Nebirol Chinese Description

Indications and usage

hypertension

BYSTOLIC is indicated for the treatment of hypertension and lowering blood pressure [see Clinical Studies (14.1)]. BYSTOLIC can be used alone or in combination with other antihypertensive drugs.

Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, mainly stroke and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a variety of pharmacological classes, including the categories to which the drug primarily belongs. No controlled trials have shown that BYSTOLIC reduces risk.

Controlling hypertension should be part of a comprehensive cardiovascular risk management, including proper lipid management, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients need more than one drug to reach their blood pressure goals. For specific recommendations on goals and management, please refer to published guidelines such as the United Nations Home Prevention, Testing, Assessment and Hypertension Treatment Committee (JNC) guidelines for the National Hypertension Education Program.

Many antihypertensive drugs, from a variety of pharmacological classes, have different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and can conclude that it is a drop in blood pressure, not Some other pharmacological properties. The drug is primarily responsible for these benefits. The greatest and most consistent cardiovascular outcome benefit is reduced stroke risk, but myocardial infarction and cardiovascular mortality are often seen.

An increase in systolic or diastolic blood pressure leads to an increase in cardiovascular risk and an increased absolute risk per mmHg when blood pressure rises, so even a modest reduction in severe hypertension can provide substantial benefits. In people with different absolute risks, the relative risk reduction of blood pressure reduction is similar, so the absolute benefit of patients who are at higher risk of hypertension (eg, patients with diabetes or hyperlipidemia) is greater, And such patients will be expected to benefit from more aggressive treatments to lower blood pressure goals.

Some antihypertensive drugs have a lower blood pressure effect in black patients (as monotherapy), and many antihypertensive drugs have additional approved indications and effects (eg, for angina, heart failure, or diabetic nephropathy). These considerations can guide the choice of treatment.

Dosage and administration

hypertension

The dose of BYSTOLIC must be personalized according to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, monotherapy or in combination with other drugs. For patients who need to further lower their blood pressure, the dose can be increased to 40 mg at 2 week intervals. More frequent dosing regimens are unlikely to be beneficial.

Renal insufficiency

In patients with severe renal insufficiency (ClCr less than 30 mL / min), the recommended initial dose is 2.5 mg per day; if necessary, slowly titrate. The BYSTOLIC study has not been performed on patients undergoing dialysis [see Clinical Pharmacology (12.4)].

Liver damage

In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg per day; if necessary, slowly titrate. BYSTOLIC has not been studied in patients with severe liver damage and is therefore not recommended for use in this population [see Clinical Pharmacology (12.4)].

Subgroup

Elderly patients

There is no need to adjust the dose of the elderly [see Use in Special Populations (8.5)].

CYP2D6 polymorphism

For patients with poor CYP2D6 metabolism, there is no need to adjust the dose. The clinical effects and safety observed in patients with poor metabolism are similar to those of a wide range of metabolizers [see Clinical Pharmacology (12.3)].

Dosage form and strength

BYSTOLIC can be used as a tablet for oral administration, containing nebivolol hydrochloride equivalent to 2.5, 5, 10 and 20 mg of nebivolol.

BYSTOLIC tablets are triangular, biconvex, unnotched, and of different colors, with "FL" engraved on one side and mg (21⁄2, 5, 10 or 20) on the other side.

Contraindications

BYSTOLIC is disabled in the following situations:

Severe bradycardia

Heart block is greater than one degree

Cardiogenic shock patient

Decompensated heart failure

Sick sinus syndrome (unless there is a permanent pacemaker)

Patients with severe liver damage (Child-Pugh> B)

A patient who is allergic to any component of this product.

Warnings and precautions

Suddenly stop treatment

Do not suddenly stop BYSTOLIC treatment in patients with coronary artery disease. After sudden discontinuation of treatment with beta blockers, patients with coronary artery disease have reported severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias. Myocardial infarction and ventricular arrhythmias can occur with or without prior deterioration of angina. Be careful not to interrupt or suddenly stop treatment in patients without significant coronary artery disease. As with other beta blockers, when planning to discontinue BYSTOLIC, carefully observe and advise patients to minimize physical activity. If possible, gradually reduce BYSTOLIC for 1 to 2 weeks. If angina worsens or acute coronary insufficiency develops, restart BYSTOLIC immediately, at least temporarily.

