valsartan 160 MG Oral Tablet
Generic Name: VALSARTAN
Brand Name: Valsartan
- Substance Name(s):
7 No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide or indomethacin.
The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism [see Clinical Pharmacology (12.3)].
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.
Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
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 drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
If co-medication is considered necessary, monitoring of serum potassium is advisable.
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, coadministration 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.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy [see Clinical Trials (14.3)].
Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.
In general, avoid combined use of RAS inhibitors.
Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS.
Do not coadminister aliskiren with valsartan in patients with diabetes.
Avoid use of aliskiren with valsartan 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 with angiotensin II receptor antagonists, including valsartan.
Monitor serum lithium levels during concomitant use.
• Potassium sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium, and in heart failure patients, increases in serum creatinine (7) • NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect (7) • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7) • Lithium: Increases in serum lithium concentrations and lithium toxicity (7) 7.1 Clinical Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.
Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking valsartan and 0.6% given placebo in controlled clinical trials of hypertensive patients.
In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of valsartan patients, compared with 0.1% and 0.1% in placebo-treated patients.
One valsartan patient discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in valsartan-treated patients.
Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of valsartan -treated patients compared to 2.9% of placebo-treated patients.
In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of valsartan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients.
10 Limited data are available related to overdosage in humans.
The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.
Depressed level of consciousness, circulatory collapse and shock have been reported.
If symptomatic hypotension should occur, supportive treatment should be instituted.
Valsartan is not removed from the plasma by hemodialysis.
Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 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.)
11 Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype.
Valsartan, USP is chemically described as L-valine, N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-.
Its empirical formula is C24H29N5O3, its molecular weight is 435.52, and its structural formula is Valsartan, USP is a white to an off-white powder.
It is soluble in ethanol and methanol and insoluble in water.
Valsartan is available as tablets for oral administration, containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan, USP.
The inactive ingredients of the tablets are croscarmellose sodium, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.
In addition to this 40 mg contains iron oxide yellow, 80 mg contains iron oxide red, 160 mg contains iron oxides (yellow and red) and 320 mg contains iron oxides (yellow, red and black).
USP dissolution test is pending.
14 14.1 Hypertension Adult Hypertension The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95 to 115 mmHg.
The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours.
The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II.
At higher doses, however (160 mg), there is little difference in peak and trough effect.
During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks.
In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to two years.
The antihypertensive effect is independent of age, gender or race.
The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites).
In pooled, randomized, controlled trials of valsartan tablets that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites.
The explanation for this difference from previous findings is unclear.
Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive.
The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo.
Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6 to 9/3 to 5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg.
In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.
Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.
In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.
There are no trials of valsartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
There was essentially no change in heart rate in valsartan-treated patients in controlled trials.
Pediatric Hypertension The antihypertensive effects of valsartan were evaluated in two randomized, double-blind clinical studies.
In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses).
Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study.
At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner.
Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mm Hg from the baseline, respectively.
Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo.
In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment.
In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment.
Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.
In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group.
[see Adverse Reactions (6.1)].
14.2 Heart Failure The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF <40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years.
Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor.
Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%).
The population studied was 80% male, 46% 65 years or older and 89% Caucasian.
At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group.
There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours.
These results are summarized in the following table.
Placebo (N=2,499) Valsartan (N=2,511) Hazard Ratio (95% CI*) Nominal p-value All-cause mortality 484 (19.4%) 495 (19.7%) 1.02 (0.90-1.15) 0.8 HF morbidity 801 (32.1%) 723 (28.8%) 0.87 (0.79-0.97) 0.009 *Cl = Confidence Interval Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.
Without ACE Inhibitor With ACE Inhibitor Placebo (N=181) Valsartan (N=185) Placebo (N=2,318) Valsartan (N=2,326 Events (%) 77 (42.5%) 46 (24.9%) 724 (31.2%) 677 (29.1%) Hazard ratio (95% CI) 0.51 (0.35, 0.73) 0.92 (0.82, 1.02) p-value 0.0002 0.0965 The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor.
Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.
Secondary end points in the subgroup not receiving ACE inhibitors were as follows.
Placebo (N=181) Valsartan (N=185) Hazard Ratio (95% CI) Components of HF morbidity All-cause mortality 49 (27.1%) 32 (17.3%) 0.59 (0.37, 0.91) Sudden death with resuscitation 2 (1.1%) 1 (0.5%) 0.47 (0.04, 5.20) CHF therapy 1 (0.6%) 0 (0.0%) – CHF hospitalization 48 (26.5%) 24 (13.0%) 0.43 (0.27, 0.71) Cardiovascular mortality 40 (22.1%) 29 (15.7%) 0.65 (0.40, 1.05) Non-fatal morbidity 49 (27.1%) 24 (13.0%) 0.42 (0.26, 0.69) In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).
Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor.
The number of black patients was small and does not permit a meaningful assessment in this subset of patients.
16 /STORAGE AND HANDLING Valsartan is available as tablets containing valsartan USP, 40 mg, 80 mg, 160 mg, or 320 mg.
