NOVAVALZ PLUS

Valsartan belongs to the angiotensin

II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, olmesartan, and irbesartan.

ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects, which include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium, among others.

Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions.

Pharmacological blockade of RAAS via

AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease.

In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function.

ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.

By comparison, the angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibit the conversion of angiotensin I to angiotensin II through inhibition of the ACE enzyme.

However, this does not prevent the formation of all angiotensin II within the body.

The angiotensin

II receptor blocker (ARB) family of drugs unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized.

Valsartan is commonly used for the management of hypertension, heart failure, and Type 2 Diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors.

ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. 1, 9, 10, 11, 12, 13, 14, 15 Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. 6, 7, 8 Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. 1, 10 Valsartan was initially approved in in Europe for the treatment of hypertension in adults.

Shortly after, in 1997, this drug was approved in the United States.

Valsartan is generally well-tolerated with a side-effect profile superior to that of other antihypertensive drugs. 3, 4.

Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

It is also indicated for the treatment of heart failure (NYHA class II-Intravenous) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. 29, 18 It is also used in combination with sacubitril.

Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours.

Removal of the negative feedback of angiotensin II causes a 2.

• to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients.

Minimal decreases in plasma aldosterone were observed after administration of valsartan.

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

Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone.

In patients with an activated renin-angiotensin system, such as volume.

• and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur.

This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision.

Caution should be observed when initiating therapy in patients with heart failure.

Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed.

In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics.

Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan.

Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan.

Some patients with heart failure have developed increases in potassium.

These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment.

Dosage reduction and/or discontinuation of valsartan may be required.

After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients.

Food decreases the exposure to

Oral administered valsartan by approximately 40% and peak plasma concentration by approximately 50%.

AUC and

Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range.

Valsartan does not accumulate appreciably in plasma following repetitive administration.

The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively.

Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. 1, 24 The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan.

In vitro metabolism studies involving recombinant

CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan.

Valsartan does not inhibit

CYP 450 isozymes at clinically relevant concentrations.

CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.

Hover over products below to view reaction partners Valsartan Valeryl-4-hydroxyvalsartan.

Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose).

The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.

After intravenous (Intravenous) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 6 hours.

Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total clearance).

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LD50 >2000 mg/kg (Gavage, rat) 24 Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day.

When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus.

When pregnancy is detected, valsartan should be discontinued as soon as possible.

is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy with concomitant use of ACE inhibitors.

Do not administer within 36 hours of switching from or to an ACE inhibitor with concomitant use of aliskiren in patients with diabetes Hypersensitivity to any component.

History of angioedema related to previous ACEi or ARB therapy.

Concomitant use with

ACE inhibitors.

Concomitant use with aliskiren in patients with diabetes.

The recommended starting dosage for adults is 49 mg/51 mg orally twice daily.

The target maintenance dose is 97 mg/103mg orally twice daily.

Adjust adult doses every to 4 weeks to the target maintenance dose, as tolerated by the patient.

For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions.

Reduce starting dose to half the usually recommended starting dosage for: patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. patients with severe renal impairment. patients with moderate hepatic impairment. 2.1 General Considerations ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor.

If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs. 2.2 Adult Heart Failure The recommended starting dose of ENTRESTO is 49/51 mg orally twice-daily.

Double the dose of

ENTRESTO after to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient. 2.3 Pediatric Heart Failure For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets, or Table 2 if using the oral pellets.

Take the recommended dose orally twice daily.

Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.

Table 1: Recommended Dose and Titration for Pediatric Patients Using Tablets † Use of the oral suspension or oral pellets is recommended in these patients.

Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan. ‡ Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets.

Dose (twice daily) Weight (kg) Starting Second Final Less than 40 kg † 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg At least 40 kg, less than 50 kg 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg ‡ At least 50 kg 49 mg/51 mg 72 mg/78 mg ‡ 97 mg/103 mg Table 2: Recommended Dose and Titration for Pediatric Patients using ENTRESTO SPRINKLE † † When using capsules, more than one capsule may be needed to achieve recommended doses.

Oral pellets are contained within each capsule.

Use the entire contents of the capsules to achieve the dose. ‡ Recommended mg/kg doses are of the combined amount of sacubitril and valsartan. * For patients 50 kg or more, see Table 1.

Dose (twice daily) Weight (kg) Starting Second Final Less than 13 (use oral suspension ‡ ) 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg to less than 19 12 mg/12 mg (Two 6 mg/6 mg capsules) 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 19 to less than 26 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 26 to less than 34 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 34 to less than 50 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 60 mg/64 mg (Four 15 mg/16 mg capsules) 2.4 Preparation of Oral Suspension Using Tablets ENTRESTO oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets.

ENTRESTO 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL).

ENTRESTO 49/51 mg tablets in the preparation of the suspension.

To make an 800 mg/200 mL (4 mg/mL) oral suspension, transfer eight tablets of ENTRESTO 49/51 mg film-coated tablets into a mortar.

Crush the tablets into a fine powder using a pestle.

Add 60 mL of Ora-Plus ® into the mortar and triturate gently with pestle for 10 minutes, to form a uniform suspension.

Add 140 mL of Ora-Sweet ® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension.

Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle.

Place a press-in bottle adapter and close the bottle with a child resistant cap.

The oral suspension can be stored for up to 15 days.

