Hydrochlorothiazide 25 MG / valsartan 160 MG Oral Tablet
DRUG INTERACTIONS
7 Valsartan-Hydrochlorothiazide: Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides.
Monitor lithium levels in patients taking valsartan and hydrochlorothiazide.
Valsartan: 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.
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.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium 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.
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.
Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and hydrochlorothiazide and other agents that affect the RAS.
Do not coadminister aliskiren with valsartan and hydrochlorothiazide in patients with diabetes.
Avoid use of aliskiren with valsartan and hydrochlorothiazide in patients with renal impairment (GFR < 60 mL/min).
Hydrochlorothiazide: When administered concurrently, the following drugs may interact with thiazide diuretics: Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.
Nonsteroidal Anti-inflammatory Drugs (NSAIDS and COX-2 selective inhibitors): When valsartan and hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Carbamazepine: May lead to symptomatic hyponatremia.
Ion exchange resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology (12.3)].
Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.
Antidiabetic drugs: Dosage adjustment of antidiabetic may be required.
( 7) Cholestyramine and colestipol: Reduced absorption of thiazides.
( 12.3) Lithium: Increased risk of lithium toxicity.
Monitor serum lithium concentrations during concurrent use.
( 7) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): May increase risk of renal impairment.
Can reduce diuretic, natriuretic and antihypertensive effects of diuretics.
( 7) Dual inhibition of the renin-angiotesin system: Increased risk of renal impairment, hypotension and hyperkalemia.
( 7)
OVERDOSAGE
10 Valsartan and Hydrochlorothiazide: 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 dialysis.
The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.
If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, were very well tolerated without any treatment-related effects.
These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the maximum recommended human dose (MRHD) of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m 2 basis.
(Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60 kg patient.) Valsartan: 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 MRHD on a mg/m 2 basis).
(Calculations assume an oral dose of 320 mg/day and a 60 kg patient.) Hydrochlorothiazide: The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which represents 2,027 and 4,054 times, respectively, the MRHD on a mg/m 2 basis.
(Calculations assume an oral dose of 25 mg/day and a 60 kg patient.)
DESCRIPTION
11 Valsartan and hydrochlorothiazide tablets, USP is a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB) acting on the AT 1 receptor subtype, and hydrochlorothiazide, a diuretic.
Valsartan, a nonpeptide molecule, is chemically described as N-[p-(o-1 H-Tetrazol-5-ylphenyl)benzyl- N-Valeryl-L-valine.
Its molecular formula is C 24H 29N 5O 3, its molecular weight is 435.5, and its structural formula is Valsartan, USP is a white to practically white fine powder.
It is soluble in ethanol and methanol and slightly soluble in water.
Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder.
It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids.
Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2 H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Hydrochlorothiazide is a thiazide diuretic.
Its molecular formula is C 7H 8ClN 3O 4S 2, its molecular weight is 297.73, and its structural formula is Valsartan and hydrochlorothiazide tablets are formulated for oral administration to contain valsartan and hydrochlorothiazide 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg.
The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium lauryl sulfate, titanium dioxide and triacetin.
The 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg and 320 mg/12.5 mg tablets also contain red iron oxide and yellow iron oxide.
The 320 mg/25 mg tablet also contains FD&C Blue No.
2 Aluminum Lake and FD&C Yellow No.
6 Aluminum Lake.
Valsartan Structural Formula Hydrochlorothiazide Structural Formula
CLINICAL STUDIES
14 14.1 Hypertension Valsartan and Hydrochlorothiazide In controlled clinical trials including over 7,600 patients, 4,372 patients were exposed to valsartan (80 mg, 160 mg and 320 mg) and concomitant hydrochlorothiazide (12.5 mg and 25 mg).
Two factorial trials compared various combinations of 80 mg/12.5 mg, 80 mg/25 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg with their respective components and placebo.
The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14 to 21/8 to 11 mmHg at 80 mg/12.5 mg to 320 mg/25 mg, compared to 7 to 10/4 to 5 mmHg for valsartan 80 mg to 320 mg and 5 to 11/2 to 5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg, alone.
Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4 to 12/2 to 5 mmHg.
The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.
In long-term follow-up studies (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide appeared to be maintained for up to 2 years.
