Nebilong H (Tablets) Instructions for Use

Marketing Authorization Holder

Micro Labs Limited (India)

ATC Code

C07BB12 (Nebivolol and thiazides)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Nebivolol (Rec.INN registered by WHO)

Dosage Form

Nebilong H

Tablets 12.5 mg + 5 mg: 10, 30, 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, with a bevel and a score on one side.

Excipients : lactose monohydrate – 60.44 mg, microcrystalline cellulose – 43.868 mg, betadex (beta-cyclodextrin) – 30 mg, croscarmellose sodium – 24 mg, docusate sodium – 2 mg, povidone – 5 mg, colloidal anhydrous silicon dioxide – 2 mg, talc – 2 mg, magnesium stearate – 2 mg.

10 pcs. – Al/Al blisters (1) – cardboard packs.
10 pcs. – Al/Al blisters (3) – cardboard packs.
10 pcs. – Al/Al blisters (5) – cardboard packs.
10 pcs. – Al/Al blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (beta-adrenoblocker+diuretic)

Pharmacological Action

Nebilong H is a combined agent, which contains Nebivolol and hydrochlorothiazide.

Nebivolol

Nebivolol is a lipophilic, cardioselective, beta₁-adrenoblocker with vasodilating properties. It has antihypertensive, antianginal and antiarrhythmic action. It reduces elevated blood pressure at rest, during physical exertion and stress. It competitively and selectively blocks synaptic and postsynaptic beta₁-adrenoblockers, making them inaccessible to catecholamines, modulates the release of the endothelial vasodilating factor nitric oxide (NO).

Nebivolol is a racemate consisting of two enantiomers: SRRR-nebivolol (D-nebivolol) and RSSS-nebivolol (L-nebivolol), combining two pharmacological actions

• D-Nebivolol is a competitive and highly selective blocker of beta₁-adrenoreceptors (affinity for beta₁-adrenoreceptors is 293 times higher than for beta₂-adrenoreceptors).
• L-Nebivolol has a mild vasodilating effect due to modulation of the release of the relaxing factor from the vascular endothelium.

The antihypertensive effect develops on the 2-5th day of treatment, a stable effect is noted after 1 month. This effect persists with long-term treatment.

The antihypertensive effect is also due to a decrease in the activity of the RAAS (directly correlates with a change in plasma renin activity).

The use of nebivolol improves systemic and intracardiac hemodynamics. Nebivolol reduces heart rate and blood pressure at rest and during physical exertion, reduces left ventricular end-diastolic pressure, reduces total peripheral vascular resistance, improves diastolic heart function (reduces filling pressure), increases ejection fraction. By reducing myocardial oxygen demand (decreased heart rate, reduced pre- and afterload), it reduces the number and severity of angina attacks and improves exercise tolerance.

The antiarrhythmic effect is due to the suppression of cardiac automatism (including in the pathological focus) and slowing of AV conduction.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. It reduces the reabsorption of sodium ions in the cortical segment of the loop of Henle, without affecting its section passing in the renal medulla. It blocks carbonic anhydrase in the proximal part of the convoluted renal tubules, increases the excretion of potassium ions, bicarbonates and phosphates by the kidneys. It practically does not affect the acid-base state. It increases the excretion of magnesium ions by the kidneys, 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, and lasts up to 10-12 hours. The diuretic effect decreases with a decrease in the glomerular filtration rate and stops at a value of less than 30 ml/min. (reduces urine volume and increases its concentration).

Pharmacokinetics

Nebivolol

After oral administration, Nebivolol is rapidly absorbed from the gastrointestinal tract. Food intake does not affect absorption, so Nebivolol can be taken regardless of meals. Bioavailability averages 12% in patients with “rapid” metabolism and is almost complete in patients with “slow” metabolism. The efficacy of nebivolol does not depend on the rate of metabolism.

Plasma clearance in most patients (with “rapid” metabolism) is achieved within 24 hours, and for hydroxymetabolites – after several days. Plasma concentrations of 1-30 µg/l are dose proportional.

Plasma protein binding (mainly with albumin) is 98.1% for D-nebivolol and 97.9% for L-nebivolol.

Nebivolol is actively metabolized, partially with the formation of active hydroxymetabolites. It is metabolized by acyclic and aromatic hydroxylation, genetically determined by oxidative polymorphism and depends on the CYP2D6 isoenzyme.

