nebivolol/valsartan (Rx)

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

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Long-term beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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

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.

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

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