Valsartan - Indication, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Introduction

Valsartan is used alone or in conjunction with other drugs to treat high blood pressure in adults and children who are one year and older. Additionally, it is also used to treat heart failure (a condition in which the heart cannot pump sufficient blood to the body) in adults and to increase survival rates following heart attacks.

Information About High Blood Pressure to the Patients:

High blood pressure is a prevalent condition that, when left untreated, can harm the kidneys, brain, heart, blood vessels, and other organs. Heart disease, heart attack, heart failure, stroke, kidney failure, vision loss, and other issues may result from damage to these organs. Along with medicines, making lifestyle changes helps to improve the condition. These changes include quitting smoking, drinking alcohol in moderation, consuming less salt and fats, maintaining a normal and healthy weight, and exercising for at least 30 minutes on most days.

Information About Valsartan to the Patients:

How Is Valsartan Used?

Valsartan is available in both tablet and suspension (liquid) forms for oral intake. For treating high blood pressure, the tablet or suspension is typically taken once every day, with or without food. For treating heart failure, it is recommended to take Valsartan twice daily with or without food. The medicine should be taken at the same time so that the patient does not forget or skip the dose. The patient must ask the doctor or chemist to explain any instructions on the prescription label that is not clear or cannot be understood properly. Follow the prescription for Valsartan as instructed by the doctor. Never take it in larger or smaller amounts or more frequently than directed by the doctor.

Before each use, shake the suspension vigorously for at least 10 seconds for even distribution of the medication. Each Valsartan product acts differently on the body. Every Valsartan product acts by releasing medicines differently in the body and hence should never be changed to a different brand unless suggested and prescribed by the doctor. If a patient is under the age of five or is unable to swallow pills, the doctor may advise them to take Valsartan suspension. The doctor might prescribe a low dose of Valsartan initially and then gradually increase the dose.

Valsartan does not treat heart failure or high blood pressure. It only controls and manages them. When treated with Valsartan, the blood pressure may decrease during the first 2 weeks of the treatment; however, it may take up to 4 weeks to fully experience the benefits of Valsartan. It should never be stopped before consulting the doctor, even if the patient feels unwell. The patient should always ask for the manufacturer’s information from the chemist or the doctor.

What Are the Other Uses of This Medicine?

Additionally, Valsartan is occasionally used to treat diabetic nephropathy (kidney disease seen in people with diabetes and high blood pressure). The risks of using this medication should be discussed with the doctor.

What Should the Patient Inform the Doctor Before Taking Valsartan?

Before taking Valsartan, the patient must inform the doctor about the following things:

• Suppose the patient is allergic to Valsartan or its ingredients. The patient must consult the doctor to know about the ingredients of the Valsartan before consuming it. They must also inform about allergy reactions to other medicines.

• Suppose the patient has diabetes and is on the drug Aliskiren. The doctor may or may not advise taking Valsartan if the patient has diabetes and is on Aliskiren.

• If the patient is pregnant or thinking of conceiving a child or breastfeeding a child. Contact the doctor if pregnancy is positive during the treatment course of this medicine. Breastfeeding is prohibited if the patient is on Valsartan.

• If the patient has or ever had heart, kidney, or liver disease as well as any obstruction of the bile duct (a condition in which bile is unable to flow from the liver to the gallbladder and small intestine due to gallstones, tumors, or injury).

• If the patient is taking any prescribed or over-the-counter medications, vitamins, and herbal supplements. The doctor might change the dosage of medications or monitor the patient carefully for any side effects.

• If the patient experiences lightheadedness, fainting, and dizziness on changing position or on suddenly getting up from a lying position. The symptoms are more frequent when the patient starts taking Valsartan during the first few weeks. It decreases gradually. The patient should get up from the bed gradually and keep their feet on the floor before they stand.

• If the patient experiences diarrhea, vomiting, and excessive sweating as it can cause a drop in blood pressure. These symptoms can lead to fainting and dizziness. Inform the doctor in case any of these symptoms or problems arise during the treatment course.

What Are the Side Effects of Valsartan?

