Biprol Plus (Tablets) Instructions for Use

Marketing Authorization Holder

Stada Arzneimittel, AG (Germany)

Manufactured By

Dragenopharm Apotheker Puschl, GmbH & Co. KG (Germany)

ATC Code

C07BB07 (Bisoprolol and thiazides)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Bisoprolol (Rec.INN registered by WHO)

Dosage Forms

	Biprol Plus	Film-coated tablets, 5 mg+12.5 mg: 30 pcs.
		Film-coated tablets, 10 mg+25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets dark pink with a brownish tint, round, biconvex; the cross-section shows a white core. On one side: marking “B-H”, “10-25” and a score, on the other – a score.

Excipients: calcium hydrogen phosphate 129.1 mg, microcrystalline cellulose 10 mg, pregelatinized starch 10 mg, colloidal silicon dioxide 2 mg, magnesium stearate 1.4 mg.

Film coating composition: hypromellose 2.2 mg, dimethicone 350 – 0.025 mg, macrogol-400 0.53 mg, titanium dioxide E 171 1 mg, iron oxide red dye E 172 0.05 mg.

10 pcs. – blisters made of PVC/PE/PVDC/aluminum (3) – cardboard packs.

10 pcs. – blisters made of PVC/PE/PVDC/aluminum (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (beta1-adrenergic blocker + diuretic)

Pharmacological Action

Biprol Plus is a combined antihypertensive agent consisting of bisoprolol and hydrochlorothiazide.

Bisoprolol is a selective beta₁-adrenergic blocker without intrinsic sympathomimetic and membrane-stabilizing activity. It has antihypertensive, antiarrhythmic, and antianginal effects. By blocking beta₁-adrenergic receptors of the heart in low doses, it reduces the catecholamine-stimulated formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP), reduces the intracellular influx of calcium ions, and has negative chronotropic, dromotropic, bathmotropic, and inotropic effects (reduces heart rate (HR), inhibits cardiac conduction, reduces myocardial excitability and contractility). At higher doses, it blocks beta₂-adrenergic receptors.

The total peripheral vascular resistance at the beginning of beta-blocker use, within the first 24 hours, increases (as a result of a reciprocal increase in alpha-adrenergic receptor activity and elimination of beta₂-adrenergic receptor stimulation), returns to the initial level after 1-3 days, and decreases with long-term use.

The antihypertensive effect is associated with a decrease in minute volume of blood, suppression of sympathetic stimulation of peripheral vessels, a reduction in the activity of the renin-angiotensin-aldosterone system by inhibiting beta-adrenergic receptors of the juxtaglomerular apparatus of the kidneys (which leads to a decrease in renin secretion), restoration of the sensitivity of baroreceptors of the aortic arch (their activity does not increase in response to a decrease in blood pressure), and an effect on the central nervous system. In arterial hypertension, the effect develops after 2-5 days, a stable effect – after 1-2 months.

Hydrochlorothiazide is a thiazide diuretic. It reduces the reabsorption of sodium ions in the cortical segment of the loop of Henle, without affecting its part passing through the renal medulla. It blocks carbonic anhydrase in the proximal part of the convoluted renal tubules, increases the renal excretion of potassium, bicarbonate, and phosphate ions. It practically does not affect the acid-base balance. It enhances the renal excretion of magnesium ions; retains calcium ions in the body and inhibits the excretion of urates. The diuretic effect develops after 1-2 hours, reaches a maximum after 4 hours, the duration of the antihypertensive effect persists for up to 24 hours. The diuretic effect decreases with a reduction in the glomerular filtration rate and stops when it is less than 30 ml/min.

Pharmacokinetics

Bisoprolol

Absorption does not depend on food intake. After oral administration, absorption from the gastrointestinal tract (GIT) is 80-90%. C_max in blood plasma is reached after 1-3 hours, plasma protein binding is about 30%. Moderately soluble in lipids, poorly penetrates the blood-brain and placental barrier, excreted in breast milk (about 1%). Metabolized in the liver. Excreted by two equivalent routes: approximately 50% of the bisoprolol dose is excreted by the kidneys unchanged and only 1-2% through the intestines. T_1/2 is 10-12 hours.

