Byvalson

Byvalson is a prescription medication used to treat hypertension (high blood pressure).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Allergan, Inc.

Serious side effects have been reported with Byvalson. See the “Byvalson Precautions” section.

The most common side effect of Byvalson is slow heartbeat.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects with Byvalson.

For more information, ask your healthcare provider or pharmacist.

You may report side effects to FDA at 1-800-FDA-1088.

WARNING: FETAL TOXICITY

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

In the U.S.

• Byvalson

Available Dosage Forms:

• Tablet

Therapeutic Class: Cardiovascular Agent

Pharmacologic Class: Beta-Adrenergic Blocker, Cardioselective

Use Byvalson as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

The following serious adverse reactions are included in more detail in the Warnings and Precautions section of the label:

• Hypotension [see Warnings and Precautions (5.2)]
• Hyperkalemia [see Warnings and Precautions (5.14)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Byvalson

Byvalson has been evaluated for safety in patients with hypertension. A total of 1,664 patients received at least 1 dose of a fixed-dose combination of nebivolol/valsartan in an 8-week trial. A total of 807 patients received at least 1 dose of nebivolol and valsartan in an open-label safety study; of these, 621 patients completed 180 days and 476 patients completed 360 days of open-label treatment with nebivolol and valsartan.

The safety of the 5 mg/ 80 mg dose of nebivolol/valsartan was evaluated during the first 4 weeks of an 8-week placebo-controlled trial. During the 4 week period, the overall incidence of adverse events on therapy with Byvalson 5 mg/ 80 mg was similar to placebo and the individual components (nebivolol 5 mg and valsartan 80 mg). Discontinuation of therapy due to a clinical adverse event occurred in 2.0% of patients treated with Byvalson 5 mg/ 80 mg versus 3.2% of patients given placebo and approximately 1% of patients given nebivolol 5 mg or valsartan 80 mg as monotherapy.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of either nebivolol or valsartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nebivolol

The following adverse reactions have been reported in post-marketing experience:

Cardiac: atrioventricular block (both second and third degree), myocardial infarction

Central Nervous System: somnolence, syncope, vertigo

Circulatory: Raynaud's 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

The following additional adverse reactions have been reported in post-marketing experience:

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

No drug interaction studies have been conducted with Byvalson and other drugs. Studies with the individual nebivolol and valsartan components are described below.

Nebivolol

CYP2D6 Inhibitors: Avoid concomitant use of nebivolol with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology (12.3)].

Hypotensive Agents: Do not use nebivolol with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of nebivolol may produce excessive reduction of sympathetic activity. In patients who are receiving nebivolol and clonidine, discontinue nebivolol for several days before the gradual tapering of clonidine.

Digitalis Glycosides: Concomitant use can increase the risk of bradycardia. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Monitor for bradycardia.

Calcium Channel Blockers: Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. Monitor for effects on heart rate and cardiac conduction.

Valsartan

Agents Increasing Serum Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other agents that may increase potassium levels (e.g., heparin) may result in hyperkalemia. Monitor serum potassium in such patients.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Use with Other Renin Angiotensin System inhibitors: Use of angiotensin receptor blockers with ACE inhibitors or with aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and ACE inhibitors or aliskiren.

Do not co-administer aliskiren with Byvalson in patients with diabetes. Avoid use of aliskiren with Byvalson in patients with renal impairment (GFR <60 mL/min).

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium angiotensin II receptor antagonists, including valsartan. Monitor serum lithium levels during concomitant use.

Pregnancy

Risk Summary

Byvalson can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to angiotensin receptor blockers use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Studies in rats and rabbits with valsartan showed fetotoxicity only at maternally toxic doses [see Data]. Embryo-fetal and perinatal lethality have been observed when nebivolol was given to pregnant rats during organogenesis at doses approximately equivalent to the MRHD. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan. When pregnancy is detected, discontinue Byvalson as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal adverse reactions

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. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly.

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.

Byvalson

In patients taking Byvalson 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. Closely observe infants with histories of in utero exposure to Byvalson for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to Byvalson, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Data

Animal Data

No reproductive animal toxicity studies have been conducted with the combination of nebivolol and valsartan. Reproductive animal toxicity studies have been conducted for nebivolol and valsartan alone.

