Sacubitril-Valsartan - An Overview

Overview:

To reduce the risk of death and hospitalization in individuals with specific forms of heart failure, Valsartan and Sacubitril are used in conjunction with additional drugs. Additionally, some forms of heart failure in children one year of age and older are treated with Valsartan and Sacubitril together. The United States Food and Drug Administration (FDA) approved using Sacubitril-Valsartan for heart failure in 2015.

Drug Group:

Valsartan belongs to the group of drugs known as angiotensin II receptor antagonists. It obstructs the actions of specific natural chemicals that constrict blood arteries, improving blood flow and cardiac pumping efficiency. Sacubitril belongs to a group of drugs known as Neprilysin inhibitors. It functions to assist in blood volume control.

Available Doses and Dosage Forms:

Sacubitril-Valsartan is available in the form of tablets. The suggested starting dose for individuals with heart failure is 49/51 milligrams (mg) taken twice daily. Depending on how well the patient tolerates it, the amount should be increased after two to four weeks to reach a maintenance dosage of 97/103 milligrams twice daily. For children under 40 kg (kilograms), the beginning dose is 1.6 mg/kg (milligrams per kilogram), rising to 2.3 mg/kg, and ultimately reaching 3.1 mg/kg. The dosage for older children is based on their weight. The starting dose for children who weigh at least 40 kg but under 50 kg is 24/26 mg; this is increased to 49/51 mg and finally up to 72/78 mg per child. The dosage for children weighing 50 kg or more is 49/51 milligrams at first, 72/78 milligrams, and 97/103 milligrams.

For Patients

What Is Heart Failure?

Heart failure, also known as congestive heart failure, occurs when the heart is unable to pump enough blood to meet the body's needs. This may happen because of the heart's incapacity to pump blood effectively or because it cannot fill with adequate blood. It is important to know that "heart failure" implies a significant challenge to the heart's ability to function at its best, rather than the heart having entirely stopped. However, because of its seriousness and its complications, heart failure requires immediate medical intervention.

There are two types of heart failure. Acute heart failure appears suddenly, and chronic heart failure weakens the heart over time. It may affect one or both of the heart's sides, and each kind may have its unique reason. Different underlying variables may cause right-sided and left-sided heart failure. Heart failure is usually the consequence of other illnesses that harm the heart. These include arrhythmias (irregular heartbeat), hypertension (increased blood pressure), cardiomyopathy (any disorder of the heart muscle), myocarditis (heart inflammation), and coronary heart disease. Heart failure may not cause any symptoms at first, but as it worsens, symptoms including exhaustion, breathing difficulties, and fluid retention in the neck, stomach, or lower body may show signs.

Heart failure still has no known cure as of yet, making it a dangerous illness. However, several therapies are available to greatly enhance the quality of life for those afflicted with this illness. Many people with heart failure can significantly improve their quality of life by implementing healthy lifestyle changes, using drugs, using certain devices, and having operations.

How Does Sacubitril-Valsartan Work?

The body's reactions to heart failure exacerbate the illness. One response involves the RAAS (rennin angiotensin aldosterone system), which makes the heart less healthy by constricting blood vessels, increasing blood pressure, and producing specific hormones. Anticipating and preventing these side effects is how medications such as ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin receptor blockers) work to lessen the severity of heart failure.

During heart failure, an additional system known as the natriuretic peptide also activates. This system works to offset the negative effects of RAAS by dilating blood vessels, aiding in the body's excretion of salt and water, and lowering blood pressure, stress hormones, and some of the hormones detrimental to heart failure.

In the Sacubitril-Valsartan combination drug, Sacubitril is a prodrug that functions as an inhibitor of Neprilysin when it is activated. It inhibits Neprilysin's function, which stops natriuretic peptides from breaking down and lengthens the time these peptides have beneficial effects.

The RAAS system is blocked by the angiotensin receptor blocker Valsartan. On the other hand, blocking neprilysin will cause angiotensin II to build up because neprilysin breaks down angiotensin II. This is why a neprilysin inhibitor needs to be used in conjunction with an ARB to prevent the effects of excess angiotensin II; it cannot be used alone.

What Are the Clinical Indications for Sacubitril-Valsartan?

The drug combination Sacubitril-Valsartan is used for treating heart failure in adults and in children who are one year old or older.

What Are the Things to Inform the Doctor Before Taking the Drug?