Hydrochlorothiazide

When taken orally, it is absorbed quickly but incompletely, absorption is 80%, plasma protein binding is 64%. The bioavailability of hydrochlorothiazide is from 60 to 80%. The time to reach C_max occurs after 2-5 hours, about 4 hours. Penetrates the placental barrier and is excreted in breast milk. T_1/2 is 9-13 hours. It is not metabolized. Excreted by the kidneys mainly (more than 95%) unchanged through glomerular filtration and active tubular secretion.

Indications

• Mild to moderate arterial hypertension.

ICD codes

Dosage Regimen

Orally, in the morning (with meals), without chewing, with a small amount of liquid, once a day.

The dose of the drug is selected individually.

The initial dose of Biprol Plus is – 1 tab. 5/12.5 (containing 5 mg of bisoprolol and 12.5 mg of hydrochlorothiazide) once a day. If the therapeutic effect is insufficient, the dose can be increased to the maximum daily dose of 10/25 – 1 tab. of Biprol Plus (containing 10 mg of bisoprolol and 25 mg of hydrochlorothiazide).

In elderly patients, dose adjustment is not required. It is recommended to start with the lowest possible dose.

In patients with renal impairment (creatinine clearance greater than 30 ml/minute), as well as mild to moderate hepatic impairment, dose adjustment of the drug is not required.

Adverse Reactions

The frequency of adverse reactions listed below was determined according to the following: very common (> 1/10); common (> 1/100, but < 1/10); uncommon: (> 1/1000, but < 1/100); rare (> 1/10000, but < 1/1000); very rare (< 1/10000), including isolated reports.

From the central and peripheral nervous system

Common: increased fatigue, dizziness, headache, which occur especially frequently at the beginning of treatment, are mild and disappear within the first 1-2 weeks of treatment;

Uncommon: sleep disturbance, depression, convulsions;

Rare: “nightmare” dreams, hallucinations.

From the cardiovascular system

Uncommon: bradycardia, AV conduction disturbance, exacerbation of chronic heart failure, ventricular extrasystole, feeling of cold and numbness of the extremities;

Uncommon: orthostatic hypotension;

Very rare: chest pain.

From the respiratory system

Uncommon: bronchospasm in patients with bronchial asthma and bronchospasm (in history);

From the digestive system

Common: nausea, vomiting, diarrhea, constipation, dry oral mucosa;

Uncommon: loss of appetite, discomfort in the gastrointestinal tract, pancreatitis.

From the musculoskeletal system

Uncommon muscle weakness, cramps in the calf muscles, arthralgia.

From the sensory organs

Rare: hearing, vision disturbances, decreased production of tear fluid (should be considered in patients using contact lenses);

Very rare: conjunctivitis.

From the reproductive system

Very rare: impotence.

From the hematopoietic system

Rare: leukopenia, thrombocytopenia;

Very rare: agranulocytosis.

Allergic reactions

Rare: skin itching, rash, facial redness, allergic rhinitis, increased sweating;

Very rare: possible exacerbation of psoriasis, alopecia, discoid and systemic lupus erythematosus.

From laboratory parameters

Common: hypertriglyceridemia, hypercholesterolemia, hyperglycemia and glucosuria, hyperuricemia, disturbance of water-electrolyte balance (especially hypokalemia, hyponatremia, hypomagnesemia, hypochloremia, as well as hypercalcemia), metabolic alkalosis;

Uncommon: increased amylase activity, reversible increase in serum creatinine and urea concentration;

Rare: increased activity of liver enzymes (alanine aminotransferase, aspartate aminotransferase).

From the liver and biliary tract

Rare: hepatitis, jaundice.

Contraindications

• Severe forms of bronchial asthma;
• Chronic obstructive pulmonary disease;
• Cardiogenic shock;
• Sick sinus syndrome (including sinoatrial block);
• Second and third degree atrioventricular block without a pacemaker;
• Severe bradycardia (HR less than 60 beats/min.);
• Pheochromocytoma (without simultaneous use of alpha-1 adrenergic blockers);
• Late stages of peripheral circulatory disorders (including Raynaud’s syndrome);
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Refractory hypokalemia, hyponatremia, hypercalcemia;
• Metabolic acidosis;
• Dehydration;
• Acute renal failure;
• Chronic renal failure (creatinine clearance (CC) less than 30 ml/min);
• Concomitant use with floctafenine, sultopride;
• Concomitant use of MAO inhibitors (except for MAO type B inhibitors);
• Age under 18 years (efficacy and safety not established);
• Severe hepatic impairment (including hepatic precoma and coma);
• Gout;
• Hypersensitivity to bisoprolol, hydrochlorothiazide and other sulfonamide derivatives, as well as to other components of the drug.