All strengths are packaged in bottles and unit dose blister packages as described below.
Valsartan Tablets USP, 40 mg are yellow coloured, capsule shaped, biconvex, film coated tablets, debossed with ‘H’ on one side and ‘182’ on the other side, 18 and 2 separated by a score line.
They are supplied as Bottle of 30 Tablets (NDC 31722-745-30) Bottle of 90 Tablets (NDC 31722-745-90) Bottle of 500 Tablets (NDC 31722-745-05) Blister Card of 10 Unit-Dose tablets (Alu-Alu) (NDC 31722-745-31) Blister Pack of 100 (10 x 10) Unit-Dose tablets (Alu-Alu) (NDC 31722-745-32) Valsartan Tablets USP, 80 mg are pink coloured, round shaped, biconvex, film coated tablets, debossed with ‘183’ on one side and ‘H’ on the other side.
They are supplied as Bottle of 30 Tablets (NDC 31722-746-30) Bottle of 90 Tablets (NDC 31722-746-90) Bottle of 500 Tablets (NDC 31722-746-05) Blister Card of 10 Unit-Dose tablets (Alu-Alu) (NDC 31722-746-31) Blister Pack of 100 (10 x 10) Unit-Dose tablets (Alu-Alu) (NDC 31722-746-32) Valsartan Tablets USP, 160 mg are yellowish brown coloured, oval shaped, biconvex, film coated tablets, debossed with ‘184’ on one side and ‘H’ on the other side.
They are supplied as Bottle of 30 Tablets (NDC 31722-747-30) Bottle of 90 Tablets (NDC 31722-747-90) Bottle of 500 Tablets (NDC 31722-747-05) Blister Card of 10 Unit-Dose tablets (Alu-Alu) (NDC 31722-747-31) Blister Pack of 100 (10 x 10) Unit-Dose tablets (Alu-Alu) (NDC 31722-747-32) Valsartan Tablets USP, 320 mg are dark grey-violet colored, capsule shaped, biconvex, film coated tablets, debossed with ‘185’ on one side and ‘H’ on the other side.
They are supplied as Bottle of 30 Tablets (NDC 31722-748-30) Bottle of 90 Tablets (NDC 31722-748-90) Bottle of 500 Tablets (NDC 31722-748-05) Blister Card of 10 Unit-Dose tablets (Alu-Alu) (NDC 31722-748-31) Blister Pack of 100 (10 x 10) Unit-Dose tablets (Alu-Alu) (NDC 31722-748-32) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from moisture.
Dispense in tight container (USP).
8.5 Geriatric Use In the controlled clinical trials of valsartan, 1,214 (36.2%) of hypertensive patients treated with valsartan were ≥65 years and 265 (7.9%) were ≥75 years.
No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older.
There were no notable differences in efficacy or safety between older and younger patients in this trial.
DOSAGE FORMS AND STRENGTHS
3 DOSAGE FORMS & STRENGTHS 40 mg are yellow coloured, capsule shaped, biconvex, film coated tablets, debossed with ‘H’ on one side and ‘182’ on the other side, 18 and 2 separated by a score line.
80 mg are pink coloured, round shaped, biconvex, film coated tablets, debossed with ‘183’ on one side and ‘H’ on the other side.
160 mg are yellowish brown coloured, oval shaped, biconvex, film coated tablets, debossed with ‘184’ on one side and ‘H’ on the other side.
320 mg are dark grey-violet colored, capsule shaped, biconvex, film coated tablets, debossed with ‘185’ on one side and ‘H’ on the other side.
Tablets (mg): 40 (scored), 80, 160, 320
MECHANISM OF ACTION
12.1 Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).
Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.
Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland.
Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis.
Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor.
The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor.
The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension.
ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE.
Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin.
Whether this difference has clinical relevance is not yet known.
Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
INDICATIONS AND USAGE
1 INDICATIONS & USAGE Valsartan tablet is an angiotensin II receptor blocker (ARB) indicated for: • Treatment of hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1) • Treatment of heart failure (NYHA class II to IV); valsartan tablets significantly reduced hospitalization for heart failure (1.2) 1.1 Hypertension Valsartan tablets are indicated for the treatment of hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which valsartan principally belongs.
There are no controlled trials in hypertensive patients demonstrating risk reduction with valsartan tablets, USP.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.
Many patients will require more than one drug to achieve blood pressure goals.
For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.
The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.
Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).
These considerations may guide selection of therapy.
Valsartan tablets may be used alone or in combination with other antihypertensive agents.
1.2 Heart Failure Valsartan tablets are indicated for the treatment of heart failure (NYHA class II to IV).
In a controlled clinical trial, valsartan tablets significantly reduced hospitalizations for heart failure.
There is no evidence that valsartan tablets provide added benefits when it is used with an adequate dose of an ACE inhibitor [see Clinical Studies (14.2)].
8.4 Pediatric Use The antihypertensive effects of valsartan have been evaluated in two randomized, double-blind clinical studies in pediatric patients from 1 to 5 and 6 to 16 years of age [see Clinical Studies (14.1)].