• If a patient has an allergy to Valsartan or any related medicine, inform the doctor before starting Sacubitril and Valsartan. Additionally, the patients must let the doctors know if they are diabetic and are on medication. If a patient uses certain blood pressure medications, such as ACE (angiotensin-converting enzyme) inhibitors, or has stopped taking them within 36 hours, they should not use Sacubitril-Valsartan.

• All medications a patient takes, including over-the-counter and supplements, should be disclosed to the doctor. Tell the doctor specifically about any medications used by the patient for high blood pressure, heart problems, diuretics, or painkillers such as Naproxen or Ibuprofen.

• Any medical history or condition should be disclosed to the doctor, including liver or kidney problems, diabetes, and hereditary angioedema.

• A patient must not use this drug if they are nursing a baby. When taking this medication for the first time, take caution not to stand up too quickly, as an individual may feel lightheaded or dizzy. Furthermore, vomiting, dehydration, or excessive perspiration due to the use of Sacubitril-Valsartan can reduce blood pressure and cause lightheadedness or fainting. Inform the doctor immediately if any of these symptoms persist.

How Is Sacubitril-Valsartan Administered?

• Oral Valsartan and Sacubitril tablets are available and remain independent of food intake. These tablets are normally taken twice a day. Timing must always be consistent, which makes it simpler to remember.

• It is recommended to follow the directions on the prescription label carefully. It is important to ask the doctor or pharmacist to clarify any unclear things. It is critical to adhere to the recommended dosage and consult a doctor before changing it.

• A pharmacist can make an oral suspension (liquid) of the drug if swallowing tablets is difficult. Give the suspension bottle a good shake before administering each dosage.

• The physician generally starts a patient on a low dosage and may progressively raise it according to the patient's response. The doctor may suggest a gradual dose increase to reduce the chance of adverse effects.

• The leaflet highlights a higher risk of significant adverse effects and advises against using this medicine with ACE inhibitors. It is advised to wait a minimum of 36 hours before or after taking an ACE inhibitor. Patients are advised to consult their physician or pharmacist for more advice.

• The combination does not provide a cure, but it does successfully treat heart failure. Even if patients feel well, they should still take Sacubitril and Valsartan. It is best to stop medicine only after talking to the doctor.

What Are the Side Effects of Sacubitril-Valsartan?

• Patients using Sacubitril and Valsartan may experience coughing, dizziness, or lightheadedness. Notifying a physician or pharmacist immediately is advised if these side effects worsen or persist. When rising from a seated or lying position, people should do so carefully to reduce the chance of experiencing lightheadedness and dizziness. It is crucial to remember that a doctor has recommended this drug because they believe its advantages outweigh any possible drawbacks. Many people who use this drug report minimal negative effects.

• If a patient has any serious adverse effects, such as fainting, symptoms of excessive potassium levels (such as weakness in the muscles or an abnormal heartbeat), or indicators of kidney problems (including alterations in urine output), get medical help right away.

• Even though serious adverse reactions to this drug are uncommon, an individual should get medical attention immediately if they experience any symptoms, including a rash, swelling (especially of the face, tongue, or neck), extreme dizziness, or trouble breathing.

Dietary Considerations:

Consult the physician before using potassium-containing salt alternatives. Carefully follow those guidelines if the physician recommends a low-sodium or low-salt diet.

Missed Dose:

A patient must take the missed dose as soon as they recall it. On the other hand, it is best not to take the missed dose and continue with the regular dosing schedule if the time for the next scheduled dose is near. Take only one dose to make up for the one that you missed.

Overdose:

If the sufferer has passed out, experienced a seizure, is having difficulty breathing, or cannot be coaxed awake, dial emergency medical assistance.

Storage:

Keep the medicine away from light and moisture, and store it at room temperature. Keep out of the bathroom. After 15 days, discard any suspension that was not used. The suspension should not be kept in the fridge. Keep any drugs out of the reach of kids and animals.

Unless directed otherwise, avoid flushing drugs into the toilet or pouring them down the drain. When the product is no longer needed or has expired, dispose of it properly. Speak with the neighborhood waste management business or pharmacy.

For Doctors:

Indication:

• Adult Heart Patients - In adult patients with chronic heart failure, Sacubitril-Valsartan is recommended to lower the likelihood of cardiovascular death as well as hospitalization due to heart failure. Patients with a left ventricular ejection fraction (LVEF) below normal show the greatest benefits. Since LVEF is a variable metric, patients are chosen based on clinical judgment.

• Pediatric Heart Patients - Sacubitril-Valsartan is prescribed to children (one year of age and older) with a specific cardiac condition known as symptomatic heart failure with systemic left ventricular systolic dysfunction. It is intended to improve their heart health by reducing NT-proBNP levels linked to cardiac issues.

