even out of any sodium depletion.
Interactions Related to Both Bisoprolol and Hydrochlorothiazide: Combinations requiring A Caution For Use: Antiarrhythmic Drugs Inducing Torsade de Pointes (Agents of the Sub Class IA: Quinidine, Hydroquinidine, Disopyramide and the Sub Class III: Increased risk of ventricular arrhthmias, notably Torsades de pointes, flavoured by bradycardia and/or hypokalemia. Clinical and ECG monitoring are required.
Non Antiarrhythmic Drugs Inducing Torsades de Pointes (eg, Astemizole, Bepridil, Cisapride, Diphemanil, IV Erythromycin, Halofantrine, Lumefantrine, Methadone, Moxifloxacin, Pentamidine, Sotalol, IV Spiramycin, Sparfloxacin, Terfenadine, Vincamine, Some Antipsychotic Like Pimozide, Haloperidol, Benzamides): Increased risk of ventricular arrhythmias, notably Torsade de pointes, favoured by bradycardia and/or hypokalemia. Clinical and ECG monitoring are required.
Digitalis Glycosides: Due to hydrochlorothiazide, there is a risk of hypokalemia, which may facilitate the toxic effects of cardiac glycosides. Due to bisoprolol, there is a risk of bradycardia and negative effect on AV conduction. A regular clinical monitoring should be made. Plasma potassium should be monitored and, if appropiate, ECG.
Combinations To be Taken Into Account: Other Antihypertensive Agents, Tricyclics, Phenothiazines, Baclofen, Amifostine: Concomitant use with these drugs that lower blood pressure, as main or side effect, may increase the risk of hypotension.
NSAID: Reduced antihypertensive efficiency by inhibition of vasodilatory prostaglandins (pyrazole derivatives also induce sodium retention).
Corticosteroids and Tetracosactide: Reduced antihypertensive efficiency by sodium retention effect.
Strict Fasting: Lodoz must be used with caution in patients under strict fasting.
Combination with Verapamil, Diltiazem or Bepridil: Such combinations require a close clinical and electrocardiogram (ECG) monitoring, notably in the elderly and at the beginning of the treatment.
Hydrochlorothiazide: A sulfonamide can cause myopia and acute angle-closure glaucoma.
Fluid and Electrolyte Balance: During long-term therapy with Lodoz, periodic monitoring of serum electrolytes (especially potassium, sodium and calcium), creatinine and urea, the serum lipids (cholesterol and triglycerides), uric acid as well as blood glucose is recommended.
Long-term, continuous administration of hydrochlorothiazide may lead to fluid and electrolyte disturbances, in particular to hypokalaemia and hyponatraemia, also to hypomagnesaemia and hypochloraemia, and hypercalcaemia.
Plasma Sodium: Plasma sodium should be determined before and periodically during therapy. Any diuretic therapy may give rise to hyponatremia, with serious consequences in some cases.
As hyponatremia may initially be asymptomatic, periodic monitoring is indispensable and should be more frequent in high-risk populations ie, the elderly and patients with liver cirrhosis.
Plasma Potassium: Potassium loss resulting in hypokalemia is the greatest risk associated with thiazide diuretics and related drugs.
The risk of hypokalemia (<3.5 mmol/L) should be anticipated in certain high-risk populations ie, elderly and/or malnourished and/or taking multiple drugs, and patients with coronary artery disease or heart failure, where hypokalemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmia.
Also at risk are patients with long QT syndrome, either congenital or iatrogenic. Hypokalemia (as well as bradycardia) facilitates the development of severe arrhythmias, particularly Torsade de pointes, which may be fatal.
More frequent plasma potassium monitoring is indicated in all of the previously mentioned populations, starting within the week after initiation of therapy.
Plasma Calcium: Thiazide diuretics and related drugs may reduce urinary calcium excretion, resulting in mild, transient hypercalcemia. Significant hypercalcemia may be related to undiagnosed hyperparathyroidism. Therapy must be interrupted before performing parathyroid function tests.
Combination with Lithium: Due to the diuretic, this combination should be avoided.
Blood Glucose: In diabetics, blood glucose must be monitored, especially in the presence of hypokalemia.
Uric Acid: In patients with hyperuricemia, the risk for attacks of gout may be increased. Dosage should be adjusted as a function of uric acid plasma concentrations.
Kidney Function and Diuretics: Full benefit from thiazide diuretics can be derived only if kidney function is normal or almost normal (serum creatinine <25 mg/L, or 220 micromol/L in adults).
Serum creatinine needs to be corrected for age, weight, and gender, using Cockcroft's formula for instance: CrCl = (14-age) x weight/0.814 x serum creatinine; where "age" is indicated in years; "weight" in kg and "serum creatinine" in micromol/L.
The previously mentioned formula gives CrCl for elderly male subjects, and needs to be corrected for elderly female subjects by multiplying with 0.85.
Hypovolemia secondary to diuretic-induced water and sodium loss at the start of therapy reduces glomerular filtration, which may result in blood urea nitrogen and serum creatinine increases.
This transient functional renal impairment is nonrelevant in patients with normal kidney function but may worsen preexisting renal insufficiency.
Combination with Other Antihypertensive Drugs: It is advisable to reduce the dosage when Lodoz is combined with another antihypertensive, at least in the initial phase of therapy.
Photosensitivity: Photosensitivity reactions have been reported with thiazide diuretics in rare cases. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a readministration of treatment is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA-light.
Competitive Athletes: Competitive athletes should be aware that Lodoz contains an agent that may give a positive reaction in doping tests.
Effects on the Ability to Drive or Operate Machinery: Depending on the individual patient's response to Lodoz treatment, the ability to drive and use machines may be impaired. This should be particularly considered at the start of treatment as well as in conjunction with alcohol.
Use in pregnancy: Lodoz contains a thiazide diuretic. The use during pregnancy is therefore not recommended.
Bisoprolol: Animal studies did not show any teratogenic effect. To date, results of well-controlled prospective studies with some β-blockers did not show any birth defect in newborns. In neonates born from mothers treated with β-blockers, β-blocking activity persists for several days postpartum and may induce bradycardia, respiratory distress and hypoglycaemia. In most cases, this impregnation is without any clinical consequences. Nevertheless, heart failure may occur, necessitating intensive care unit management, avoiding plasma expanders (risk of acute pulmonary oedema).
Hydrochlorothiazide: Diuretics may give rise to foetoplacental ischemia with the attendant risk of foetal hypotrophy. Rare cases of severe neonate thrombocytopenia have been reported.
Use in lactation: It is not known if bisoprolol is excreted in human milk. Thiazide diuretics are excreted in human milk. Thus, Lodoz should not be given to lactating women.
Bisoprolol: The risk for hypoglycaemia and bradycardia in suckling infant has not been evaluated.
Hydrochlorothiazide: Thiazide diuretics may produce the following: A decrease or even suppression of milk secretion; adverse biological effects (hypokalemia); hemolysis (G6PD defect) and hypersensitivity due to sulphonamide properties.
Use in children: Lodoz is not recommended in children since there are no available data concerning its utilization in pediatrics.
Use in the elderly: No dose adjustment is normally required. However, elderly patients should be closely monitored (see previous text under fluid and electrolyte balance).