With caution first-degree atrioventricular AV block, variant angina (Prinzmetal’s angina), ischemic heart disease (IHD), diabetes mellitus, water-electrolyte imbalance, hepatic and/or renal (CC greater than 30 ml/min) impairment, thyrotoxicosis, pheochromocytoma (during treatment with alpha-adrenergic blockers), strict diet, reduced circulating blood volume (vomiting, diarrhea, dehydration), bronchospasm (in history), psoriasis, elderly age.

Use in Pregnancy and Lactation

The use of Biprol Plus during pregnancy and lactation is contraindicated.

Use in Hepatic Impairment

In patients with mild to moderate hepatic impairment, dose adjustment of the drug is not required.

Use in Renal Impairment

In patients with renal impairment (creatinine clearance greater than 30 ml/minute), dose adjustment of the drug is not required.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Usually, dose adjustment is not required. It is recommended to start with the lowest possible dose.

Special Precautions

During therapy with Biprol Plus, monitoring of HR and BP is necessary (at the beginning of treatment – daily, then – once every 3-4 months), blood glucose concentration in patients with diabetes mellitus (once every 4-5 months). In elderly patients, it is recommended to monitor renal function (once every 4-5 months). The patient should be taught the method of counting HR.

The dose of Biprol Plus (due to the bisoprolol content) should be reduced from 10 to 5 mg if the resting HR does not exceed 50-55 beats/min for 2 weeks.

Special attention is required for patients with IHD, as abrupt withdrawal can lead to a sudden deterioration of the patient’s condition. During therapy with Biprol Plus, it is also necessary to monitor acid-base balance parameters and electrolyte levels (potassium, sodium, calcium).

During treatment with Biprol Plus, patients should consume an adequate amount of fluid and food rich in potassium (e.g., bananas, vegetables, nuts), which is necessary to compensate for potassium losses.

The risk of hypokalemia can be prevented or reduced by the simultaneous administration of potassium-sparing diuretics. Before prescribing Biprol Plus, the circulating blood volume must be compensated.

In patients with peripheral circulatory disorders, caution should be exercised when prescribing Biprol Plus. In thyrotoxicosis, Biprol Plus (due to the bisoprolol content) may mask the clinical signs of the disease (e.g., tachycardia).

Biprol Plus should not be prescribed to patients with pheochromocytoma until treatment with alpha-adrenergic blockers has been initiated. In this case, BP should be monitored.

It is recommended to discontinue therapy with Biprol Plus if depression develops caused by the beta-adrenergic blocker (due to the bisoprolol content).

In elderly patients, treatment with Biprol Plus should be started with the drug form containing a low dose of bisoprolol (5 mg). In this case, regular monitoring of the patient’s condition is necessary.

Special attention is required in cases of surgical intervention under general anesthesia in patients taking beta-adrenergic blockers. Such patients should discontinue Biprol Plus 48 hours before surgery, inform the anesthesiologist that the patient is taking Biprol Plus. An agent with minimal negative inotropic effect should be chosen for general anesthesia.

During therapy with beta-adrenergic blockers, exacerbation of psoriasis may occur. Biprol Plus should be prescribed with caution to patients with this disease.

With a history of anaphylactic reactions, regardless of the cause, especially when conducting desensitizing therapy, treatment with Biprol Plus (due to the bisoprolol content) may increase the risk of allergic reactions and contribute to the development of resistance to treatment with epinephrine in usual doses.

Patients using contact lenses should exercise caution when using Biprol Plus, as beta-adrenergic blockers can reduce the production of tear fluid.

Clonidine – increased risk of “rebound” hypertension, as well as worsening of bradycardia and AV conduction disorders. First, gradual withdrawal of clonidine should be carried out, and only then can Biprol Plus be used.

During long-term therapy with Biprol Plus, regular monitoring of creatinine and urea concentration, lipids (cholesterol and triglycerides), and uric acid should be performed.

In bronchial asthma or other chronic obstructive pulmonary diseases characterized by a risk of deterioration, bronchodilator therapy should be carried out in parallel. Hypokalemia may contribute to the development of severe arrhythmias, in particular, torsades de pointes arrhythmia.

Worsening of the course of metabolic alkalosis due to water-electrolyte imbalance is possible.