Dose:

Concomitant use of an angiotensin-converting enzyme (ACE) inhibitor with Sacubitril-Valsartan is not recommended. When transferring from an ACE inhibitor to Sacubitril-Valsartan, a complete 36-hour time gap is allowed to let the two medications wash out.

• Adult - The recommended starting dose for men with heart failure is 49/51 mg (milligrams) taken twice daily by mouth. After two to four weeks, the dose should be raised to achieve the target maintenance dosage of 97/103 mg twice daily, depending on the patient's tolerance.

• Pediatric Population -

  • Children Under 40 kilograms (kg) - The starting dose is 1.6 milligrams per kilogram, the second dose is 2.3 milligrams per kilogram, and the final dose is 3.1 milligrams per kilogram.

  • Children at Least 40 Kg, Less Than 50 Kg - The starting dose is 24/26 milligrams, the second dose is 49/51 milligrams, and the final dose is 72/78 milligrams.

  • Children at Least 50 kg - The starting dose is 49/51 milligrams, the second dose is 72/78 milligrams, and the final dose is 97/103 milligrams.

Other Dosing Considerations:

• Sacubitril-Valsartan should be started at half the recommended starting dose in adults or children who have not received certain heart drugs (ACE inhibitors or ARBs) or were previously taking them at low doses. The recommended dose can then be reached by progressively increasing the dose over a few weeks.

• Sacubitril-Valsartan also begins at half the recommended starting dose for adults and children with serious kidney problems. The dosing increases with time.

• Adults and children with mild liver disease should begin taking Sacubitril-Valsartan at half the recommended starting dose and gradually increase it as directed. However, using Sacubitril-Valsartan at all is not advised for those with serious liver problems.

What Are the Pharmacological Aspects of Sacubitril-Valsartan?

• Pharmacodynamics - A trial conducted in healthy men suggests that Sacubitril-Valsartan does not affect QT prolongation. An increase in Aβ1-38 in the brain has been linked to Sacubitril-Valsartan, although its practical effects are unknown. Compared to taking Sacubitril-Valsartan by itself, combining it with Sildenafil (for hypertension) may further lower blood pressure. Nevertheless, the effects of Sacubitril-Valsartan on blood pressure do not appear to be considerably altered when combined with intravenous nitroglycerin. Sacubitril-Valsartan appears to be useful in raising heart function in patients suffering from heart failure. When taken in conjunction with other drugs, it may also have some extra effects on brain chemicals and blood pressure.

• Mechanism of Action - Sacubitril, which is a neprilysin inhibitor, and Valsartan, which is an angiotensin receptor blocker, are both present in Sacubitril-Valsartan. Sacubitril-Valsartan acts through LBQ657, an active metabolite of the prodrug Sacubitril, to inhibit neprilysin (neutral endopeptidase; NEP), and through Valsartan to block the angiotensin II type-1 (AT1) receptor. Due to the simultaneous reduction of angiotensin II's effects by Valsartan and elevated levels of peptides that neprilysin degrades, such as natriuretic peptides, by LBP657, Sacubitril-Valsartan is associated with cardiovascular and renal side effects in patients with heart failure. By specifically inhibiting the AT1 receptor, Valsartan blocks the effects of angiotensin II and prevents the release of aldosterone dependent on angiotensin II.

• Pharmacokinetics - Sacubitril, Valsartan, and LBQ657 are the breakdown products of Sacubitril-Valsartan, and all reach their peak blood levels at distinct times, which are 0.5 hours, 2 hours, and 1.5 hours, respectively. When taken orally, the body absorbs at least 60 percent of Sacubitril. Compared to other tablet formulations, Sacubitril-Valsartan, Valsartan is absorbed more effectively. After three days, steady levels of Valsartan, LBQ657, and Sacubitril are reached with twice-daily dosages of Sacubitril-Valsartan. Valsartan and Sacubitril do not accumulate significantly; however, LBQ657 increases by approximately 1.6 times in steady states.

  • Distribution: Most binding sites for sacubitril, LBQ657, and valsartan are blood proteins. Only 0.28 percent of LBQ657 passes the blood-brain barrier.

  • Metabolism: Sacubitril readily transforms into LBQ657, and LBQ657 does not undergo much metabolism. Valsartan does not undergo much metabolism, and very little of it is changed into other substances.