Angina pectoris and acute myocardial infarction

BYSTOLIC has not been studied in patients with angina or recent myocardial infarction.

Bronchospasm

In general, patients with bronchospasm should not receive beta-blockers.

Anesthesia and major surgery

Because withdrawal of beta blockers is associated with an increased risk of MI and chest pain, patients who have taken beta blockers should generally continue treatment throughout the perioperative period. If BYSTOLIC continues to be used during the perioperative period, patients are closely monitored when using anesthetics that inhibit myocardial function, such as diethyl ether, cyclopropane, and trichloroethylene. If the beta-blocking therapy is withdrawn prior to major surgery, impaired cardiac responsiveness to reflex adrenergic stimulation may increase the risk of general anesthesia and surgery.

The beta-blocking effect of BYSTOLIC can be reversed by beta-agonists such as dobutamine or isoproterenol. However, these patients may suffer from persistent severe hypotension. In addition, beta blockers have been reported to be difficult to restart and maintain heartbeat.

Diabetes and hypoglycemia

Beta-blockers may mask some of the symptoms of hypoglycemia, especially tachycardia. Non-selective beta blockers may potentiate insulin-induced hypoglycemia and delay recovery of blood glucose levels. It is not clear whether nebivolol has these effects. Patients with spontaneous hypoglycemia and diabetics receiving insulin or oral hypoglycemic agents are advised to understand these possibilities.

Thyrotoxicosis

Beta blockers may mask the clinical symptoms of hyperthyroidism, such as tachycardia. Sudden withdrawal of beta blockers may lead to worsening symptoms of hyperthyroidism or may lead to thyroid storms.

Peripheral vascular disease

Beta-blockers can cause or aggravate the symptoms of arterial insufficiency in patients with peripheral vascular disease.

Non-dihydropyridine calcium channel blocker

Because patients treated with beta blockers and verapamil and diltiazem calcium channel blockers have significant negative inotropic and chronotropic effects, monitoring ECG and patients treated with these drugs simultaneously blood pressure.

Used with CYP2D6 inhibitors

Nebivolol exposure increases with inhibition of CYP2D6 [see Drug Interactions (7)]. It may be necessary to reduce the dose of BYSTOLIC.

Impaired renal function

Nebilol's renal clearance was reduced in patients with severe renal insufficiency. The BYSTOLIC study has not been performed on patients undergoing dialysis [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)].

Impaired liver function

Nebirolol metabolism is reduced in patients with moderate hepatic impairment. The BYSTOLIC study has not been performed on patients with severe liver damage [see Clinical Pharmacology (12.4) and Dosage and Administration (2.1)].

Risk of allergic reactions

While taking beta-blockers, patients with a history of severe allergic reactions to various allergies may be more responsive to repeated accident, diagnosis or treatment challenges. These patients may not respond to the usual adrenaline dose used to treat allergic reactions.

Pheochromocytoma

In patients with known or suspected pheochromocytoma, alpha-blockers are initiated prior to the use of any beta blockers.

Adverse reactions

Clinical research experience

BYSTOLIC has been evaluated as safe for patients with hypertension and heart failure. The observed adverse reaction characteristics were consistent with the pharmacology of the drug and the health of the patient in the clinical trial. Adverse reactions reported for each of these patient populations are provided below. Adverse reactions that are considered too general to provide information and adverse reactions unrelated to the use of the drug are not included as they are associated with the condition being treated or are very common in the treated population.

The data described below reflects the global clinical trial exposure of BYSTOLIC in 6545 patients, including 5,038 patients receiving hypertension therapy and the remaining 1507 patients receiving other cardiovascular disease treatments. The dosage range is from 0.5 mg to 40 mg. Patients were treated with BYSTOLIC for up to 24 months, more than 1,900 patients were treated for at least 6 months, and approximately 1,300 patients were treated for more than one year.