Athletes should be informed that Biprol Plus contains Hydrochlorothiazide, which may give positive results during doping control.

Effect on ability to drive vehicles and operate machinery

During treatment with Biprol Plus, caution should be exercised when driving vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions due to the possibility of dizziness.

Overdose

Symptoms pronounced decrease in BP, bradycardia, acute heart failure, ventricular extrasystole, atrioventricular block, convulsions, bronchospasm.

Treatment immediately after overdose (within 2 hours) gastric lavage, administration of adsorbents, symptomatic therapy.

In case of a pronounced decrease in BP, the patient should be placed in a horizontal position with legs elevated, and circulating blood volume should be replenished.

For bradycardia, atropine is administered intravenously at a dose of 1-2 mg, glucagon 1 mg (slowly, bolus), if necessary – as an infusion of 1-10 mg/h. Subsequently, epinephrine is prescribed at a dose of 15-85 mcg (which can be repeated, but its total amount should not exceed – 300 mcg) or dopamine at a dose of 2.5-10 mcg/kg/min.

For acute heart failure, cardiac glycosides, diuretics, and glucagon are indicated.

If there are no signs of pulmonary edema, then plasma-substituting solutions are prescribed intravenously; if they are ineffective – epinephrine, dopamine, dobutamine.

For ventricular extrasystole, lidocaine is used. For developed atrioventricular block, 1-2 mg of atropine, epinephrine should be administered intravenously or a temporary pacemaker should be installed. For convulsions, intravenous diazepam is recommended. For bronchospasm, beta₂-adrenergic agonists are administered by inhalation.

Drug Interactions

Interaction with the combination of bisoprolol and hydrochlorothiazide.

Biprol Plus is contraindicated for use in combination with floctafenine, sultopride, monoamine oxidase (MAO) inhibitors (except for MAO type B inhibitors).

Enhancement of the antihypertensive effect of Biprol Plus is possible with simultaneous use with tricyclic antidepressants, antipsychotics, slow calcium channel blockers (amlodipine, felodipine, nifedipine, nicardipine, nimodipine, nitrendipine), angiotensin-converting enzyme (ACE) inhibitors (including captopril, enalapril), irbesartan, diuretics, clonidine, sympatholytics, hydralazine and other antihypertensive agents.

Weakening of the antihypertensive effect of Biprol Plus is possible with simultaneous administration with glucocorticosteroids (for systemic use), estrogens, non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin, piroxicam, naproxen, phenylbutazone) and tetracosactide.

In the case of hypovolemia, the combined use of NSAIDs may induce the development of acute renal failure. The combination of bisoprolol and hydrochlorothiazide with glucocorticosteroids, ACTH, carbenoxolone, amphotericin B, furosemide, and laxatives may lead to hypokalemia. With simultaneous use with Biprol Plus, the action of non-depolarizing muscle relaxants and the anticoagulant effect of coumarin derivatives may be enhanced.

Cardiac glycosides, methyldopa, reserpine, guanfacine, slow calcium channel blockers (verapamil, diltiazem, amlodipine, felodipine, nifedipine, nicardipine, nimodipine, nitrendipine), antiarrhythmic agents, as well as agents that can initiate torsades de pointes arrhythmias (astemizole, bepridil, erythromycin (IV), halofantrine, pentamidine, sparfloxacin, terfenadine) increase the risk of development and/or worsening of bradycardia, AV block, and chronic heart failure.

With simultaneous use with sotalol, hypokalemia and the development of torsades de pointes ventricular arrhythmia are possible.

Cytostatics (in particular, cyclophosphamide, fluorouracil, methotrexate) – possible enhancement of myelotoxicity.

With simultaneous use of Biprol Plus with lithium salts, an increase in their concentration in the blood to toxic levels is possible.

With simultaneous use of Biprol Plus with allergens used for immunotherapy or with allergen extracts for skin tests, as well as with allopurinol or with iodine-containing X-ray contrast diagnostic agents for intravenous administration, the risk of developing allergic reactions increases. With simultaneous administration of Biprol Plus with carbamazepine, hyponatremia may develop; with cyclosporine – an increase in serum creatinine content is possible.

Bisoprolol

Concomitant use of Biprol Plus with phenytoin (when administered intravenously) and agents for inhalation anesthesia (hydrocarbon derivatives) may enhance the cardiodepressive effect and increase the likelihood of excessive blood pressure reduction.

