Bisoprolol Fumarate + Amlodipine Besilate

Bisoprolol & Amlodipine combination is indicated for the 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

This consists of Amlodipine and Bisoprolol Fumarate. Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine acts directly on vessels to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Bisoprolol Fumarate is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilizing 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 airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

One tablet once daily in patients whose blood pressure is adequately controlled with separately administered monocomponent products of the same doses as the recommended fixed-dose combination.

Combinations not recommended: Calcium antagonists of the verapamil and diltiazem type, centrally-acting antihypertensive drugs.

Combinations to be used with caution: Strong or moderate CYP3A4 inhibitors, CYP3A4 inducers, simvastatin, Tacrolimus, Cyclosporine, class I antiarrhythmic drugs, class III antiarrhythmic drugs, parasympathomimetic drugs, topical beta-blockers (e.g. eye drops), insulin and oral antidiabetic drugs, anesthetic agents, digitalis glycosides, non-steroidal anti-inflammatory drugs (NSAIDs), sympathomimetic agents, antihypertensive agents and other drugs with blood pressure lowering potential.

Combinations to be considered: Mefloquine, Rifampicin, Ergotamine derivatives, MAO inhibitors (except MAO-B inhibitor).

Acute heart failure or during episodes of heart failure decompensation, obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis), cardiogenic shock, second or third degree AV block, sick sinus syndrome, sinoatrial block, symptomatic bradycardia or hypotension, severe bronchial asthma, severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome, untreated phaeochromocytoma metabolic acidosis, hypersensitivity to bisoprolol, amlodipine, dihydropyridine derivates or to any of the excipients.

Common: Dizziness, headache, somnolence, palpitations, flushing, feeling of coldness or numbness in the extremities, gastrointestinal complaints such as nausea, vomiting, diarrhea, constipation, abdominal pain; edema (e.g. ankle edema), fatigue.

Uncommon: Insomnia, mood changes (incl. anxiety), depression, sleep disorders, hypaesthesia, paresthesia, dysgeusia, tremor, visual disturbances (incl. diplopia), tinnitus, AV conduction disturbances, worsening of pre existing heart failure, bradycardia, hypotension, syncope, dyspnea, bronchospasm in patients with bronchial asthma or a history of obstructive airway disease, rhinitis, dyspepsia, dry mouth, alopecia, purpura, skin discoloration, pruritus, exanthema, arthralgia, myalgia, muscular weakness, muscle cramps, back pain, micturition disorder, nocturia, pollakisuria, potency disorders, gynecomastia, asthenia, chest pain, pain, malaise, weight increase, weight decrease.

Rare: Allergic reactions mainly affecting the skin, nightmares, hallucinations, confusion, decreased tear secretion, hearing disorders, allergic rhinitis, hepatitis, increased triglycerides, increased liver enzymes (ALAT, ASAT).

Pregnancy and Lactation: Not recommended.

Patients with heart failure should be treated with caution. An increased risk of a further deterioration of the ventricular pump function cannot be excluded. Since the abrupt withdrawal of bisoprolol may lead to a transitory worsening of the clinical condition, especially in patients with ischemic heart disease, the treatment must not be stopped abruptly. Caution is advised in patients with impaired hepatic function. Beta-blockers should be avoided in patients with obstructive airways diseases unless there are compelling clinical reasons for their use. Due to the bisoprolol component treatment must be used with caution in: bronchospasm (bronchial asthma, chronic obstructive airways disease; concomitant bronchodilating therapy may be recommended); diabetes mellitus showing large fluctuations in blood glucose values, symptoms of hypoglycemia can be masked; strict fasting; ongoing desensitization therapy; first degree AV block; Prinzmetal’s angina; peripheral arterial occlusive disease. Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits and risks. Symptoms of thyrotoxicosis may be masked. In patients undergoing general anesthesia, the anesthetist must be aware of beta-blockade. If it is thought necessary to withdraw beta blocker therapy before surgery, this should be done gradually and completed about 48 hours before anesthesia.

Most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency, hypoglycemia. According to available data gross overdose of amlodipine could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. In general, if overdose occurs, discontinuation of treatment and supportive and symptomatic treatment is recommended.

Anti-hypertensive

Geriatric use: The usual doses can be administered to elderly people; however, caution is advised when the dose is increased.

Pediatric use: The safety and efficacy of Bisoprolol fumarate/amlodipine in children and adolescents below the age of 18 years have not been established. No data are available.

Patients with Liver disease: In case of hepatic impairment elimination of amlodipine may be elongated. Exact dosage recommendations concerning amlodipine have not been established, but the drug should therefore be administered with special caution in these patients. In case of severe hepatic impairment, the daily dose of bisoprolol must not exceed 10 mg.

Patients with Kidney disease: No dosage adjustment is required for patients with mild to moderate renal impairment. Amlodipine is not dialyzable. Amlodipine should be administered with particular caution to patients undergoing dialysis. In case of severe renal impairment (creatinine clearance <20 ml/min) the daily dose of bisoprolol must not exceed 10 mg

Keep in a dry place, below 30°C. Protect from light. Keep out of the reach of children.