Hypertension: In a placebo-controlled clinical trial comparing BYSTOLIC with placebo, it was reported that 2.8% of patients treated with nebivolol discontinued treatment, and adverse effects treatment discontinued treatment, compared with 2.2% in the placebo group. The most common adverse reactions leading to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Table 1 lists the treatment-induced adverse effects reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients receiving 5 mg, 10 mg or 20-40 mg BYSTOLIC and 205 receiving placebo Patient. The incidence was at least 1% in patients treated with nebivolol and was higher in at least one dose group than in patients treated with placebo.

Laboratory abnormality

In a controlled monotherapy trial of hypertensive patients, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides, and a decrease in HDL cholesterol and platelet counts.

Post-marketing experience

The following adverse reactions were found in BYSTOLIC's spontaneous reports received globally and were not listed elsewhere. These adverse effects were chosen due to the combination of severity, reporting frequency or potential causal relationship with BYSTOLIC. Adverse reactions common in the population are generally omitted. Since these adverse reactions are voluntarily reported by people of uncertain size, it is not possible to estimate the frequency or causal relationship with BYSTOLIC exposure: abnormal liver function (including elevated AST, ALT and bilirubin), acute pulmonary edema , acute kidney failure, atrioventricular block (second and third), bronchospasm, erectile dysfunction, allergies (including urticaria, allergic vasculitis and rare angioedema), hypotension, myocardial infarction, Itching, psoriasis, Raynaud's phenomenon, peripheral ischemia / lameness, lethargy, syncope, thrombocytopenia, various rashes and skin diseases, dizziness and vomiting.

medicine interactions

CYP2D6 inhibitor

When BYSTOLIC and CYP2D6 inhibitors (Quinidine, propafenone,Fluoxetine, paroxetine, etc.) be careful when co-administered [see Clinical Pharmacology (12.5)].

Hypotension drug

Do not use BYSTOLIC with other beta blockers. Patients with catecholamine-depleting drugs (such as reserpine or guanethidine) are closely monitored because the increased beta-blocking effect of BYSTOLIC may result in an excessive reduction in sympathetic activity. In patients receiving BYSTOLIC and clonidine, BYSTOLIC was discontinued for a few days before the gradual reduction of clonidine.

Digitalis glycosides

Both digitalis glycosides and beta-blockers slow down atrioventricular conduction and reduce heart rate. Simultaneous use increases the risk of bradycardia.

Calcium channel blocker

BYSTOLIC can aggravate the effects of myocardial inhibitors or AV-conducting inhibitors, such as certain calcium antagonists (especially phenylalkylamines [vilapamil] and benzothiazepines [diltiazem]), or anti-heart rhythm An abnormal drug, such as propiamine.

For a specific group of people

pregnancy

Risk summary

The available data on the use of BYSTOLIC in pregnant women is not sufficient to determine if there is a risk of adverse developmental outcomes associated with the drug. Poor control of hypertension during pregnancy leads to a risk to the mother and the fetus. The use of beta blockers during the third trimester of pregnancy may increase the risk of neonatal hypotension, bradycardia, hypoglycemia and respiratory depression [see clinical considerations]. Oral administration of nebivolol to pregnant mice during organogenesis results in fetal fetal and perinatal mortality rates approximately equal to the maximum recommended human dose (MRHD).

The estimated background risk of major birth defects and abortions in the current population is unclear. In the US general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical considerations

Maternal and/or embryo/fetal risk associated with disease Pregnancy hypertension increases the risk of pre-pregnancy pre-eclampsia, gestational diabetes, premature birth and childbirth complications such as cesarean section and postpartum hemorrhage. Hypertension increases the risk of intrauterine growth restriction and intrauterine death. Pregnant women with high blood pressure should be carefully monitored and managed.