Use in pregnancy: Lodoz contains a thiazide diuretic. The use during pregnancy is therefore not recommended.
Bisoprolol: Animal studies did not show any teratogenic effect. To date, results of well-controlled prospective studies with some β-blockers did not show any birth defect in newborns. In neonates born from mothers treated with β-blockers, β-blocking activity persists for several days postpartum and may induce bradycardia, respiratory distress and hypoglycaemia. In most cases, this impregnation is without any clinical consequences. Nevertheless, heart failure may occur, necessitating intensive care unit management, avoiding plasma expanders (risk of acute pulmonary oedema).
Hydrochlorothiazide: Diuretics may give rise to foetoplacental ischemia with the attendant risk of foetal hypotrophy. Rare cases of severe neonate thrombocytopenia have been reported.
Use in lactation: It is not known if bisoprolol is excreted in human milk. Thiazide diuretics are excreted in human milk. Thus, Lodoz should not be given to lactating women.
Bisoprolol: The risk for hypoglycaemia and bradycardia in suckling infant has not been evaluated.
Hydrochlorothiazide: Thiazide diuretics may produce the following: A decrease or even suppression of milk secretion; adverse biological effects (hypokalemia); hemolysis (G6PD defect) and hypersensitivity due to sulphonamide properties.

Common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%) including isolated cases.
Blood and Lymphatic System Disorders: Rare: Leucopenia, thrombocytopenia. Very Rare: Agranulocytosis.
Metabolism and Nutrition Disorders: Uncommon: Loss of appetite, hyperglycaemia, hyperuricaemia, disturbances of fluid and electrolyte balance (in particular, hypokalaemia and hyponatraemia, also hypomagnesaemia and hypochloraemia as well as hypercalcaemia). Very Rare: Metabolic alkalosis.
Psychiatric Disorders: Uncommon: Depression, sleep disorders. Rare: Nightmares, hallucinations.
Nervous System Disorders: Common: Dizziness*, headache*.
Eye Disorders: Rare: Reduced tear flow (to be taken into consideration in patients wearing contact lenses), visual disturbances. Very Rare: Conjunctivitis.
Ear and Labyrinth Disorders: Rare: Hearing disorders.
Cardiac Disorders: Uncommon: Bradycardia, AV-conduction disturbances, worsening of preexisting heart failure.
Vascular Disorders: Common: Feeling of coldness or numbness in extremities. Uncommon: Orthostatic hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Bronchospasm in patients with bronchial asthma or history of obstructive airways disease. Rare: Allergic rhinitis.
Gastrointestinal Disorders: Common: Gastrointestinal complaints eg, nausea, vomiting, diarrhoea, constipation. Uncommon: Abdominal complaints. Very Rare: Pancreatitis.
Hepatobilary Disorders: Rare: Hepatitis, jaundice.
Skin and Subcutaneous Tissue Disorders: Rare: Hypersensitivity reactions eg, itching, flush, rash, photodermatitis, purpura, urticaria. Very Rare: Anaphylactic reactions, toxic epidermic necrolysis (Lyell syndrome), alopecia, cutaneous lupus erythematosus. β-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Muscle weakness, muscle cramps.
Reproductive System and Breast Disorders: Rare: Potency disorders.
General Disorders: Common: Fatigue*. Uncommon: Asthenia. Very Rare: Chest pain.
Investigations: Uncommon: Increased amylase, reversible increase of serum creatinine and urea, increased triglyceride and cholesterol levels, glucosuria. Rare: Increased liver enzymes (ASAT, ALAT).
*These symptoms occur in particular at the start of treatment. These are generally mild and mostly disappear within 1-2 weeks.