After administration, 38% (the amount of unchanged active substance is less than 0.5%) of the dose is excreted by the kidneys and 48% – through the intestine.

In patients with “rapid” metabolism, the values of the half-life (T_1/2) of nebivolol enantiomers from plasma average 10 hours. In patients with “slow” metabolism, these values increase by 3-5 times.

In patients with “rapid” metabolism, the T_1/2 values of hydroxymetabolites of both enantiomers from plasma average 24 hours, in patients with “slow” metabolism these values approximately double.

The pharmacokinetics of nebivolol is not influenced by the age and sex of patients.

Hydrochlorothiazide

When taken orally, it is absorbed quickly but incompletely. The time to reach maximum plasma concentration is about 4 hours. The bioavailability of hydrochlorothiazide is 60-80%. Plasma protein binding is 40%.

It penetrates the placental barrier and is excreted in breast milk. It is not metabolized. It is excreted by the kidneys mainly unchanged through glomerular filtration and active tubular secretion. The half-life is about 8 hours.

Indications

• Arterial hypertension (for patients who require combination therapy).

ICD codes

Dosage Regimen

Orally, preferably at the same time, once a day regardless of meals, without chewing and with a sufficient amount of liquid. At the beginning of therapy, 1 tablet should be taken per day.

If the therapeutic effect is insufficient after 2 weeks, the dose can be increased to 2 tablets.

The maximum daily dose is 2 tablets per day.

For patients with severe renal impairment (creatinine clearance less than 30 ml/min), the use of the drug is not recommended (see section Contraindications).

Adverse Reactions

Nebivolol

The frequency of side effects is presented in the following gradation: very common (more than 10%), common (more than 1% and less than 10%), uncommon (more than 0.1% and less than 1%), rare (more than 0.01% and less than 0.1%), very rare (less than 0.01%), including isolated reports.

From the nervous system common: headache, dizziness, increased fatigue, weakness, paresthesia; uncommon: depression, vivid dreams, confusion, insomnia; very rare: syncope, hallucinations, amnesia.

From the gastrointestinal tract common: nausea, constipation, diarrhea; uncommon: flatulence, dyspepsia, vomiting.

From the cardiovascular system uncommon: bradycardia, heart failure, AV block, orthostatic hypotension, peripheral circulation disorders (feeling of “cold” in the extremities, cyanosis), dyspnea, heart rhythm disorders, Raynaud’s syndrome, peripheral edema, cardialgia, worsening of chronic heart failure, pronounced decrease in blood pressure.

From the skin uncommon: skin rash of an erythematous nature, skin itching, skin hyperemia; very rare: worsening of psoriasis, alopecia; in some cases: angioedema.

From the respiratory system uncommon: bronchospasm (including in the absence of a history of obstructive pulmonary diseases), bronchospasm in patients with a history of bronchial asthma or airway obstruction.

Other photodermatosis, hyperhidrosis, vision disorders (dry eyes), sexual dysfunction.

Hydrochlorothiazide

Water-electrolyte imbalance

• Hypokalemia, hyponatremia, hypercalcemia and hypochloremic alkalosis: dry oral mucosa, feeling of thirst, irregular heart rhythm, lability of mood or psyche, convulsions and muscle pain, nausea, vomiting, unusual fatigue or weakness. Hypochloremic alkalosis can cause hepatic encephalopathy or hepatic coma;
• Hyponatremia: confusion, convulsions, slowed thinking process, increased fatigue, increased excitability, convulsions, lethargy.

Metabolic phenomena: hyperglycemia, glucosuria, hyperuricemia with exacerbation of gout.

Treatment with thiazides can reduce glucose tolerance and latent diabetes mellitus can manifest. When using high doses, serum lipid concentrations may increase.

From the digestive tract cholecystitis or pancreatitis, cholestatic jaundice, diarrhea, sialadenitis, constipation, anorexia.

From the cardiovascular system arrhythmias, orthostatic hypotension, vasculitis.

From the nervous system dizziness, temporary blurred vision, headache, paresthesia.

From the hematopoietic organs very rare: leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia.

Allergic reactions urticaria, purpura, necrotizing vasculitis, Stevens-Johnson syndrome, respiratory distress syndrome (including pneumonitis and non-cardiogenic pulmonary edema), photosensitivity, anaphylactic reactions up to shock.

Other decreased potency, impaired renal function, interstitial nephritis.