Fetal/neonatal adverse reactions

Neonates with hypertensive women who are treated with beta blockers during the third trimester of pregnancy may have an increased risk of hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe whether the newborn has hypotension, bradycardia, hypoglycemia and respiratory depression, and deal with it accordingly.

data

Animal data

Nebivolol showed an increase in embryonic fetal-fetal and perinatal mortality of approximately 1.2-fold or 40 mg/day (mg/m2) of MRHD. At the time of perinatal (late pregnancy, childbirth and lactation) exposure, the rats lost 1.25 and 2.5 mg / kg. At 5 mg / kg and higher doses (1.2 times MRHD), prolonged pregnancy, dystocia and reduced maternal care, correspondingly increased late fetal death and stillbirth, and reduced birth weight, live births And the survival rate of the pups. These events occur only during the perinatal period (late pregnancy, childbirth and lactation) when nebibilol is administered. There were not enough pups to survive at 5 mg/kg to assess the reproductive performance of the offspring.

Fetal weight loss, sternal and thoracic vertebrae were observed in maternal toxic doses of 20 and 40 mg / kg / day (5 and 10 times MRHD) in the study of nebibilol in pregnant rats during organogenesis. The reversibility delay is small. At 40 mg / kg / day (10 times MRHD), the fetus lost weight and the resorption increased little.

In the study of the pregnant rabbits in which the nebivolol was administered at doses up to 20 mg/kg/day, no adverse effects on embryonic-fetal survival, sex, body weight or morphology were observed (10-fold MRHD).

Lactation

Risk summary

There is no information on the effects of nebivolol in human milk on breast-fed infants or on milk production. Nebivolol is present in mouse milk [see data]. Since beta blockers may cause serious adverse reactions in lactating infants, especially bradycardia, BYSTOLIC is not recommended during care.

data

In lactating rats, the maximum milk level of unaltered nebivolol was observed 4 hours after a single and repeated dose of 2.5 mg / kg / day. For unaltered nebivolol, the daily dose (mg/kg body weight) taken by the rat pups was 0.3% of the high dose.

Pediatric medication

The safety and efficacy of pediatric patients have not been determined. Pediatric studies from neonates to 18 years of age have not been conducted because developmental toxicity is incomplete and may have adverse effects on long-term fertility [see Nonclinical Toxicology (13.1)].

Juvenile animal toxicity data

From day 14 after birth to day 27 post-natal, daily oral doses of nebivolol showed a sudden unexplained death on young rats at the time of exposure, comparable to a single dose of 10 mg of human metabolizer. No mortality was seen in half of the adult exposure.

Cardiac disease was observed in surviving rats exposed to greater than or equal to human exposure. Male rats exposed to twice as much human exposure showed a decrease in total sperm count and a decrease in the total number and percentage of active sperm.

Elderly use

The safety and efficacy of pediatric patients have not been determined. Pediatric studies from neonates to 18 years of age have not been conducted because developmental toxicity is incomplete and may have adverse effects on long-term fertility [see Nonclinical Toxicology (13.1)].

Juvenile animal toxicity data

From day 14 after birth to day 27 post-natal, daily oral doses of nebivolol showed a sudden unexplained death on young rats at the time of exposure, comparable to a single dose of 10 mg of human metabolizer. No mortality was seen in half of the adult exposure.

Cardiac disease was observed in surviving rats exposed to greater than or equal to human exposure. Male rats exposed to twice as much human exposure showed a decrease in total sperm count and a decrease in the total number and percentage of active sperm.

Elderly use

In clinical trials and post-marketing experience, there have been reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdose are bradycardia and hypotension. Other important adverse effects of BYSTOLIC overdose include heart failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse effects associated with excess beta blockers include bronchospasm and heart block.

The world's largest known BYSTOLIC intake includes a patient who has taken up to 500 mg of BYSTOLIC and several tablets of 100 mg of acetylsalicylic acid tablets at the time of suicide. The patient developed hyperhidrosis, paleness, low levels of consciousness, decreased motor function, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Hemodialysis is not expected to enhance the clearance of nebivolol due to the combination of a wide range of drugs with plasma proteins.