Related to Bisoprolol: Contraindicated Combinations: Sultopride: Increased risk of ventricular arrhythmias, notably torsade de pointes.
Not Recommended Combinations: Verapamil, Diltiazem: Risk of bradycardia, as well as negative effects on heart contractility and auriculoventricular conduction. Such a combination requires a close clinical and ECG monitoring, notably in the elderly and at the beginning of the treatment.
Bepridil: Risk of bradycardia, as well as negative effects on heart contractility and auriculoventricular conduction. In addition, increased risk of ventricular arrhythmias, notably torsade de pointes. Such combination requires a close clinical and ECG monitoring, notably in the elderly and at the beginning of the treatment.
Combinations Requiring a Caution for Use: Centrally-Acting Antihypertensive Drugs (eg, Clonidine, Methyldopa, Moxonidine, Rilmenidine): Concomitant use of centrally-acting antihypertensive drugs with bisoprolol may further decrease the central sympathetic tonus, and may thus lead to an additive reduction in heart rate and cardiac output and to vasodilatation/hypotension.
Abrupt withdrawal, particularly if prior to β-blocker discontinuation, may increase the risk of rebound hypertension. Avoid any sudden interruption of the centrally-acting antihypertensive agent.
Propafenone, Cibenzoline and Flecainide: Risk of bradycardia, as well as negative effects on heart contractility and auriculoventricular conduction.
Clinical monitoring and ECG, if appropriate are required.
Lidocaine: Increased lidocaine plasma levels will increase the likelihood of neurologic and cardiac side effects due to reduced hepatic blood flow by the β-blocking agent and subsequent reduced clearance of lidocaine.
Clinical and biological monitoring and ECG, if appropriate, are required, with dosage adjustment of lidocaine, if necessary.
Antidiabetics (Insulin, Sulphonylureas and Glinides): All β-blockers may mask warning signs of hypoglycemia, notably palpitations and tachycardia. Diabetic patients should be aware of the risk of hypoglycemic episodes and of the increased need for careful home glucose monitoring, especially in the initial phase of therapy.
Other Bradycardia-Inducing Drugs (Anticholinesterases, Digitalis Glycosides and Mefloquine): Increased risk of bradycardia. Regular clinical monitoring should be conducted.
Calcium-Channel Blockers of the Dihydropyridine Type (eg, Nifedipine, Amlodipine): Concomitant use may increase the risk of hypotension and a further risk of deterioration of the ventricular pump function in patients with heart failure cannot be excluded.
Topical β-blockers (eg, Eye Drops for Glaucoma Treatment): They may add their effects to the systemic ones of bisoprolol.
Related to Hydrochlorothiazide: Not Recommended Combinations: Lithium: Increased lithium plasma levels with signs of overdosage, as occur on a low-sodium diet, due to reduced urinary lithium excretion. If this combination cannot be avoided, provide close lithium plasma level monitoring and adjust dosage as necessary.
Combinations Requiring a Caution for Use: Nonsteroidal Anti-Inflamatory Drugs (NSAIDs) (Systemic), Acetylsalicylic Acid at Anti-inflammatory Dosage Regimen: Acute renal failure in dehydrated patients (NSAIDs reduce glomerular blood flow by inhibiting vasodilatory prostaglandins). Patients should be rehydrated and the kidney function monitored at the start of the therapy.
Potassium-Sparing Diuretics (Alone or Combined): Such a combination, possibly useful, does not preclude hypo- or hyperkalemia, the latter being more frequent in case of diabetes or renal impairment. Kalemia should be monitored and, if appropriate, ECG. Treatment may possibly have to be reconsidered.