  • Elimination: A considerable amount of Valsartan and Sacubitril (as LBQ657) and their metabolites are eliminated in the urine and feces. Sacubitril has an elimination half-life of about 1.4 hours, LBQ657 of 11.5 hours, and Valsartan of 9.9 hours.

Carcinogenesis and Mutagenesis:

According to research done on the subject, there were no indications that the medicine Sacubitril-Valsartan may alter genes, induce cancer, or impair animal reproduction. It did not cause these side effects in mice or rats, even at doses larger than those typically administered to humans. In short, it appears that Sacubitril-Valsartan did not result in cancer, mutations, or reproduction problems in the studied animals.

Clinical Studies:

Research that used a medicine called Sacubitril-Valsartan to treat heart problems tracked fifty participants for a year. Nothing major occurred. A few stopped due to kidney problems or low blood pressure. Roughly 42 percent of patients took the drug as prescribed. According to their findings, a heart strain marker initially decreased but returned to normal after a year. Heart ultrasounds showed improvements in the right ventricle's functioning and the heart's ability to pump blood.

Additionally, the drug appeared beneficial for heart valve leaks, particularly in those with congenitally repaired transposition of the great arteries, a particular kind of heart disease.

The right ventricle grew smaller and had improved pumping capacity, according to the 3D cardiac imaging. Patients reported feeling better as well. They reported that they could walk farther, and the quality of their lives improved after one year. All patients showed benefits, irrespective of their particular cardiac condition; however, the effects were more pronounced in those who took the recommended dosage of the drug. The study concluded that Sacubitril-Valsartan was generally safe for these patients and appeared to improve their cardiac function and overall quality of life.

What Are the Contraindications of Sacubitril-Valsartan?

• Hypersensitivity: Patients with a history of recognized hypersensitivity or allergy to any of Sacubitril-Valsartan ingredients should not use the medication.

• History of Angioedema: It is not recommended for individuals who have experienced angioedema in the past, particularly when it was brought on by ACE inhibitor or angiotensin receptor blocker therapy. This dangerous allergic reaction causes swelling of the skin's deeper layers, frequently around the lips and eyes and occasionally on the tongue and neck.

• Concurrent ACE Inhibitor Use: Sacubitril-Valsartan should not be taken for more than 36 hours after beginning or ending an ACE inhibitor. Preventing any problems or interactions between these drugs is crucial.

• Concurrent Usage of Aliskiren and Sacubitril-Valsartan in Diabetic Patients: Patients with diabetes who concurrently take Aliskiren should not take Sacubitril-Valsartan. Combining Sacubitril-Valsartan with another hypertension medicine, like Aliskiren, can cause specific difficulties in diabetic people.

Warnings and Precautions:

• Fetal Toxicity - When given to a pregnant woman, Sacubitril-Valsartan can harm the fetus. Fetal renal function is decreased, and fetal and neonatal morbidity and death are increased when medications that affect the renin-angiotensin system are used during the second and third trimesters of pregnancy. Consider an alternate medication regimen and stop using Sacubitril-Valsartan as soon as pregnancy is detected. A doctor must inform the pregnant woman about the possible danger to the fetus, nevertheless, if there is no suitable substitute for therapy with medications that influence the renin-angiotensin system and if the medication is thought to be lifesaving for the mother.

• Angioedema - A heart failure drug called Sacubitril-Valsartan may result in angioedema, a swelling of certain body parts. If this occurs, immediately cease taking Sacubitril-Valsartan, get the necessary assistance, and make sure the patients have no breathing problems. Antihistamines can help reduce the symptoms if the swelling is limited to the lips and face. Usually, the swelling goes down on its own. On the other hand, swelling of the tongue or throat could obstruct breathing and pose a serious risk to life. Adrenaline or epinephrine injections are required. A person should not use Sacubitril-Valsartan if they have previously had angioedema brought on by ACE inhibitors or ARBs. Additionally, this drug should not be used by those who have hereditary angioedema, a kind of angioedema.

• Hypotension - Sacubitril-Valsartan reduces blood pressure and has the potential to produce hypotension symptoms. Individuals who are volume- and/or salt-depleted (for example, receiving high doses of diuretics) or who have an active renin-angiotensin system are more vulnerable. Adjust volume or salt depletion before administering Sacubitril-Valsartan, or begin with a smaller dosage. If hypotension develops, treat hypovolemia and other potential causes of hypotension in addition to adjusting the dosage of diuretics and concurrent antihypertensive medications. If the hypotension does not go away with these measures, lower the dosage or temporarily stop taking Sacubitril-Valsartan. Usually, there is no need to stop therapy permanently.