Contraindications

• Hypersensitivity to nebivolol or one of the components of the drug, as well as to other beta-blockers, hypersensitivity to hydrochlorothiazide and other sulfonamide derivatives;
• Severe liver dysfunction;
• Acute heart failure;
• Cardiogenic shock;
• Chronic heart failure in the stage of decompensation (requiring inotropic therapy);
• Sick sinus syndrome, including sinoatrial block;
• AV block II and III degree (without an artificial pacemaker);
• Severe forms of bronchial asthma and COPD;
• Pheochromocytoma (without simultaneous use of alpha-blockers);
• Depression;
• Metabolic acidosis;
• Bradycardia (heart rate less than 60 beats/min);
• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
• Severe peripheral circulation disorders (intermittent claudication, Raynaud’s syndrome);
• Age under 18 years (efficacy and safety have not been established);
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose);
• Simultaneous administration with floctafenine, sulpiride (see section Drug Interactions);
• Hypovolemia;
• Poorly controlled diabetes mellitus;
• Acute renal failure;
• Addison’s disease;
• Anuria, chronic renal failure (creatinine clearance less than 30 ml/min);
• Refractory hypokalemia, hyponatremia, hypercalcemia.

With caution

Nebivolol renal failure, liver dysfunction, diabetes mellitus, hyperthyroidism, history of bronchospasm episodes, history of allergic diseases (possible increase in sensitivity to allergens, worsening of allergic reactions and decrease in therapeutic response to epinephrine), psoriasis, first-degree AV block, Prinzmetal’s angina, COPD, in elderly patients (over 65 years), peripheral atherosclerosis, pheochromocytoma (during therapy with alpha-blockers).

Hydrochlorothiazide: first-degree AV block, coronary artery disease, hepatic failure, renal failure (creatinine clearance more than 30 ml/min), thyrotoxicosis, pheochromocytoma (during treatment with alpha-blockers), water-electrolyte disturbances (hyponatremia, hypokalemia, hypercalcemia), depression (including in history), myasthenia, gout, psoriasis, old age, simultaneous administration of cardiac glycosides.

Use in Pregnancy and Lactation

Nebivolol

During pregnancy, the drug is prescribed only for strict indications, when the benefit to the mother outweighs the risk to the fetus (due to the possible development of bradycardia, arterial hypotension, hypoglycemia and respiratory paralysis in the newborn). Treatment should be discontinued 48-72 hours before delivery. In cases where this is not possible, strict monitoring of the newborn should be provided for 48-72 hours after delivery.

There are no data on the excretion of nebivolol into breast milk. Therefore, the use of the drug is not recommended for women during breastfeeding. If the use of the drug Nebivolol during lactation is necessary, then breastfeeding should be discontinued.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier. The use of the drug is contraindicated in the first trimester of pregnancy. In the second and third trimesters of pregnancy, the drug can be prescribed only in case of urgent need, when the benefit to the mother outweighs the potential risk to the fetus and/or child. There is a risk of jaundice in the fetus or newborns, thrombocytopenia and other consequences.

Hydrochlorothiazide passes into breast milk, therefore, if the use of the drug is absolutely necessary, breastfeeding should be discontinued.

Special Precautions

Withdrawal of beta-blockers should be carried out gradually, over 10 days (up to 2 weeks in patients with coronary artery disease).

Control of blood pressure and heart rate at the beginning of the drug should be daily.

In elderly patients, control of renal function is necessary (once every 4-5 months).

In exertional angina, the selected dose of the drug should provide a resting heart rate within 55-60 beats/min, and under load 110 beats/min.

Patients using contact lenses should take into account that against the background of the use of beta-blockers, a decrease in the production of tear fluid is possible.

Nebivolol does not affect plasma glucose concentration in patients with diabetes mellitus. Nevertheless, caution should be exercised when treating these patients, since Nebivolol may mask certain symptoms of hypoglycemia (for example, tachycardia) caused by the use of hypoglycemic agents.

Control of plasma glucose concentration should be carried out once every 4-5 months (in patients with diabetes mellitus).

Beta-blockers should be used with caution in patients with COPD, as bronchospasm may increase.

In hyperfunction of the thyroid gland, the drug neutralizes tachycardia.

The effectiveness of beta-blockers in smokers is lower than in non-smoking patients.

Against the background of therapy with beta-blockers, an exacerbation of psoriasis is possible. Patients with this disease Nebilong H should be prescribed with caution.

