Nebivolol (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m 2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC 0-120 min , serum LH, or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at ≥ 40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible.

Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/- , in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

14 CLINICAL STUDIES

14.1 Hypertension

The antihypertensive effectiveness of nebivolol as monotherapy has been demonstrated in three randomized, double-blind, multi-center, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2, and 3). A fourth placebo-controlled trial demonstrated additional antihypertensive effects of nebivolol at doses ranging from 5 to 20 mg when administered concomitantly with up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) in patients with inadequate blood pressure control.

The three monotherapy trials included a total of 2016 patients (1811 nebivolol tablets, 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg. Patients received either nebivolol tablets or placebo once daily for twelve weeks. Two of these monotherapy trials (Studies 1 and 2) studied 1716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as PMs. The third monotherapy trial (Study 3) studied 300 Black patients with a mean age of 51 years, 45% males, 14% diabetics, and 3% as PMs.

Placebo-subtracted blood pressure reductions by dose for each study are presented in Table 2. Most studies showed increasing response to doses above 5 mg.

Table 2. Placebo-Subtracted Least-Square Mean Reductions in Trough Sitting Systolic/Diastolic Blood Pressure (SiSBP/SiDBP mmHg) by Dose in Studies with Once Daily Nebivolol Tablets

Nebivolol dose (mg)

1.25

2.5

5.0

10

20

30-40

Study 1

-6.6*/-5.1*

-8.5*/-5.6*

-8.1*/-5.5*

-9.2*/-6.3*

-8.7*/-6.9*

-11.7*/-8.3*

Study 2

-3.8/-3.2*

-3.1/-3.9*

-6.3*/-4.5*

Study 3

-1.5/-2.9

-2.6/-4.9*

-6.0*/-6.1*

-7.2*/-6.1*

-6.8*/-5.5*

Study 4 ^

-5.7*/-3.3*

-3.7*/-3.5*

-6.2*/-4.6*

* p<0.05 based on pair-wise comparison vs. placebo
Study enrolled only African Americans.
^ Study on top of one or two other antihypertensive medications.

Study 4 enrolled 669 patients with a mean age of 54 years, 55% males, 54% Caucasians, 29% Blacks, 15% Hispanics, 1% Asians, 14% diabetics, and 5% PMs. Nebivolol tablets, 5 mg to 20 mg, administered once daily concomitantly with stable doses of up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) resulted in significant additional antihypertensive effects over placebo compared to baseline blood pressure.

Effectiveness was similar in subgroups analyzed by age and sex. Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians.

The blood pressure lowering effect of nebivolol was seen within two weeks of treatment and was maintained over the 24-hour dosing interval.

There are no trials of nebivolol tablets demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

16 HOW SUPPLIED/STORAGE AND HANDLING

Nebivolol Tablets are available for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

2.5 mg tablets: White to off-white, round, unscored tablets debossed with “A4” on one side with the other side blank, are supplied in the following package size:
Bottles of 30 NDC 51407-483-30

5 mg tablets: White to off-white, round, unscored tablets debossed with “A49” on one side with the other side blank, are supplied in the following package sizes:
Bottles of 30 NDC 51407-484-30
Bottles of 90 NDC 51407-484-90

10 mg tablets: White to off-white, round, unscored tablets debossed with “A50” on one side with the other side blank, are supplied in the following package sizes:
Bottles of 30 NDC 51407-485-30
Bottles of 90 NDC 51407-485-90

20mg tablets: White to off-white, round, unscored tablets debossed with “A51” on one side with the other side blank, are supplied in the following package sizes:
Bottles of 30 NDC 51407-486-30
Bottles of 90 NDC 51407-486-90

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

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