There are many side effects of Valsartan. Doctors should be notified immediately if any of these symptoms appear and remain for a longer period.

• Headache and extreme tiredness.

• Vomiting and nausea.

• Diarrhea and pain in the stomach.

• Joint pain and discomfort.

• Pain in the back.

• Cloudy or blurry vision.

• Cough and rashes.

The serious side effects of Valsartan, which should be notified immediately to the doctors, are mentioned below.

• The face, throat, tongue, lips, eyes, hands, ankles, or lower legs get swollen.

• Hoarseness of the voice.

• Difficulty in breathing and swallowing.

• Weight gain without any specific cause.

What Are the Symptoms of Drug Overdosing?

• Dizziness.

• Fainting.

• Decreased or increased heart rate.

What Are the General Instructions for the Patients?

• The patient must visit the physician and the lab as per the schedule. Regular checking of the blood pressure is a must as it helps to determine the response of Valsartan in maintaining the blood pressure.

• Please ensure that nobody else takes the medicine accidentally. Any queries regarding the prescription refills should be directed to the chemist.

• Every medication taken by the patient, including over-the-counter (OTC) items, prescription medications, and dietary supplements like vitamins and minerals, should be documented in writing. When the patients visit the doctor or are admitted to the hospital, they should always bring this list with them. The patient should always have this information in case of emergencies.

• Salt substitutes should not be taken without consulting the doctor. Any particular diet (low-sodium or low-salt diet) or food prescribed by the doctor should be avoided or included in the diet.

Information for Doctors:

Description of Valsartan:

Valsartan is a nonpeptide, orally administered, and particular AT1 (angiotensin 1) receptor subtype angiotensin II receptor blocker. The chemical formula for Valsartan is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its molecular weight is 435.5, and its empirical formula is C24H29N5O3. Valsartan comes in the form of a fine white powder. It is slightly soluble in water and soluble in ethanol and methanol.

Valsartan comes in oral tablet form in doses of 40, 80, 160, or 320 mg. Colloidal silicon dioxide, iron oxides (yellow, black, and/or red), magnesium stearate, methylcellulose, hydroxypropyl, crospovidone, titanium dioxide, microcrystalline cellulose, and polyethylene glycol 8000 are the inactive components of the tablets.

Clinical Pharmacology:

Mechanism of Action:

Angiotensin-converting enzyme (ACE, kininase II) catalyzes the conversion of angiotensin I into angiotensin II. The major pressor agent of the renin-angiotensin system is angiotensin II, which causes vasoconstriction, stimulates the production and release of aldosterone, stimulates the heart, and causes sodium to be reabsorbed by the kidneys. Valsartan blocks the actions of angiotensin II that result in the discharge of aldosterone and vasoconstriction by specifically inhibiting angiotensin II from attaching to the AT1 receptor in various tissues, such as vascular smooth muscle and the adrenal gland. Therefore, it has no effect on the pathways that produce angiotensin II.

Numerous tissues also contain the AT2 receptor, but AT2 is not known to be connected to cardiovascular homeostasis. The AT1 receptor is much more responsive to Valsartan (about 20,000-fold) than the AT2 receptor. The unblocked AT2 receptor may be stimulated by the elevated plasma levels of angiotensin II that occur after Valsartan blocks the AT1 receptor. The primary metabolite of Valsartan is basically inactive, with an affinity for the AT1 receptor approximately one-200th that of Valsartan itself.

Pharmacodynamics:

The pressor effect of angiotensin II infusions is inhibited by Valsartan. An oral dose of 80 mg reduces the pressor effect by about 80% at its peak, with about 30% of that reduction remaining after 24 hours. No data are available regarding the effects of higher doses.

In hypertensive patients, removal of the angiotensin II negative feedback results in a 2 to 3-fold increase in plasma renin and a subsequent increase in the plasma concentration of angiotensin II. Valsartan administration resulted in a minimal decrease in plasma aldosterone concentration and had very little impact on serum potassium.

In multiple-dose research studies in hypertensive patients with stable renal insufficiency as well as those with renovascular hypertension, Valsartan did not have clinically major impacts on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.