If overdose occurs, please provide general supportive and specific symptomatic treatment. Based on the expected drug effects and recommendations for other beta blockers, consider the following general measures when clinically warranted, including stopping BYSTOLIC:

Bradycardia: intravenous atropine. If the reaction is not sufficient, isoproterenol or other agents with positive chronotropic properties can be administered with caution. In some cases, a transthoracic or transvenous pacemaker may be required.

Hypotension: Intravenous infusion and vasopressor are given. Intravenous glucagon may be useful.

Cardiac block (secondary or tertiary): Monitoring and treatment with isoproterenol infusion. In some cases, a transthoracic or transvenous pacemaker may be required.

Congestive heart failure: treatment with digitalis glycosides and diuretics. In some cases, consider using contractile forces and vasodilators.

Bronchospasm: Treatment with a bronchodilator, such as a short-acting inhaled beta2-agonist and/or aminophylline.

Hypoglycemia: Give intravenous glucose. Repeated doses of IV glucose or possibly glucagon may be required. Support measures should continue to be taken until clinical stability is achieved. The half-life of low dose nebivolol is 12-19 hours.

Description

The chemical name of the active ingredient in BYSTOLIC tablets is (1RS, 1'RS)-1,1' – [(2RS, 2'SR)bis(6-fluoro-3,4-dihydro-2H -1) - benzopyran-2-yl)]-2,2'-iminodiethanol hydrochloride. Nebivolol is a racemate consisting of d-nabirolol and 1-nabirol, which have the stereochemical names of [SRRR] – nebivolol and [RSSS] nebivolol, respectively. The molecular formula of nebivolol is (C22H25F2NO4•HCl) and the structural formula is as follows:

Nebivolol hydrochloride is a white to almost white powder, soluble in methanol, dimethyl sulfoxide and N,N-dimethylformamide, slightly soluble in ethanol, propylene glycol and polyethylene glycol, very small Soluble in hexane, dichloromethane and toluene.

BYSTOLIC as an oral tablet contains nebivolol hydrochloride equivalent to 2.5, 5, 10 and 20 mg of nebivolol base. In addition, BYSTOLIC contains the following inactive ingredients: colloidal silica, croscarmellose sodium, D&C Red#27 Lake, FD&C Blue#2 Lake, FD&C Yellow#6 Lake, hypromellose, lactose monohydrate , magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate.

Clinical pharmacology

Nebivolol is a beta-adrenergic receptor blocker. In a wide range of metabolizers (most populations) and at doses less than or equal to 10 mg, nebivolol is preferably β1 selective. In poorer metabolizers and higher doses, nebivolol inhibits β1 – and β2 – adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, BYSTOLIC does not exhibit alpha1-adrenergic receptor blocking activity. Various metabolites including glucuronide contribute to β-blocking activity.

Action mechanism

The mechanism of action of BYSTOLIC in antihypertensive response has not been clearly established. Possible factors include:

(1) Heart rate is reduced,

(2) myocardial contractility decreases,

(3) The cerebral vasomotor center has less tonic sympathetic efflux,

(4) inhibition of renin activity and

(5) Vasodilation and reduction of peripheral vascular resistance.

12.3 Pharmacokinetics

Nebivolol is metabolized by a variety of pathways including glucuronidation and hydroxylation of CYP2D6. The active isomer (d-nabirolol) has an effective half-life of approximately 12 hours in the CYP2D6 extensive metabolizer (most people) and is poorly exposed in the case of poor metabolism for 19 hours and in d-nebivolol Significant increase in metabolizers. However, this is less important than usual because metabolites, including hydroxy metabolites and glucuronide (the major circulating metabolite), contribute to beta-blocking activity.

