Dosing and uses of Byvalson (nebivolol/valsartan)
Adult dosage forms and strengths
nebivolol/valsartan
tablet
- 5mg/80mg
Hypertension
Indicated for hypertension, to lower blood pressure and reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarction
May be used as initial therapy (if not controlled on valsartan 80 mg or ≤10 mg nebivolol) or be substituted for its components in patients already receiving nebivolol 5 mg and valsartan 80 mg
1 tablet (ie, 5 mg/80 mg) PO qDay
Dosage modifications
Hepatic impairment
- Mild (Child-Pugh A): No dosage adjustment required
- Moderate (Child-Pugh B): Not recommended as initial treatment because recommended starting dose for these patients is nebivolol 2.5 mg/day
- Severe (Child-Pugh C): Contraindicated
Renal impairment
- Mild or moderate (CrCl >60 mL/min): No dosage adjustment required
- Moderate and severe: Not studied
Pediatric dosage forms and strengths
Safety and efficacy not established
Byvalson (nebivolol/valsartan) adverse (side) effects
1-10%
Increased serum potassium by >20% (4.4%)
Frequency not defined
Symptomatic hypotension
Postmarketing Reports
NebivoloL
- Cardiac: Atrioventricular block (both second and third degree), myocardial infarction
- Central nervous system: Somnolence, syncope, vertigo
- Circulatory: Raynaud phenomenon, peripheral ischemia/claudication, thrombocytopenia
- Dermatologic: Pruritus, psoriasis, various rashes and skin disorders
- Digestive: Vomiting Hepatic: Abnormal hepatic function (including increased AST, ALT and bilirubin)
- Hypersensitivity: Hypersensitivity (including urticaria, allergic vasculitis, and rare reports of angioedema)
- Renal: Acute renal failure
- Respiratory: Acute pulmonary edema, bronchospasm
- Sexual dysfunction: Erectile dysfunction
Valsartan
- Hypersensitivity: Angioedema
- Digestive: Elevated liver enzymes, hepatitis
- Renal: Impaired renal function, renal failure
- Clinical laboratory tests: Hyperkalemia
- Dermatologic: Alopecia, bullous dermatitis
- Blood and lymphatic: Thrombocytopenia
- Vascular: Vasculitis
Warnings
Black box warnings
Discontinue as soon as possible when pregnancy is detected; valsartan affects renin-angiotensin system, causing oligohydramnios, which may result in fetal injury or death
Contraindications
Severe bradycardia
Heart block greater than first degree (if no pacemaker)
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
Do not coadminister aliskiren with an angiotensin receptor blocker (ARB) (eg, valsartan) in patients with diabetes; dual blockade of renin-angiotensin system increases risk of hypotension, hyperkalemia, and renal impairment
Cautions
Fetal toxicity: ARB (eg, valsartan) use during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see Black box warnings, Pregnancy)
Increased risk of symptomatic hypotension in patients with activated renin-angiotensin-aldosterone system (eg, volume/ and/or salt-depleted)
Do not abruptly discontinue nebivolol in patients with coronary artery disease; severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias reported
Worsening heart failure or fluid retention may occur during nebivolol therapy because of its beta-blocking effects
Generally, patients with bronchospastic diseases should not receive beta-blockers
Long-term beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures
Beta-blockers may mask manifestations of hypoglycemia, particularly tachycardia
Beta-blockers may mask clinical signs of hyperthyroidism (eg, tachycardia)
Do not abruptly discontinue beta-blockers
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge; these patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions
In patients with known or suspected pheochromocytoma, initiate an alpha-blocker prior to the use of any beta-blocker
ARBs associated with increased serum potassium levels; monitor closely
Drug interaction overview
- Nebivolol
- Nebivolol is a CYP2D6 substrate; avoid coadministration with CYP2D6 inhibitors (eg, quinidine, propafenone, fluoxetine, paroxetine)
- Do not use with other beta-blockers
- Monitor closely if coadministered with catecholamine-depleting drugs (eg, reserpine, guanethidine); the added beta-blocking action of nebivolol may produce excessive reduction of sympathetic activity
- If coadministered with clonidine, discontinue nebivolol for several days before the gradual tapering of clonidine
- Digitalis glycosides: Coadministration increases risk of bradycardia; monitor
- Nebivolol can exacerbate effects of myocardial depressants or inhibitors of atrioventricular conduction (eg, certain calcium channel blockers, especially the phenylalkylamine class [eg, verapamil] and benzothiazepine class [eg, diltiazem])
- Valsartan
- Concomitant use with other agents that block the renin-angiotensin system, potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other agents that may increase potassium levels (eg, heparin) may result in hyperkalemia
- Coadministration with NSAIDs or COX-2 inhibitors may result in renal function deterioration, especially in elderly patients, volume-depleted (including diuretics) patients, or those with renal impairment
- Use of ARBs with ACE inhibitors or with aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function
- Coadministration with aliskiren in patients with diabetes is contraindicated
- Coadministration with lithium increase serum lithium levels and toxicity
Pregnancy and lactation
Pregnancy
Nebivolol: Neonates of women with hypertension who are treated with beta-blockers during pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression
Valsartan
- Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, and skeletal deformations, including skull hypoplasia, hypotension, and death
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus
- In patients taking an ARB during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment
- Fetal testing may be appropriate, based on the week of gestation
- Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury
Lactation
Unknown if distributed in human breast milk
Because of the potential for beta-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, and the potential for valsartan to affect postnatal renal development in nursing infants, advise females not to breastfeed during treatment
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Byvalson (nebivolol/valsartan)
Mechanism of action
Nebivolol: Competitive and selective beta1-receptor antagonist; has little or no effect on beta2 receptors at doses <10 mg; lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations; reduces systemic vascular resistance
Valsartan: Blocks binding of angiotensin II to type 1 angiotensin receptors, causing a lowering in blood pressure; blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II
Absorption
Peak plasma time: 1-6 hr (nebivolol); 2-4 hr (valsartan)
Maximal antihypertensive effects (initial therapy): 2-4 wk
Distribution
Vd: 98% (nebivolol); 95% (valsartan) – mostly to albumin
Metabolism
Nebivolol: Predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via CYP2D6
Valsartan: CYP2C9 isozyme is responsible for the formation of the primary metabolite (valeryl-4-hydroxy valsartan), which is ~9% of the dose
Elimination
Half-life
- d-Nebivolol: 12 hr (CYP2D6 extensive metabolizers [EMs]); 19 hr (CYP2D6 poor metabolizers [PMs])
- Valsartan: 6 hr
Clearance (valsartan)
- Plasma clearance: 2 L/hr
- Renal clearance: 0.62 L/hr (30% of total clearance)
Excretion
- Nebivolol (EMs)
- 38% urine; 44% feces
- Nebivolol (PMs)
- 67% urine; 13% feces
- Valsartan
- 13% urine; 83% feces
Pharmacogenomics
NebivoloL
- In extensive metabolizers (most of the population) and at doses ≤10 mg, nebivolol is preferentially beta1-selective
- In poor metabolizers and at higher doses, nebivolol inhibits both beta1- and beta2- adrenergic receptors
Administration
Oral Administration
May take with or without food
Storage
Store at controlled room temperature (20-25°C [68-77°F])
Dispense in a tightly closed container