During therapy with Nebilong H, it is necessary to control the indicators of the acid-base state and the content of electrolytes (potassium, sodium, calcium).

During long-term course treatment, it is necessary to carefully monitor the clinical symptoms of water-electrolyte imbalance, primarily in patients at increased risk: patients with cardiovascular diseases and impaired liver function; in case of severe vomiting or if signs of water-electrolyte imbalance appear, such as dry oral mucosa, feeling of thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, gastrointestinal complaints.

Hypokalemia can be avoided by using potassium-containing drugs or food rich in potassium (fruits, vegetables), especially in case of increased potassium loss (increased diuresis, prolonged treatment or simultaneous treatment with cardiac glycosides or corticosteroid drugs.

It has been shown that thiazides increase the excretion of magnesium by the kidneys: this can lead to hypomagnesemia.

In case of reduced renal function, control of creatinine clearance is necessary. In such patients, the drug can cause azotemia, and cumulative effects can also develop. If renal impairment is obvious, with the onset of oliguria, the possibility of drug withdrawal should be considered. In patients with impaired liver function or with progressive liver diseases, thiazides are prescribed with caution, since a slight violation of water-electrolyte balance, as well as the content of ammonium in the blood serum, can cause hepatic coma.

In patients with peripheral circulation disorders, caution should be exercised when prescribing Nebilong H.

Alcohol, barbiturates, narcotic drugs enhance the orthostatic hypotensive effect of thiazide diuretics.

Thiazides can reduce the amount of iodine bound to serum proteins without showing signs of thyroid dysfunction (due to hydrochlorothiazide).

Patients with pheochromocytoma should not be prescribed Nebilong H until treatment with alpha-blockers has been prescribed. In this case, blood pressure must be monitored. It is recommended to discontinue therapy with Nebilong H if depression develops caused by taking a beta-blocker (due to the nebivolol content in it). Special attention is required in cases of surgical intervention under general anesthesia in patients taking beta-blockers. Such patients should discontinue Nebilong H 48 hours before surgery, inform the anesthesiologist that the patient is taking Nebilong H. The agent for general anesthesia should be chosen with minimal negative inotropic action. In case of a history of anaphylactic reactions, regardless of the cause of their occurrence, especially when carrying out desensitizing therapy, treatment with Nebilong H (due to the nebivolol content in it) may increase the risk of allergic reactions and contribute to the development of resistance to treatment with epinephrine (adrenaline) in usual doses.

In patients with hyperuricemia, the risk of developing gout attack exacerbations is increased. In this case, the dose of the drug Nebilong N should be selected individually under the control of serum uric acid concentration. Before investigating parathyroid function, treatment with Nebilong N should be discontinued, as transient hypercalcemia may occur during its administration.

Effect on the ability to drive vehicles and mechanisms

During therapy, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Nebivolol

Symptoms pronounced decrease in BP, bradycardia, severe cardiac conduction disorders, shock, asystole, respiratory arrest, bronchospasm, loss of consciousness, convulsions, coma, nausea, vomiting, cyanosis, hypoglycemia, hyperkalemia.

Treatment gastric lavage, administration of activated charcoal. In case of a pronounced decrease in BP, the patient should be placed in a horizontal position with legs elevated; if necessary, intravenous administration of fluids or vasopressors.

For bradycardia, administer 0.5-2 mg of atropine intravenously; if there is no positive effect, placement of a transvenous or intracardiac artificial pacemaker is possible.

For AV block (II-III degree), intravenous administration of beta-adrenomimetics is recommended; if they are ineffective, the issue of placing an artificial pacemaker should be considered. For heart failure, treatment begins with the administration of cardiac glycosides and diuretics; if there is no effect, the administration of dopamine, dobutamine, or vasodilators is advisable. For bronchospasm, intravenous beta₂-adrenomimetics are administered.

For convulsions, intravenous administration of diazepam.

For ventricular extrasystole, lidocaine (class IA antiarrhythmic agents should not be administered).

Hydrochlorothiazide

The most noticeable manifestation of hydrochlorothiazide overdose is acute tachycardia, pronounced decrease in BP, shock, weakness, confusion, dizziness and calf muscle cramps, paresthesia, consciousness disorders, increased fatigue, nausea, vomiting, feeling of thirst, polyuria, oliguria or anuria (due to hemoconcentration), hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (especially in patients with renal failure).

Treatment there is no specific antidote.

