TEMERIT

Nebivolol is a racemic mixture of 2 enantiomers where one is a beta adrenergic antagonist and the other acts as a cardiac stimulant without beta adrenergic activity.

Treatment with nebivolol leads to a greater decrease in systolic and diastolic blood pressure than atenolol, propranolol, or pindolol.

Nebivolol and other beta blockers are generally not first line therapies as many patients are first treated with thiazide diuretics.

Nebivolol was granted

FDA approval on 17 December 2007.

Nebivolol is indicated to treat hypertension. 1, 2, 9,

Nebivolol is a selective beta-1 adrenergic receptor antagonist that decreases vascular resistance, increases stroke volume and cardiac output, and does not negatively affect left ventricular function. 2, 3 It has a long duration of action as effects can be seen 48 hours after stopping the medication and a wide therapeutic window as patients generally take 5-40 mg daily. 2, 9 Patients should not abruptly stop taking this medication as this may lead to exacerbation of coronary artery disease.

Diabetic patients should monitor their blood glucose levels as beta blockers may mask signs of hypoglycemia.

The absorption of nebivolol is not affected by food.

Nebivolol has a

T max of 1.5-4 hours.

Bioavailability can range from 12-96% for extensive to poor CYP2D6 metabolizers. 6, 7 For a 20 mg dose, d-nebivolol has a C max of 2.75±1.55ng/mL, l-nebivolol has a C max of 5.29±2.06ng/mL, both enantiomers have a C max of 8.02±3.47ng/mL, and nebivolol glucuronides have a C max of 68.34±44.68ng/mL.

For a 20 mg dose, d-nebivolol has an AUC of 13.78±15.27ngh/mL, l-nebivolol has an AUC of 27.72±15.32ngh/mL, both enantiomers have an AUC of 41.50±29.76ngh/mL, and nebivolol glucuronides have an AUC of 396.78±297.94ngh/mL.

For a 20 mg dose, d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72 L, l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50 L, and both enantiomers together have a volume of distribution of 10,423.42±6796.50 L.

Nebivolol is metabolized mainly by glucuronidation and CYP2D6 mediated hydroxylation. 1, 4 Metabolism involves n-dealkylation, hydroxylation, oxidation, and glucuronidation.

Aromatic hydroxyl and acyclic oxide metabolites are active, while n-dealkylated and glucuronides are inactive.

Hover over products below to view reaction partners Nebivolol 4-hydroxy Nebivolol.

In extensive

CYP2D6 metabolizers, 38% is eliminated in the urine and 44% in the feces.

In poor

CYP2D6 metabolizers, 67% is eliminated in the urine and 13% in the feces. 9 <1% of a dose is excreted as the unmetabolized drug.

d-nebivolol has a half life of 12 hours in CYP2D6 extensive metabolizers and 19 hours in poor metabolizers. 5, 9.

For a 20 mg dose, the clearance of d-nebivolol is 1241.63±749.77 L/h, l-nebivolol is 435.53±180.93 L/h, and both enantiomers is 635.31±300.25 L/h.

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Patients experiencing an overdose may present with bradycardia, hypotension, cardiac failure, dizziness, hypoglycemia, fatigue, vomiting, bronchospasm and heart block.

Treat overdose with general supportive measures including intravenous atropine for bradycardia, vasopressors and intravenous fluids for hypotension, isoproterenol infusion for heart block, digitalis glycosides and diuretics for congestive heart failure, bronchodilators for bronchospasm, and intravenous glucose for hypoglycemia.

Nebivolol Tablets is contraindicated in the following conditions: Severe bradycardia Heart block greater than first degree Patients with cardiogenic shock Decompensated cardiac failure Sick sinus syndrome (unless a permanent pacemaker is in place) Patients with severe hepatic impairment (Child-Pugh >B) Patients who are hypersensitive to any component of this product.

Severe bradycardia Heart block greater than first degree Patients with cardiogenic shock Decompensated cardiac failure Sick sinus syndrome (unless a permanent pacemaker is in place) Patients with severe hepatic impairment (Child-Pugh >B) Hypersensitive to any component of this product.

Can be taken with and without food.

Individualize to the needs of the patient and monitor during up-titration.

Most patients start at 5 mg once daily.

Dose can be increased at 2-week intervals up to 40 mg. 2.1 Hypertension The dose of nebivolol tablets must be individualized to the needs of the patient.

For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents.

For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.

Nebivolol tablets have not been studied in patients receiving dialysis.

In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed.

Nebivolol tablets have not been studied in patients with severe hepatic impairment and Therefore it is not recommended in that population. 2.2 Subpopulations Geriatric Patients It is not necessary to adjust the dose in the elderly.

CYP2D6 Polymorphism No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers.

The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers.

Nebivolol is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 10 mg of nebivolol.

Nebivolol tablets are white to off white,round, biconvex, unscored tablet debossed with "C52"(for 10 mg) on one side and plain on the other side.

NDC: 72162-2414-3: 30 Tablets in a BOTTLE NDC: 72162-2414-9: 90 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) .

Dispense in a tight,light-resistant containerasdefinedintheUSPusing a child-resistant closure.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Available data regarding use of nebivolol tablets in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes.

There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy.The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate.

Oral administration of nebivolol to pregnant rats during organogenesis resulted in embryofetal and perinatal lethality at doses approximately equivalent to the maximum recommended human dose (MRHD).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal adverse reactions Neonates of women with hypertension, who are treated with beta-blockers during the third trimester of pregnancy, may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression.

Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly.

Nebivolol was shown to increase embryo-fetal and perinatal lethality in rats at approximately 1.2 times the MRHD or 40 mg/day on a mg/m 2 basis.

Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation).

At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival.

These events occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).

Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD).

No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Safety and effectiveness in pediatric patients have not been established.

Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility.

Daily oral doses of nebivolol to juvenile rats from post-natal day to post-natal day 27 showed sudden unexplained death at exposures equal to those in human poor metabolizers given a single dose of 10 mg. No mortality was seen at half the adult human exposure.

In surviving rats, cardiomyopathy was seen at exposures greater than or equal to the human exposure.

Male rat pups exposed to twice the human exposure showed decreases in total sperm count as well as decreases in the total and percentage of motile sperm.

Of the 2,800 patients in the U.S. sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older.

No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.