Antihypertensive combination products (newer agents)

When pregnancy is detected, discontinue BYVALSON as soon as possible (5.1, 8.1).
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Initial U.S. Approval:  2016

Mechanism of Action:
Nebivolol
Nebivolol is a ß-adrenergic receptor blocking agent. In extensive metabolizers (most of the population) and at doses less than or equal to 10 mg, nebivolol is preferentially ß1 selective. In poor metabolizers and at higher doses, nebivolol inhibits both ß1- and ß2- adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, nebivolol does not demonstrate a1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to ß-blocking activity.

The mechanism of action of the antihypertensive response of nebivolol has not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) decreased sympathetic activity, (4) suppression of renin activity, and (5) vasodilation and decreased peripheral vascular resistance.

Valsartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one- 200th that of valsartan itself.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

INDICATIONS AND USAGE:
BYVALSON is a beta adrenergic blocker and an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

DOSAGE AND ADMINISTRATION
As initial therapy and in patients not adequately controlled on valsartan 80 mg or nebivolol up to and including 10 mg, the recommended dose is 5 mg/ 80 mg taken orally once daily. (2)
Maximum antihypertensive effects are attained within 2 to 4 weeks. (2)
BYVALSON may be substituted for its components in patients already receiving 5 mg nebivolol and 80 mg valsartan. (2)

HOW SUPPLIED:
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg/ 80 mg