Nebivolol

Nebivolol was shown to increase embryo-fetal and perinatal lethality in rats at approximately 1.2 times the maximum recommended human dose (MRHD) or 40 mg/day on a mg/m2 basis. Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. These events occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD).

No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Valsartan

No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.

Lactation

Risk Summary

There is no information regarding the presence of Byvalson or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Nebivolol and valsartan are present in rat milk [see Data]. Because of the potential for β-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 a nursing woman not to breastfeed during treatment with Byvalson.

Data

In lactating rats, maximum milk levels of unchanged nebivolol were observed at 4 hours after single and repeat doses of 2.5 mg/kg/day. The daily dose (mg/kg body weight) ingested by a rat pup is 0.3% of the dam dose for unchanged nebivolol. For valsartan, drug was detected in the milk of lactating rats 15 minutes after administration of a 3 mg/kg dose.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Byvalson

In clinical trials of Byvalson, 204 (8.3%) patients who were treated with Byvalson were ≥ 65 years and 16 (0.6%) were ≥ 75 years.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients, and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Safety and effectiveness of Byvalson in patients with moderate and severe renal impairment (creatinine clearance [CrCl] ≤ 60 mL/min) have not been studied. No dosage adjustment is required for patients with mild or moderate renal impairment.

Byvalson is not recommended as initial treatment in patients with severe renal impairment, because the recommended starting dose of nebivolol in this population, 2.5 mg once daily, is lower than the dose of nebivolol contained in Byvalson.

Hepatic Impairment

There are no studies of Byvalson in patients with hepatic insufficiency. No initial dosage adjustment is required for patients with mild hepatic impairment.

Byvalson is not recommended as initial treatment in patients with moderate hepatic impairment, because the recommended starting dose of nebivolol, 2.5 mg once daily, is not available.

Byvalson is not recommended for use in patients with severe hepatic impairment [see Contraindications (4)].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with Byvalson [see Use in Specific Populations (8.2)].

Symptomatic Hypotension

Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs to discontinue Byvalson until the physician has been consulted.

Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia

Advise patents not to use salt substitutes containing potassium without consulting their physician.

Distributed by:
Allergan USA, Inc.
Irvine, CA 92612

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© 2016 Allergan. All rights reserved.

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.

Byvalson contains a combination of nebivolol and valsartan. 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.

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

Byvalson is sometimes given together with other blood pressure medications.

Take Byvalson exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Byvalson with or without food.

You should not stop using Byvalson suddenly, even if you feel fine. Stopping suddenly may cause you to have chest pain or a heart attack. If you need to stop taking the medicine, follow your doctor's instructions about tapering your dose.

Your blood pressure will need to be checked often. Your potassium levels and kidney function may also need to be checked.

You may have very low blood pressure while taking Byvalson. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

It may take 2 to 4 weeks of using this medicine before your blood pressure is under control. Keep using the medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

Usual Adult Dose for Hypertension:

1 tablet orally daily with or without food

Comments:
-Maximum antihypertensive effects are attained within 2 to 4 weeks.
-Increasing the dose does not result in any meaningful further blood pressure reduction.

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 Byvalson, 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.

More frequent side effects include: increased serum potassium. See below for a comprehensive list of adverse effects.

Hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, postpartum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed. Nebivolol: Beta blockers can cause hypotension, bradycardia, hypoglycemia, and respiratory depression in neonates. Valsartan: Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (i.e., skull hypoplasia, hypotension), and death. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. US FDA pregnancy category: Not Assigned Comments: -This drug can cause fetal harm when administered to a pregnant woman. -When pregnancy is detected, this drug should be discontinued as soon as possible. Risk Summary: No reproductive animal toxicity studies have been conducted with the combination of nebivolol and valsartan. -Nebivolol: When used during the second and third trimesters of pregnancy, drugs that act on the renin-angiotensin system can reduce fetal renal function and increase fetal and neonatal morbidity and death. -Valsartan: No teratogenic effects were observed in animal studies; however, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed during organogenesis or late gestation.