The antihypertensive effect is independent of age or gender.
The overall response to the combination was similar for Black and non-Black patients.
There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.
There are no trials of the valsartan and hydrochlorothiazide combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the hydrochlorothiazide component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.
Valsartan The antihypertensive effects of valsartan were demonstrated principally in seven placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95 to 115.
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 2 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 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 seven 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 mg, 160 mg 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 mg to 160 mg and 9/6 mmHg at 320 mg.
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 another 4-week study, 1,876 patients randomized to valsartan 320 mg once daily had an incremental blood pressure reduction 3/1 mmHg lower than did 1,900 patients randomized to valsartan 160 mg once daily.
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 was essentially no change in heart rate in valsartan-treated patients in controlled trials.
14.2 Initial Therapy – Hypertension The safety and efficacy of valsartan and hydrochlorothiazide as initial therapy for patients with severe hypertension (defined as a sitting diastolic blood pressure ≥ 110 mmHg and systolic blood pressure ≥ 140 mmHg off all antihypertensive therapy) was studied in a 6-week multicenter, randomized, double-blind study.
Patients were randomized to either valsartan and hydrochlorothiazide 160 mg/12.5 mg once daily or to valsartan (160 mg once daily) and followed for blood pressure response.
Patients were force-titrated at 2 week intervals.
Patients on combination therapy were subsequently titrated to 160 mg/25 mg followed by 320 mg/25 mg valsartan and hydrochlorothiazide.
Patients on monotherapy were subsequently titrated to 320 mg valsartan followed by a titration to 320 mg valsartan to maintain the blind.
The study randomized 608 patients, including 261 (43%) females, 147 (24%) Blacks and 75 (12%) ≥ 65 years of age.
The mean blood pressure at baseline for the total population was 168/112 mmHg.
The mean age was 52 years.
After 4 weeks of therapy, reductions in systolic and diastolic blood pressure were 9/5 mmHg greater in the group treated with valsartan and hydrochlorothiazide compared to valsartan.
Similar trends were seen when the patients were grouped according to gender, race or age.
HOW SUPPLIED
16 /STORAGE AND HANDLING Valsartan and Hydrochlorothiazide Tablets, USP are available containing 80 mg/12.5 mg, 160 mg/12.5 mg or 160 mg/25 mg of valsartan, USP and hydrochlorothiazide, USP The 80 mg/12.5 mg tablets are an orange film-coated, round, unscored tablets, debossed with M on one side of the tablet and V21 on the other side.
They are available as follows: NDC 51079-192-03 – Unit dose blister packages of 30 (3 cards of 10 tablets each).
The 160 mg/12.5 mg tablets are an orange film-coated, round, unscored tablets, debossed with M on one side of the tablet and V22 on the other side.
They are available as follows: NDC 51079-193-03 – Unit dose blister packages of 30 (3 cards of 10 tablets each).
The 160 mg/25 mg tablets are an orange film-coated, oval, unscored tablets, debossed with M on one side of the tablet and V23 on the other side.
They are available as follows: NDC 51079-194-03 – Unit dose blister packages of 30 (3 cards of 10 tablets each).
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from light, moisture and heat.
PHARMACIST: Dispense the Patient Information Leaflet with each prescription.
GERIATRIC USE
8.5 Geriatric Use In the controlled clinical trials of valsartan and hydrochlorothiazide, 764 (17.5%) patients treated with valsartan and hydrochlorothiazide were ≥ 65 years and 118 (2.7%) were ≥ 75 years.
No overall difference in the efficacy or safety of valsartan and hydrochlorothiazide was observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
DOSAGE FORMS AND STRENGTHS
3 80 mg/12.5 mg tablets, debossed with M on one side of the tablet and V21 on the other side.
160 mg/12.5 mg tablets, debossed with M on one side of the tablet and V22 on the other side.
160 mg/25 mg tablets, debossed with M on one side of the tablet and V23 on the other side.
320 mg/12.5 mg tablets, debossed with M on one side of the tablet and V24 on the other side.
320 mg/25 mg tablets, debossed with M on one side of the tablet and V25 on the other side.
Tablets (valsartan and HCTZ): 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, 320 mg/25 mg ( 3)
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 AT 1 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 AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis.