In multiple-dose studies with hypertensive patients, valsartan had no discernible effects on total cholesterol levels, fasting triglycerides, fasting serum glucose, or uric acid.

Pharmacokinetics:

The peak plasma concentration of Valsartan reaches only after 2 to 4 hours of initial dosing. Upon intravenous administration of the drug, the average half-life is about 6 hours. Valsartan has an absolute bioavailability range of 25% (10% to 35%). Suspension of the drug has better bioavailability than its oral counterpart. Even after repeated administration, the drug does not get accumulated in the plasma.

Metabolism and Elimination:

When given orally, the majority of the dose of Valsartan is excreted in the feces (83 % of the dose) and urine (13 % of the dose). Only about 20 % of the dose is recovered as metabolites; the majority of the drug is recovered unchanged. Valeryl 4-hydroxy Valsartan, which makes up about 9% of the dose, is the main metabolite. Although the enzyme(s) involved in the metabolism of Valsartan has not been discovered, they do not appear to be CYP 450 isozymes. Valsartan's plasma clearance after intravenous administration is approximately 2 Liter/hour, and its renal clearance is 0.62 Liter/hour (representing about 30 % of total clearance).

Distribution:

The small volume (17 liters) of distribution of Valsartan after intravenous administration suggests that the drug does not penetrate tissues deeply. 95 % of the serum proteins, primarily serum albumin, have a high affinity for Valsartan.

Ingredients in the Drug Valsartan:

• Active Ingredient - Valsartan

• Inactive Ingredient - Colloidal silicon dioxide, crospovidone, magnesium stearate, hydroxypropyl methylcellulose, iron oxides (yellow, black, and/or red), titanium dioxide, polyethylene glycol 8000, and microcrystalline cellulose

Storage and Disposal of the Drug:

Store the medicine in its original container and away from children. Keep the tablets away from excessive heat and moisture at room temperature. The suspension must be discarded after 30 days of storage at room temperature or 75 days of storage in a refrigerator.

Drug Use in Specific Population:

• Pregnancy - Valsartan is a teratogenic drug and can harm the fetus. When taken during the second or third trimester of pregnancy, Valsartan, like other medications that affect the renin-angiotensin system, can result in morbidity and death for the fetus and the newborn. If this drug is taken during pregnancy or if an individual turns pregnant while using this medication, the person getting treatment should be informed of any potential risks to the fetus. The drug should be stopped immediately if the patient conceives during the treatment. Based on the period of gestational exposure to Valsartan, the doctor should inform the patient of any possible risks to the fetus (first trimester only or later). An ultrasound should be performed if exposure occurs after the first trimester. Valsartan treatment should be stopped as soon as possible if pregnancy develops in a patient taking it. Based on the period of gestational exposure to Valsartan, the doctor should inform the patient of any possible risks to the fetus (first trimester only or later). An ultrasound should be performed if exposure occurs after the first trimester.

• Nursing Mothers - The presence of Valsartan in breast milk is unknown. The presence of the drug has been reported in rat’s milk, but drug levels in animal breast milk might not be entirely representative of levels in human breast milk. Given that many medications are excreted in human milk and that Valsartan may cause negative effects in nursing infants, a choice should be made regarding whether to stop nursing or stop taking the medication, taking into account the significance of the medication to the mother.

• Pediatric Use - Valsartan's antihypertensive effects on pediatric patients between the ages of 1 and 5 and 6 and 16 were assessed in two randomized, double-blind clinical studies. Valsartan's pharmacokinetics have been examined in pediatric patients between the ages of 1 and 16. Children aged 6 to 16 years generally tolerated Valsartan well, and the adverse experience profile was similar to that for adults. Due to safety findings for which a causal relationship to the treatment could not be ruled out, Valsartan is not advised for pediatric patients younger than six years of age. Due to a lack of data, Valsartan is not advised for the treatment of kids whose glomerular filtration rates are below 30 milliliter/minute/1.73-meter square.