The pharmacokinetics of valsartan have been evaluated in pediatric patients 1 to 16 years of age [see Pharmacokinetics, Special Populations, Pediatric (12.3)].
Valsartan were generally well tolerated in children 6 to 16 years and the adverse experience profile was similar to that described for adults.
In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.
Valsartan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded [see Adverse Reactions, Pediatric Hypertension (6.1)].
No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2.
There is limited clinical experience with valsartan in pediatric patients with mild to moderate hepatic impairment [See Warnings and Precautions (5.3)].
Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage.
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.
Since this period coincides with up to 44 weeks after conception in humans, it is not considered to point toward an increased safety concern in 6 to 16 year old children.
Neonates with a history of in utero exposure to valsartan: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
8.1 Pregnancy: Teratogenic Effects Pregnancy Category D 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.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue valsartan as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy.
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.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
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.
Perform serial ultrasound examinations to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue valsartan, unless it is considered lifesaving for the mother.
Fetal testing may be appropriate, based on the week of pregnancy.
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 valsartan for hypotension, oliguria, and hyperkalemia.
[see Use in Specific Populations (8.4)]
8.3 Nursing Mothers It is not known whether valsartan is excreted in human milk.
Valsartan was excreted in the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels.
Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from valsartan, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue valsartan tablets as soon as possible.
( 5.1 ) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
( 5.1 ) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue valsartan tablets as soon as possible.
(5.1) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Observe for signs and symptoms of hypotension (5.2) • Monitor renal function and potassium in susceptible patients (5.3, 5.4) 5.1 Fetal Toxicity Pregnancy Category D 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.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue valsartan tablets as soon as possible.
[see Use in Specific Populations (8.1)].
5.2 Hypotension 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.
5.3 Impaired Renal Function 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 tablets [see Drug Interactions (7)].
5.4 Hyperkalemia 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 tablets may be required.
[see Adverse Reactions (6.1)]
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Information for Patients Advise the patient to read the FDA-approved patient labeling (Patient Information).
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan tablets during pregnancy.
Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
Manufactured for: Camber Pharmaceuticals, Inc., Piscataway, NJ 08854 By:HETEROTM 2040228 Hetero Labs Limited,Unit V, Polepally, Jadcherla, Mahaboob Nagar-509 301, India.
Barcode Revised: February 2017 address1
DOSAGE AND ADMINISTRATION
2 DOSAGE & ADMINISTRATION Indication Starting Dose Dose Range Target Maintenance Dose* Adult Hypertension (2.1) 80 or 160 mg once daily 80-320 mg once daily — Pediatric Hypertension (6-16 years) (2.2) 1.3 mg/kg once daily (up to 40 mg total) 1.3-2.7 mg/kg once daily (up to 40-160 mg total) — Heart Failure (2.3) 40 mg twice daily 40-160 mg twice daily 160 mg twice daily * as tolerated by patient 2.1 Adult Hypertension The recommended starting dose of valsartan tablets is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted.
Patients requiring greater reductions may be started at the higher dose.
Valsartan tablet may be used over a dose range of 80 mg to 320 mg daily, administered once a day.
The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks.
If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added.
Addition of a diuretic has a greater effect than dose increases beyond 80 mg.
No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency.
Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment.
Valsartan tablets may be administered with other antihypertensive agents.
Valsartan tablets may be administered with or without food.
2.2 Pediatric Hypertension 6 to 16 years of Age For children who can swallow tablets, the usual recommended starting dose is 1.3 mg/kg once daily (up to 40 mg total).
The dosage should be adjusted according to blood pressure response.
Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
For children who cannot swallow tablets, or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan, the use of a suspension is recommended.
Follow the suspension preparation instructions below (see Preparation of Suspension) to administer valsartan as a suspension.
When the suspension is replaced by a tablet, the dose of valsartan may have to be increased.
The exposure to valsartan with the suspension is 1.6 times greater than with the tablet.
No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2.
[See Pediatric Use (8.4)] Valsartan tablets are not recommended for patients <6 years old.
[See Adverse Reactions (6.1), Clinical Studies (14.1)] Preparation of Suspension (for 160 mL of a 4 mg/mL suspension) Add 80 mL of Ora-Plus®* oral suspending vehicle to an amber glass bottle containing 8 valsartan 80 mg tablets, and shake for a minimum of 2 minutes.
Allow the suspension to stand for a minimum of 1 hour.
After the standing time, shake the suspension for a minimum of 1 additional minute.
Add 80 mL of Ora-Sweet SF®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients.
The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2 to 8°C/35 to 46°F) in the glass bottle with a child-resistant screw-cap closure.
Shake the bottle well (at least 10 seconds) prior to dispensing the suspension.
*Ora-Sweet SF® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc.
2.3 Heart Failure The recommended starting dose of valsartan tablets is 40 mg twice daily.
Uptitration to 80 mg and 160 mg twice daily should be done to the highest dose, as tolerated by the patient.
Consideration should be given to reducing the dose of concomitant diuretics.
The maximum daily dose administered in clinical trials is 320 mg in divided doses.