For doses up to 20 mg, plasma levels of d-nabilol increased proportionally to doses in EMs and PM. Exposure to l-nebivolol is higher than d-nebivolol, but l-nebivolol contributes little to the activity of the drug because the β-receptor affinity of d-nebivolol is 1000-fold higher than that of l-nebivolol. For the same dose, PM is 10 times higher than the Cmax of D-Nebivolol, and AUC is 10 times higher than EMs. d-Nebivolol accumulates approximately 1.5 times and is administered once daily in EMs.

absorb

The absorption of BYSTOLIC is similar to oral solutions. Absolute bioavailability has not been determined. The mean peak plasma nebivolol concentration occurred approximately 1.5 to 4 hours after administration in EMs and PM. Food does not alter the pharmacokinetics of nebivolol. Under the eating conditions, nebivolol glucuronide was slightly reduced. BYSTOLIC can be carried out without considering the diet.

distribution

The in vitro human plasma protein binding of nebivolol is about 98%, mainly albumin, and is independent of the concentration of nebivolol.

metabolism

Nebivolol is primarily metabolized by direct glucuronidation of the parent and, to a lesser extent, by N-dealkylation and by cytochrome P450 2D6. Its stereospecific metabolites contribute to pharmacological activity [see Drug Interactions (7)].

eliminate

After a single oral administration of 14C-nepirol, 38% of the dose was recovered in urine, 44% of the EMs in the feces and 67% of the urine and 13% of the PMs in the feces. Essentially all nebivolol is excreted as a plurality of oxidative metabolites or their corresponding glucuronide conjugates.

Pharmacokinetics of special populations

Liver disease

The peak plasma concentration of d-Nebivolol was increased by a factor of 3, the exposure (AUC) was increased 10-fold, and the apparent clearance of patients with moderate hepatic impairment was reduced by 86% (Child-Pugh grade B). There were no formal studies of patients with severe liver damage, and nebivolol was banned in these patients [see Dosage and Administration (2.1)].

Kidney disease

After a single dose of BYSTOLIC in patients with mild renal insufficiency (ClCr 50 to 80 mL / min, n = 7), the apparent clearance of nebivolol did not change and was moderate Patients (ClCr 30 to 50 mL) were negligible / min, n = 9), but clearance for patients with severe renal insufficiency (ClCr <30 mL / min, n = 5) was reduced by 53%. No studies have been performed on dialysis patients [see Dosage and Administration (2.1)].

medicine interactions

It is expected that drugs that inhibit CYP2D6 will increase the plasma levels of nebivolol. When BYSTOLIC is administered with an inhibitor or inducer of the enzyme, the patient is closely monitored and the nebivolol dose is adjusted according to the blood pressure response. In vitro studies have demonstrated that d- and l- nebivolol do not inhibit any cytochrome P450 pathway at therapeutically relevant concentrations.

Digoxin: BYSTOLIC (10 mg per day) and digoxin (0.25 mg once daily) were administered to 14 healthy adult individuals for 10 days, resulting in no significant pharmacokinetics of digoxin or nebivolol. Change [see drug interactions (7)].

Warfarin: BYSTOLIC (10 mg once daily for 10 days) resulted in no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin after a single 10 mg dose of warfarin . Similarly, nebivolol had no significant effect on the anticoagulant activity of warfarin, such as prothrombin time and INR curves from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers. Assessed.

Diuretics: In healthy adults, nebivolol (10 mg daily for 10 days) and furosemide (40 mg single dose), hydrochlorothiazide (25 mg once daily for 10 days) orSpironolactone(25 mg once daily for 10 days) no pharmacokinetic interactions were observed).

Ramipril: BYSTOLIC (10 mg per day) and ramipril (5 mg once daily) were administered to 15 healthy adult volunteers for 10 days without producing pharmacokinetic interactions.

Losartan: Simultaneous administration of BYSTOLIC (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions.

FluoxetineA CYP2D6 inhibitor administered to 10 healthy adults at a dose of 10 mg of nebivolol, 20 mg per day for 21 days, resulting in an 8-fold increase in AUC and a 3-fold increase in Cmax. Nebivolol [see drug interactions (7)].

Histamine-2 Receptor Antagonist: The pharmacokinetics of nebivolol (5 mg single dose) was not affected by co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) resulted in a 23% increase in plasma levels of d-nabilolol.