• Geriatric Use- In the Valsartan-controlled clinical trials, 265 (7.9%) and 1,214 (36.2%) of the hypertensive patients receiving Valsartan were over the age of 75. There was no overall difference in Valsartan efficacy or safety in this patient population, but some older people might be more sensitive. Regarding safety and effectiveness, there were no significant variations between the younger people and the older population.

Overdosage:

There is a shortage of data on human overdose. Hypotension and tachycardia would be the most common overdose symptoms, while bradycardia could result from parasympathetic (vagal) stimulation. There have been reports of shock, circulatory collapse, and a depressed level of consciousness. Supportive care should be started if symptomatic hypotension should occur. Hemodialysis does not remove Valsartan from the plasma.

Indications and Usage of Valsartan:

• Hypertension - It is recommended to use Valsartan to treat hypertension and lower blood pressure. Since blood pressure decreases, the chances of both fatal and nonfatal cardiovascular events, particularly strokes and myocardial infarctions, are also reduced. This event has been clearly demonstrated in clinical trials. Valsartan can be used either by itself or in conjunction with other antihypertensive medications.

• Heart Failure - Valsartan is prescribed to treat heart failure. Valsartan significantly decreased heart failure hospitalizations in a controlled clinical trial. There is no proof that taking Valsartan along with an adequate dosage of an ACE inhibitor has any added advantages.

• Post-Myocardial Infarction - In clinically stable patients,Valsartan reduces the cardiovascular mortality caused due to left ventricular failure after a heart attack.

Dosage Forms and Strengths:

• 40 milligrams (mg) Tablets - Yellow oval-like tablets with beveled edges. NVR/DO is imprinted on both sides, i.e. side 1 and side 2.

• 80 mg Tablets - Tablets are pale red almond-shaped with beveled edges. NVR/ DV is imprinted.

• 160 mg Tablets - Tablets are gray-orange almond-shaped with beveled edges. NVR/ DX is imprinted.

• 320 mg Tablets - Tablets are dark gray-violet almond-shaped with beveled edges. NVR/ DXL is imprinted.

Dosage and Availability:

• Hypertension in Adults - When used as monotherapy in patients who are not volume-depleted, Valsartan should be administered at a starting dose of either 80 mg or 160 mg once daily. Patients who require larger dose reductions might begin at the higher dose. Administration of 80 mg to 320 mg of Valsartan once daily is the recommended dosage range for this medication. The antihypertensive effect is largely noticeable till two weeks, and after four weeks, the maximum reduction is typically attained. The maximum dose can be increased up to 320 mg; however, it is always suggested to use a combination of drugs rather than a dose increase if high blood pressure cannot be controlled by monotherapy. The patient can take Valsartan with or without food.

• Pediatric Hypertension - The typical starting dose advised for kids who can swallow pills is 1.3 milligrams per kilogram (mg/kg) once daily (up to 40 mg total). Depending on how the blood pressure responds, the dosage should be changed. Studies have not been conducted on pediatric patients aged 6 to 16 for doses greater than 2.7 mg/kg (up to 160 mg) once daily. It is advised to use a suspension in children who do not swallow tablets or in children for whom the calculated dosage (mg/kg) does not match the strengths of the Valsartan tablets that are currently available. The Valsartan dosage may need to be increased if a tablet is used in place of the suspension. The exposure to Valsartan is 1.6 times higher with the suspension than with the tablet.

• Heart Failure - Valsartan should be taken at a starting dose of 40 mg twice daily. Depending on how well the patient tolerates it, the dose can be raised to 80 mg and 160 mg twice a day. The dose of concurrent diuretics should be taken into consideration. 320 mg in divided doses is the maximum daily dosage used in clinical trials.

• Post Myocardial Infarction - Valsartan can be started with a dose of 20 mg twice daily. It can be started as early as 12 hours following a myocardial infarction. Within 7 days, the dose can be increased as high as 40 mg twice daily with a maintenance dose of 160 mg twice daily. In the event of symptomatic hypotension or impaired kidney function, dosage reduction should be taken into consideration. Aspirin, beta-blockers, thrombolytics, and statins are all common post-myocardial infarction treatments that can be combined with Valsartan.