Hypokalemic Drugs (IV Amphotericin, Systemic Corticosteroids, Tetracosactide, Stimulating Laxatives): Increased risk of hypokalemia. Monitor and if appropriate, correct plasma potassium. This is notably of importance with the concomitant use of digitalis glycosides. Rather use nonstimulating laxatives.
Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin-II Receptors Antagonists (AIIA): Risk of significant blood pressure decrease and/or acute renal failure during initiation of ACE inhibitors therapy in patients with preexisting sodium depletion (particularly in patients with renal artery stenosis).
If prior diuretic therapy may have produced sodium depletion, either stop the diuretic 3 days before starting ACE inhibitors or AIIA therapy and reintroduce the diuretic later if necessary, or start patient on a reduced ACE inhibitors or AIIA dose to be gradually increased thereafter.
Carbamazepine: Risk of symptomatic hyponatremia.
Clinical and biological monitoring is required. Another class of diuretics should be eventually used.
Iodinated Contrast Media: In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration.
Resins: Reduction of the absorption of hydrochlorothiazide.
A time interval of at least 2 hrs should separate the resin intake from Lodoz administration.
Uric Acid-Lowering Agents: The effect may be attenuated with the concomitant administration of hydrochlorothiazide.
Calcium Salts: Risk of hypercalcemia due to reduced urinary excretion.
Cyclosporine: Risk of increased creatininemia without change of cyclosporine levels, even out of any sodium depletion.
Interactions Related to Both Bisoprolol and Hydrochlorothiazide: Combinations Requiring Caution for Use: Antiarrhythmic Drugs Inducing Torsade de Pointes (Agents of the Subclass IA: Quinidine, Hydroquinidine, Disopyramide and of the Subclass III: Amiodarone, Sotalol, Dofetilide, Ibutilide): Increased risk of ventricular arrhythmias, notably torsade de pointes, favoured by bradycardia and/or hypokalemia. Clinical and ECG monitoring are required.
Non-Antiarrhythmic Drugs Inducing Torsade De Pointes (eg, Astemizole, Bepridil, Cisapride, Diphemanil, IV Erythromycin, Halofantrine, Lumefantrine, Methadone, Moxifloxacin, Pentamidine, Sotalol, IV Spiramycin, Sparfloxacin, Terfenadine, Vincamine, Some Antipsychotics like Pimozide, Haloperidol, Benzamides): Increased risk of ventricular arrhythmias, notably Torsade de pointes, favoured by bradycardia and/or hypokalemia.
Clinical and ECG monitoring are required.
Digitalis Glycosides: Due to hydroclorothiazide, there is a risk of hypokalemia, which may facilitate the toxic effects of cardiac glycosides. Due to bisoprolol, there is a risk of bradycardia and negative effect on AV conduction.
A regular clinical monitoring should be made. Plasma potassium should be monitored and, if appropriate, ECG.
Combinations to be Taken Into Account: Other Antihypertensive Agents, Tricyclics, Phenothiazines, Baclofene, Amifostine: Concomitant use with these drugs that lower blood pressure, as main or side effect, may increase the risk of hypotension.
Nonsteroidal Anti-Inflamatory Drugs: Reduced antihypertensive efficiency by inhibition of vasodilatory prostaglandins (pyrazole derivatives also induce sodium retention).
Corticosteroids, Tetracosactide: Reduced antihypertensive efficiency by a sodium retention effect.

Do not store above 25°C.
Shelf-Life: Lodoz 2.5 mg/6.25 mg, film-coated tablet: 2 years.
Lodoz 5 mg/6.25 mg, film-coated tablet: 4 years.

Beta-Blockers / Diuretics

C07BB07 - bisoprolol and thiazides ; Belongs to the class of selective beta-blocking agents in combination with thiazides. Used in the treatment of cardiovascular diseases.

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