Valsartan has much greater affinity (about 20,000-fold) for the AT 1 receptor than for the AT 2 receptor.
The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1 receptor about one 200 th 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.
Hydrochlorothiazide is a thiazide diuretic.
Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.
Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss and decreases in serum potassium.
The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
INDICATIONS AND USAGE
1 Valsartan and hydrochlorothiazide 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 hydrochlorothiazide and the ARB class to which valsartan principally belongs.
There are no controlled trials demonstrating risk reduction with valsartan and hydrochlorothiazide tablets.
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 have also 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 (for example, 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.
Add-On Therapy: Valsartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy.
Replacement Therapy: Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components.
Initial Therapy: Valsartan and hydrochlorothiazide tablets may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals.
The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks.
Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant.
The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy.
Individual blood pressure goals may vary based upon the patient’s risk.
Data from the high dose multifactorial trial [see Clinical Studies (14.1)] provides estimates of the probability of reaching a target blood pressure with valsartan and hydrochlorothiazide tablets compared to valsartan or hydrochlorothiazide monotherapy.
The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with valsartan and hydrochlorothiazide tablets 320 mg/25 mg, based upon baseline systolic or diastolic blood pressure.
The curve of each treatment group was estimated by logistic regression modeling.
The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures.
For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 41% likelihood of achieving a goal of < 140 mmHg (systolic) and 60% likelihood of achieving < 90 mmHg (diastolic) on valsartan alone and the likelihood of achieving these goals on HCTZ alone is about 50% (systolic) or 57% (diastolic).
The likelihood of achieving these goals on valsartan and hydrochlorothiazide tablets rises to about 84% (systolic) or 80% (diastolic).
The likelihood of achieving these goals on placebo is about 23% (systolic) or 36% (diastolic).
Valsartan and hydrochlorothiazide is the combination tablet of valsartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ), a diuretic.
Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure: In patients not adequately controlled with monotherapy ( 1) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals ( 1) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
Figure 1.
Probability of Achieving Systolic Blood Pressure 140 mm/Hg at Week 8 Figure 2.
Probability of Achieving Diastolic Blood Pressure 90 mm/Hg at Week 8 Figure 3.
Probability of Achieving Systolic Blood Pressure 130 mm/Hg at Week 8 Figure 4.
Probability of Achieving Diastolic Blood Pressure 80 mm/Hg at Week 8
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of valsartan and hydrochlorothiazide in pediatric patients have not been established.
Neonates with a history of in utero exposure to valsartan and hydrochlorothiazide: 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.
PREGNANCY
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 and hydrochlorothiazide as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimester 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 and hydrochlorothiazide, 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 and hydrochlorothiazide for hypotension, oliguria and hyperkalemia [see Use in Specific Populations (8.4)] .
Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma.
Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion.
It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma.
Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia.
Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women.
The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether valsartan is excreted in human milk.
Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels.
Hydrochlorothiazide is excreted in human breast milk.
Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from valsartan and hydrochlorothiazide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
WARNING: FETAL TOXICITY When pregnancy is detected, discontinue valsartan and hydrochlorothiazide 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 and hydrochlorothiazide 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 AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2) Observe for signs of fluid or electrolyte imbalance ( 5.9) Monitor renal function and potassium in susceptible patients ( 5.3, 5.7) Exacerbation or activation of systemic lupus erythematosus ( 5.5) Acute angle-closure glaucoma ( 5.8) 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 and hydrochlorothiazide as soon as possible [see Use in Specific Populations (8.1)] .
Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
5.2 Hypotension in Volume- and/or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated hypertension treated with valsartan and hydrochlorothiazide in controlled trials.
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 and hydrochlorothiazide, or the treatment should start under close medical supervision.
If 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 and hydrochlorothiazide.
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 and hydrochlorothiazide [see Drug Interactions (7)] .
5.4 Hypersensitivity Reaction Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
5.5 Systemic Lupus Erythematosus Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
5.6 Lithium Interaction Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics.
Monitor lithium levels in patients receiving valsartan and hydrochlorothiazide and lithium [see Drug Interactions (7)] .