Warnings and Precautions:

• Fetal or Neonatal Mortality and Morbidity - When given to a pregnant woman, Valsartan has the potential to harm the fetus. If this medication is taken during pregnancy or if the patient turns pregnant while on this medication, the patient should be made aware of the potential risk to the fetus.

• Hypotension - In individuals with uncomplicated hypertension treated with Valsartan alone, excessive hypotension was infrequently observed (0.1 %). Individuals with an activated renin-angiotensin system, including those that are volume- and/or salt-depleted and taking excessive amounts of diuretics, may experience symptomatic hypotension. Before taking Valsartan, this condition needs to be treated, or the treatment should begin while being closely monitored by a doctor. Patients with heart failure or those who have recently experienced a myocardial infarction should be started on Valsartan with caution. Valsartan commonly lowers blood pressure in heart failure or post-myocardial infarction patients, but therapy discontinuation due to persistent symptomatic hypotension is typically not required.

If excessive hypotension occurs, the patient should be placed in the supine position and, if needed, should receive an intravenous infusion of normal saline. A brief hypotensive response does not deprive further therapy, which is typically easy to continue after the blood pressure has stabilized.

• Impaired Hepatic Function - Patients with mild-to-moderate hepatic impairment, including those with biliary obstructive disorders, exhibited lower Valsartan clearance because the majority of Valsartan is eliminated in the bile. Valsartan should be administered to these patients with caution.

• Impaired Renal Function - Research studies of ACE inhibitors in patients with hypertension alongside unilateral or bilateral renal artery stenosis have shown a rise in serum creatinine or blood urea nitrogen. In a 4-day trial of Valsartan, neither the blood urea nitrogen level nor the serum creatinine level significantly increased in any of the 12 hypertensive patients with unilateral renal artery stenosis. Although Valsartan has not been used for an extended period of time in patients with unilateral or bilateral renal artery stenosis, a similar effect to that of ACE inhibitors should be expected.

Clinical Trials:

• Adult Hypertension:

  • The antihypertensive impact of Valsartan was primarily shown in 7 placebo-controlled, 4 to 12 week trials with dosages ranging from 10 to 320 mg/day in patients with diastolic blood pressures of 95 to 115 at baseline.

  • The studies enabled evaluation of the incremental effects of Hydrochlorothiazide as well as comparison of once-daily and twice-daily regimens of 160 mg/day of Valsartan, comparison of peak and trough effects, and comparison of response by gender, age, and race.

  • When Valsartan is administered to patients with primary hypertension, there is a significant reduction in systolic and diastolic blood pressure while sitting, lying down, and standing. However, there is little to no change in their orthostatic blood pressure.

  • Upon withdrawal, a significant increase in blood pressure has not been associated.

• Pediatric Hypertension:

  • Patients under 35 kg were given 10, 40, or 80 mg of valsartan every day (low, medium, and high doses), and patients over 35 kg received 20, 80, and 160 mg of Valsartan daily in a clinical study involving 261 hypertensive pediatric patients aged between 6 to 16 years of age.

  • The most prevalent underlying causes of hypertension in the children included in this study were renal and urinary disorders, essential hypertension, and essential hypertension with or without obesity.

  • Valsartan decreased both systolic and diastolic blood pressure at the end of two weeks in a dose-dependent manner.

  • After two weeks, it was noted that there was a dose-dependent reduction for both systolic and diastolic blood pressure. Overall, the three Valsartan dose levels (low, medium, and high) significantly lowered systolic blood pressure from the baseline by -8, -10, and -12 mm Hg, respectively.

  • Re-randomization was used to assign patients to either receive the same dosage of Valsartan or a placebo. Systolic blood pressure remained lower for patients who received medium and high doses of Valsartan than the patients who were treated with a placebo.

  • For patients who received a low dose of Valsartan, the blood pressure trough was found to be similar to the ones receiving placebo treatment.

  • All of the demographic subgroups experienced Valsartan’s dose-dependent antihypertensive effect.