Induction of vomiting, gastric lavage, administration of activated charcoal. In case of a pronounced decrease in BP or shock, the volume of circulating blood and electrolytes (potassium, sodium) should be replenished.

Control of water-electrolyte balance (especially serum potassium content) and renal function is necessary.

Drug Interactions

Nebivolol

Floctafenine in case of shock or arterial hypotension caused by floctafenine intake, beta-blockers weaken the compensatory mechanisms of the cardiovascular system.

Sultopride increased risk of ventricular arrhythmia, especially of the “torsades de pointes” type.

With simultaneous use of beta-blockers with slow calcium channel blockers (verapamil and diltiazem), the negative effect on myocardial contractility and AV conduction is enhanced. Intravenous administration of verapamil during nebivolol intake is contraindicated. With single use with antihypertensive agents, nitroglycerin, or slow calcium channel blockers, pronounced arterial hypotension may develop (special caution is necessary when combined with prazosin).

With simultaneous use with antiarrhythmic agents, the risk of cardiodepressive action and bradycardia increases when combined with any antiarrhythmic agent. With amiodarone, the risk of AV block also increases. The risk of ventricular arrhythmia caused by sotalol is increased by amiodarone, dronedarone, procainamide, and quinidine (avoid concomitant use).

With simultaneous use of nebivolol with cardiac glycosides, no enhancement of the effect on slowing AV conduction was detected.

Simultaneous use of nebivolol and drugs for general anesthesia can cause suppression of reflex tachycardia and increase the risk of arterial hypotension.

No clinically significant interaction between nebivolol and NSAIDs has been established. Acetylsalicylic acid as an antiplatelet agent can be used simultaneously with nebivolol.

Corticosteroids and estrogens, progestogens weaken the antihypertensive effect of beta-blockers.

Simultaneous use of tricyclic antidepressants, barbiturates, and phenothiazine derivatives, ethanol, anxiolytics, hypnotics can enhance the antihypertensive effect of nebivolol.

Allergens used for immunotherapy or allergen extracts for skin tests increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving Nebivolol.

Iodine-containing X-ray contrast agents for intravenous administration increase the risk of anaphylactic reactions.

Pharmacokinetic interaction

With simultaneous use with drugs that inhibit serotonin reuptake, or other agents biotransformed with the participation of CYP2D6 isoenzymes, the metabolism of nebivolol slows down, which may lead to a risk of bradycardia.

With simultaneous use, Nebivolol did not affect the pharmacokinetic parameters of digoxin.

With simultaneous use with cimetidine, the plasma concentration of nebivolol increases (data on the effect on the pharmacological effects of the drug are lacking). Simultaneous use of ranitidine did not affect the pharmacological parameters of nebivolol.

With simultaneous use of nebivolol with nicardipine, the plasma concentrations of the active substances increased somewhat, but this has no clinical significance.

Simultaneous intake of ethanol, furosemide, or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol.

No clinically significant interaction between nebivolol and warfarin has been established.

With simultaneous use, sympathomimetic agents suppress the activity of nebivolol.

With concomitant use of nebivolol with insulin and oral hypoglycemic agents, symptoms of hypoglycemia (tachycardia, tremor) may be masked.

Hydrochlorothiazide

Concomitant use with should be avoided

• Lithium salts (renal clearance of lithium decreases, its toxicity increases).

Use with caution with the following drugs:

• Antihypertensive drugs (their action is potentiated, dose adjustment may be necessary);
• Cardiac glycosides (hypokalemia and hypomagnesemia associated with the action of thiazide diuretics may enhance the toxicity of cardiac glycosides);
• Amiodarone (its use simultaneously with thiazide diuretics may lead to an increased risk of arrhythmias associated with hypokalemia);
• Oral hypoglycemic agents (their effectiveness decreases, hyperglycemia may develop);
• Corticosteroid agents, calcitonin (increase the degree of potassium excretion);
• NSAIDs (may weaken the diuretic and antihypertensive action of thiazides);
• Non-depolarizing muscle relaxants (their effect may be enhanced);
• Amantadine (the clearance of amantadine may be reduced by hydrochlorothiazide, leading to an increase in amantadine plasma concentration and possible toxicity);
• Cholestyramine, which reduces the absorption of hydrochlorothiazide;
• Ethanol, barbiturates, and narcotic agents, which increase the risk of orthostatic hypotension.

Storage Conditions

In a place protected from light, at a temperature not exceeding 25°C (77°F). Store out of the 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.