Charcoal: The pharmacokinetics of nebivolol (10 mg single dose) was not subject to repeated co-administration (4, 8, 12, 16, 22, 28, 36 and 48 hours after nebivolol administration) of activated carbon ( The impact of Actidose-Aqua®).

Sildenafil: The combination of nebivolol and sildenafil reduced the AUC and Cmax of sildenafil by 21% and 23%, respectively. The effect on Cmax and AUC of d-nabilolol is also small (<20%). The effect on vital signs (such as pulse and blood pressure) is approximately the sum of the effects of sildenafil and nebivolol.

Other concomitant drugs: Using population pharmacokinetic analysis from hypertensive patients, the following drugs were observed to have no effect on the pharmacokinetics of nebivolol: acetaminophen, acetylsalicylic acid, atorvastatin, angstrom Someprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol.

Protein binding: in high concentrations of diazepam, digoxin, diphenylhydantoin, enalapril, hydrochlorothiazide, imipramine, indomethacin, propranolol, sulfamethazine, tolbutamide Or in the presence of warfarin, it was noted that there was no significant change in the in vitro binding of nebivolol to human plasma proteins. . In addition, nebivolol did not significantly alter the protein binding of the following drugs: diazepam, digoxin, diphenylhydantoin, hydrochlorothiazide, imipramine or warfarin.

Nonclinical toxicology

Carcinogenic, mutagenic, impaired fertility

In a two-year study of the nebivolol mouse, a statistically significant increase in testicular Leydig cell proliferation and adenoma incidence was observed at 40 mg / kg / day (maximum recommended human dose was 40 mg / mg) / m2 5 times) basis). No similar findings were reported in mice given a dose equal to about 0.3 or 1.2 times the maximum recommended human dose. No evidence of tumorigenic effects was observed in a 24-month study of Wistar rats receiving a dose of nebivolol at 2.5, 10 and 40 mg / kg / day (equivalent to 0.6, 2.4 and 10 times the maximum recommended human dose) . Co-administration of dihydrotestosterone reduced blood LH levels and prevented Leydig cell proliferation, consistent with the indirect LH-mediated effects of nebivolol in mice and not considered clinically relevant in humans.

A randomized, double-blind, placebo-controlled, and active-controlled, parallel-group study was conducted in healthy male volunteers to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. The study showed that 6 mg of nebivolol administered daily for 6 weeks had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH or serum total testosterone.

The effect on spermatogenesis was observed in male rats and mice ≥ 40 mg/kg/day (10-fold and 5-fold, respectively, of MRHD). For rats, the effect on spermatogenesis was not reversed and may worsen during four weeks of recovery. However, the effect of nebivolol on mouse sperm is partially reversible.

Mutagenesis: Nebivolol was tested for genotoxicity in a series of tests (Ames, in vitro mouse lymphoma TK + /, human peripheral lymphocyte chromosomal aberrations in vitro, Drosophila chain-linked recessive lethality, and mouse bone marrow micronucleus test in vivo) ).

Clinical research

hypertension

The antihypertensive efficacy of BYSTOLIC as a monotherapy has been demonstrated in three randomized, double-blind, multicenter, placebo-controlled trials ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2 and 3). A fourth placebo-controlled trial demonstrated that when patients with inadequate blood pressure control take up to two other antihypertensive drugs (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics), BYSTOLIC The dose range is 5 to 20 mg with additional antihypertensive effects. .

Three monotherapy trials were included in 2016 patients (1811 BYSTOLIC, 205 placebo) with mild to moderate hypertension and a baseline diastolic blood pressure (DBP) of 95 to 109 mmHg. Patients received BYSTOLIC or placebo once a day for 12 weeks. Two of the monotherapy trials (Studies 1 and 2) studied 1716 patients with general hypertension, with an average age of 54 years, 55% of men, 26% of non-Caucasians, 7% of diabetics, and 6% of genotypes were PMs. The third monotherapy trial (Study 3) studied 300 black patients with an average age of 51 years, 45% male, 14% diabetic, and 3% PM.