The clearance of lidocaine and xanthines (except diphylline) may decrease due to a possible increase in their plasma concentration, especially in patients with initially increased theophylline clearance (due to smoking).

Class I antiarrhythmic agents (e.g., quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone) when used concomitantly with bisoprolol may reduce AV conduction and myocardial contractility.

Class III antiarrhythmic agents (e.g., amiodarone) may enhance the impairment of AV conduction.

Slow calcium channel blockers (CCBs) of the verapamil type and, to a lesser extent, diltiazem, when used concomitantly with bisoprolol, may lead to reduced myocardial contractility and impaired AV conduction.

In particular, intravenous administration of verapamil to patients taking beta-blockers may lead to significant arterial hypotension and AV block.

Parasympathomimetics when used concomitantly with bisoprolol may enhance the impairment of AV conduction and increase the risk of bradycardia.

The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced. Signs of hypoglycemia – particularly tachycardia – may be masked or suppressed. Such interactions are more likely with the use of non-selective beta-blockers.

The effects of topical beta-blockers (e.g., eye drops for glaucoma treatment) may enhance the systemic effects of bisoprolol.

Digitalis preparations when used concomitantly with bisoprolol may lead to increased impulse conduction time, and thus, bradycardia.

Antihypertensive agents, as well as other agents with possible antihypertensive effects (e.g., tricyclic antidepressants, barbiturates, phenothiazines) may enhance the antihypertensive effect of bisoprolol.

Mefloquine when used concomitantly with bisoprolol may increase the risk of bradycardia.

The combination of bisoprolol with sympathomimetics affecting both beta and alpha-adrenergic receptors (e.g., norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these agents mediated by alpha-adrenergic receptors, leading to increased blood pressure.

Such interactions are more likely with the use of non-selective beta-blockers. Higher doses of epinephrine (adrenaline) may be required to treat hypersensitivity reactions.

Concomitant use of bisoprolol with beta-sympathomimetics (e.g., isoprenaline, dobutamine) may lead to a reduction in the effect of both drugs.

Sulfasalazine increases the plasma concentration of bisoprolol; rifampicin shortens the half-life of bisoprolol.

Hydrochlorothiazide

Concomitant use of calcium preparations and/or vitamin D in high doses may lead to hypercalcemia and increase the risk of metabolic acidosis.

Non-hydrogenated ergot alkaloids increase the risk of peripheral circulatory disorders.

Concomitant use of hydrochlorothiazide with lithium salts increases its toxicity, as the renal clearance of lithium is reduced. Hydrochlorothiazide should be used with caution in combination with the following drugs

• Antihypertensive agents (their effect is potentiated, dose adjustment may be necessary);
• With cardiac glycosides, as the possibility of digitalis toxicity manifestations associated with hypokalemia and hypomagnesemia may increase;
• With non-depolarizing muscle relaxants (enhances their action);
• With amiodarone (increased risk of arrhythmias associated with hypokalemia).
• Oral hypoglycemic agents (their effectiveness is reduced, hyperglycemia may develop);
• With corticosteroids or calcitonin (increased risk of hypokalemia);
• With salicylates (enhances their neurotoxicity);
• With quinidine (reduces its excretion);
• With methyldopa (hemolysis may develop).
• With amantadine (the clearance of amantadine may be reduced by hydrochlorothiazide, leading to an increase in amantadine plasma concentration and potential toxicity);

Cholestyramine and colestipol, which reduce the absorption of hydrochlorothiazide;

• Ethanol, barbiturates, and narcotic analgesics, which increase the risk of orthostatic hypotension.

Drugs that are highly protein-bound (indirect anticoagulants, clofibrate) enhance the diuretic effect. Vasodilators, beta-blockers, barbiturates, phenothiazines, tricyclic antidepressants, ethanol enhance the antihypertensive effect.

Non-steroidal anti-inflammatory drugs, especially indomethacin, reduce the antihypertensive and diuretic effect. Concomitant use of diflunisal with hydrochlorothiazide causes a significant increase in the plasma level of the latter and reduces its hyperuricemic effect.

Hydrochlorothiazide weakens the effect of oral contraceptives,

Norepinephrine, epinephrine, and anti-gout agents.

Thiazides may reduce the level of protein-bound iodine in the blood plasma.

Storage Conditions

Store at a temperature not exceeding 25°C (77°F). Keep out of reach of children!

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.