Do not store above 25°C (77°F) and do not refrigerate.

Shake before each use. * Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc. 2.5 Preparation and Administration of Oral Pellets ENTRESTO SPRINKLE are oral pellets contained within capsules.

Do not swallow the capsules.

Do not chew or crush the oral pellets.

SPRINKLE can also be substituted in patients unable to swallow tablets.

Use the entire contents of the capsules to achieve the dose.

To administer

ENTRESTO oral pellets, open the capsule and sprinkle the full content onto to 2 teaspoons of soft food.

Consume the food containing the oral pellets immediately after adding them.

Empty capsule shells must be discarded after use and not swallowed.

Do not administer

ENTRESTO oral pellets via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes. 2.6 Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start ENTRESTO at half the usually recommended starting dose.

After initiation, increase the dose every to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter.

Initiate pediatric patients weighing to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets. 2.7 Dose Adjustment for Severe Renal Impairment In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m 2 ), start ENTRESTO at half the usually recommended starting dose.

After initiation, increase the dose to follow the recommended dose escalation thereafter.

Initiate pediatric patients weighing to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets.

No starting dose adjustment is needed for mild or moderate renal impairment. 2.8 Dose Adjustment for Hepatic Impairment In adults and pediatric patients with moderate hepatic impairment (Child-Pugh B classification), start ENTRESTO at half the usually recommended starting dose.

No starting dose adjustment is needed for mild hepatic impairment.

Use in patients with severe hepatic impairment is not recommended.

(sacubitril/valsartan) tablets are unscored, ovaloid, biconvex, and film-coated.

ENTRESTO film-coated oral pellets are round, biconvex in shape, and provided in a hard capsule.

All strengths are packaged in bottles as described below.

Sacubitril/valsartan mg/mg Color Debossment Side 1/side 2 NDC 0078-XXXX-XX Bottle of 60 Bottle of 180 24/26 Violet white NVR/LZ 0659-20 0659-67 49/51 Pale yellow NVR/L1 0777-20 0777-67 97/103 Light pink NVR/L11 0696-20 0696-67 ENTRESTO SPRINKLE Sacubitril/valsartan mg/mg Color Print NDC 0078-XXXX-XX Bottle of 60 6/6 White cap and transparent body “NVR” and both parts with arrows and “04” 1231-20 15/16 Yellow cap and transparent body “NVR” and both parts with arrows and “10” 1238-20 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) .

Protect from moisture.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) .

Protect from moisture.

ENTRESTO can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the renin-angiotensin system during the 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 antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

In animal reproduction studies, ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits.

When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO.

However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Fetal/Neonatal Adverse Reactions 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, skeletal deformations, including skull hypoplasia, hypotension, and death.

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.

If oligohydramnios is observed, consider alternative drug treatment.

Closely observe neonates with histories of in utero exposure to ENTRESTO for hypotension, oliguria, and hyperkalemia.

In neonates with a history of in utero exposure to ENTRESTO, if oliguria or hypotension occurs, support blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.

ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).

ENTRESTO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an ENTRESTO dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity.

• and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with ENTRESTO during organogenesis, gestation and lactation may affect pup development and survival.

The safety and effectiveness of

ENTRESTO have been established for the treatment of heart failure in pediatric patients 1 year to less than 18 years.

Use of

ENTRESTO was evaluated in a multinational, randomized, double-blind trial comparing ENTRESTO and enalapril in 375 patients aged 1 month to less than 18 years (ENTRESTO n = 187; Enalapril n = 188) (PANORAMA-HF) .

The safety profile in pediatric patients (1 year to less than 18 years) receiving ENTRESTO was similar to that seen in adult patients.

Limited safety and efficacy data in patients aged 1 month to less than 1 year were inadequate to support conclusions on safety and efficacy in this.

Sacubitril given orally to juvenile rats from postnatal day (PND) 7 to PND 35 or PND 70 (an age approximately equivalent to neonatal through pre-pubertal development or adulthood in humans) at doses greater than or equal to 400 mg/kg/day (approximately 2-fold the AUC exposure to the active metabolite of sacubitril, LBQ657, at an ENTRESTO pediatric clinical dose of 3.1 mg/kg twice daily) resulted in decreases in body weight, bone length, and bone mass.

The decrease in body weight was transient from PND to PND and the effects for most bone parameters were reversible after treatment stopped.

Exposure at the

No-Observed-Adverse-Effect-Level (NOAEL) of 100 mg/kg/day was approximately 0.5-fold the AUC exposure to LBQ657 at the 3.1 mg/kg twice daily dose of ENTRESTO.

The mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown.

Valsartan given orally to juvenile rats from PND to PND 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels.

Exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at 3.1 mg/kg twice daily dose of ENTRESTO based on AUC.

These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.

This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.

In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age.

It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney.

There were and 3,971 heart failure patients 65 years of age and older in PARADIGM-HF and PARAGON-HF, respectively.

Of the total number of

ENTRESTO-treated patients, 2,087 (49.6%) and 1,995 (82.9%) were 65 years of age and older, while 786 (18.7%) and 1,100 (45.7%) were 75 years of age and older in PARADIGM-HF and PARAGON-HF, respectively.

No overall differences in safety or effectiveness of ENTRESTO have been observed between patients 65 years of age and older and younger adult patients in either study.

No relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population.