• Impaired Renal Function - Sacubitril-Valsartan reduces blood pressure and has the potential to produce hypotension symptoms. Individuals who are volume or salt-depleted (for example, receiving high doses of diuretics) or who have an active renin-angiotensin system are more vulnerable. Adjust volume or salt depletion before administering Sacubitril-Valsartan, or begin with a smaller dosage. If hypotension develops, treat hypovolemia and other potential causes of hypotension in addition to adjusting the dosage of diuretics and concurrent antihypertensive medications. If the hypotension does not go away with these measures, lower the dosage or temporarily stop taking Sacubitril-Valsartan. Usually, there is no need to stop therapy permanently.

• Hyperkalemia - Sacubitril-Valsartan may cause hyperkalemia due to its effects on the RAAS. Serum potassium levels should be routinely checked and treated as necessary, particularly in individuals who have high potassium diets, diabetes, severe renal impairment, or hypoaldosteronism as risk factors for hyperkalemia. It might be necessary to stop taking Sacubitril-Valsartan or reduce the dosage.

What Are the Drug Interactions of Sacubitril-Valsartan?

• Dual Blockade of the Renin-Angiotensin-Aldosterone System - Due to a higher probability of angioedema, using Sacubitril-Valsartan and an ACE inhibitor simultaneously is not recommended. Due to the presence of Valsartan in Sacubitril-Valsartan, it should not be used along with an angiotensin II receptor blocker. It is not recommended for people with diabetes to take Aliskiren and Sacubitril-Valsartan at the same time. Patients with kidney damage should not use Aliskiren.

• Potassium-Sparing Diuretics - Combining potassium-sparing diuretics such as (Spirolactone, Amiloride, and Triamterene), salt substitutes containing potassium, or potassium supplements with other medications that suppress angiotensin II or its effects can raise serum potassium levels.

• Lithium - When Lithium and angiotensin II receptor antagonists are administered simultaneously, there have been reports of increases in serum levels of lithium and lithium toxicity. The doctors must monitor the lithium levels in the blood while the patient is on Sacubitril-Valsartan.

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - Concomitant use of NSAIDs, especially COX-2 inhibitors, with Sacubitril-Valsartan may deteriorate renal function in individuals who are old, volume-depleted (including those on diuretic medication), or have poor renal function. This could result in acute renal failure. Usually, these effects are reversible. The doctor should regularly check the renal function.

Specific Considerations:

• Pregnancy - Sacubitril-Valsartan use during pregnancy carries a risk to the developing fetus. Utilizing drugs that target a particular bodily system in the latter stages of pregnancy can lower kidney function and raise concerns for the health and survival of the unborn child. Animal studies revealed that the use of Sacubitril-Valsartan during pregnancy increased the number of fetal deaths in rats and rabbits and resulted in birth abnormalities in them. It is advised that a woman should stop taking Sacubitril-Valsartan and look into other treatments if she finds out she is pregnant while taking the medication. But if the mother's health is at stake and there is no alternative way to treat a serious illness affecting the renin-angiotensin system, she should be made aware of the possible risk to the fetus.

• Lactation - The effects of Sacubitril-Valsartan on nursing babies and the mother's ability to produce milk are unknown, nor is it known if these drugs are excreted in human breast milk. This drug was detected in rat milk during rat experiments. Women are advised to refrain from breastfeeding while taking Sacubitril-Valsartan because there is a possibility that breastfed newborns might get exposed to Sacubitril-Valsartan.

• Pediatric Population - There is data to support the safety and efficacy of Sacubitril-Valsartan for children with heart failure ages one to 18. This proof is based on a 12-week trial in which NT-proBNP was tested before and after treatment. However, there is insufficient data to determine whether Sacubitril-Valsartan is safe or effective for infants under a year old.

• Geriatric Population - When comparing the population in general to senior patients (those 65 years of age or older), no noticeable pharmacokinetic changes have been found.

• Renal Impairment - The drug dosage does not need to be changed for people with mild to moderate kidney problems. Nonetheless, the recommended starting dose for individuals with severe kidney disease is a particular quantity taken twice a day. Accordingly, a lower dose of the medicine may be necessary to begin for those with significant kidney impairment.

• Hepatic Impairment - It is unnecessary to adjust the Sacubitril-Valsartan dosage for people with moderate liver problems. However, the recommended starting dose for people with moderate liver disease is a fixed quantity taken twice a day. However, since Sacubitril-Valsartan has not been studied in individuals with severe liver problems, it is not recommended for them to use it because it is unclear how safe or effective it would be in their situation.