Nebivolol/valsartan

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

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

Nebivolol is a beta-blocker that affects the heart and circulation (blood flow through arteries and veins).

Valsartan is an angiotensin II receptor antagonist. Valsartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Nebivolol and valsartan is a combination medicine used to treat high blood pressure (hypertension) in adults. Lowering blood pressure may lower your risk of a stroke or heart attack.

Nebivolol and valsartan is sometimes given together with other blood pressure medications.

Nebivolol and valsartan may also be used for purposes not listed in this medication guide.

Do not use if you are pregnant. Stop using and tell your doctor right away if you become pregnant. Valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

If you have diabetes, do not use nebivolol and valsartan together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

You should not use this medicine if you are allergic to nebivolol or valsartan, or if you have:

• a serious heart condition such as "sick sinus syndrome" (unless you have a pacemaker);
• a heart condition called heart block or "AV block" (2nd or 3rd degree);
• severe heart failure (that required you to be in the hospital);
• severe liver disease; or
• a history of slow heart beats that have caused you to faint.

If you have diabetes, do not use nebivolol and valsartan together with any medication that contains aliskiren (such as Amturnide, Tekturna, Tekamlo).

You may also need to avoid taking nebivolol and valsartan with aliskiren if you have kidney disease.

To make sure nebivolol and valsartan is safe for you, tell your doctor if you have:

• low levels of potassium in your blood;
• kidney disease (or if you are on dialysis);
• liver disease;
• a heart condition other than the one being treated with nebivolol and valsartan;
• overactive thyroid;
• if you are on a low-salt-diet;
• if you are dehydrated; or
• if you have ever had a severe allergic reaction to any blood pressure medication.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

It is not known whether nebivolol and valsartan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Nebivolol and valsartan is not approved for use by anyone younger than 18 years old.

Get emergency medical help if you have signs of an allergic reaction: hives; trouble breathing or swallowing; stomach pain, vomiting; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;
• very slow heartbeats;
• chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
• shortness of breath (even with mild exertion);
• swelling or numbness in your legs or feet;
• rapid weight gain; or
• high potassium--nausea, slow or unusual heart rate, weakness, loss of movement.

Common side effects may include:

• slow heartbeats.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of this medicine.

Do not use potassium supplements or salt substitutes while you are taking nebivolol and valsartan, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• cyclosporine;
• fluoxetine;
• lithium;
• rifampin;
• ritonavir;
• a diuretic or "water pill";
• other heart or blood pressure medications;
• a potassium supplement or any medicine that contains potassium; or
• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with nebivolol and valsartan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.