5.7 Potassium Abnormalities Valsartan and Hydrochlorothiazide In the controlled trials of various doses of valsartan and hydrochlorothiazide the incidence of hypertensive patients who developed hypokalemia (serum potassium 5.7 mEq/L) was 0.4%.
Hydrochlorothiazide can cause hypokalemia and hyponatremia.
Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion.
Drugs that inhibit the renin-angiotensin system can cause hyperkalemia.
Monitor serum electrolytes periodically.
If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis or ECG alterations), valsartan and hydrochlorothiazide should be discontinued.
Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.
Some patients with heart failure have developed increases in potassium with valsartan therapy.
These effects are usually minor and transient, and they are more likely to occur in patients with preexisting renal impairment.
Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required [see Adverse Reactions (6.1)].
5.8 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible.
Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.
Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
5.9 Metabolic Disturbances Hydrochlorothiazide Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium.
Monitor calcium levels in patients with hypercalcemia receiving valsartan and hydrochlorothiazide.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Information for Patients: Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan and hydrochlorothiazide 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.
Symptomatic Hypotension: A patient receiving valsartan and hydrochlorothiazide should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician.
The patients should be told that if syncope occurs, valsartan and hydrochlorothiazide should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
Potassium Supplements: A patient receiving valsartan and hydrochlorothiazide should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
FDA-Approved Patient Labeling PATIENT INFORMATION LEAFLET VALSARTAN AND HYDROCHLOROTHIAZIDE TABLETS, USP (val sar’ tan) (hye” droe klor” oh thye’ a zide) 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg Read the Patient Information that comes with valsartan and hydrochlorothiazide tablets before you start taking it and each time you get a refill.
There may be new information.
This leaflet does not take the place of talking with your doctor about your condition and treatment.
If you have any questions about valsartan and hydrochlorothiazide tablets, ask your doctor or pharmacist.
What is the most important information I should know about valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets can cause harm or death to an unborn baby.
Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
If you get pregnant while taking valsartan and hydrochlorothiazide tablets, tell your doctor right away.
What are valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets contains two prescription medicines: 1.
valsartan, an angiotensin receptor blocker (ARB) 2.
hydrochlorothiazide (HCTZ), a water pill (diuretic) Valsartan and hydrochlorothiazide tablets may be used to lower high blood pressure (hypertension) in adults- when one medicine to lower your high blood pressure is not enough as the first medicine to lower high blood pressure if your doctor decides you are likely to need more than one medicine.
Valsartan and hydrochlorothiazide tablets has not been studied in children under 18 years of age.
Who should not take valsartan and hydrochlorothiazide tablets? Do not take valsartan and hydrochlorothiazide tablets if you: are allergic to any of the ingredients in valsartan and hydrochlorothiazide tablets.
See the end of this leaflet for a complete list of ingredients in valsartan and hydrochlorothiazide tablets.
make less urine due to kidney problems are allergic to medicines that contain sulfonamides.
What should I tell my doctor before taking valsartan and hydrochlorothiazide tablets? Tell your doctor about all your medical conditions including if you: are pregnant or plan to become pregnant.
See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” are breast-feeding.
Valsartan and hydrochlorothiazide passes into breast milk.
You should choose either to take valsartan and hydrochlorothiazide tablets or breast-feed, but not both.
have liver problems have kidney problems have or had gallstones have Lupus have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm) or magnesium in your blood have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching).
have high levels of uric acid in the blood.
have ever had a reaction called angioedema to another blood pressure medication.
Angioedema causes swelling of the face, lips, tongue, throat, and may cause difficulty breathing.
Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements.
Some of your other medicines and valsartan and hydrochlorothiazide tablets could affect each other, causing serious side effects.
Especially, tell your doctor if you take: other medicines for high blood pressure or a heart problem water pills (diuretics) potassium supplements.
Your doctor may check the amount of potassium in your blood periodically.
a salt substitute.
Your doctor may check the amount of potassium in your blood periodically.
antidiabetic medicines including insulin narcotic pain medicines sleeping pills lithium, a medicine used in some types of depression (Eskalith ®*, Lithobid ®*, Lithium Carbonate, Lithium Citrate) aspirin or other medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), like ibuprofen or naproxen digoxin or other digitalis glycosides (a heart medicine) muscle relaxants (medicines used during operations) certain cancer medicines, like cyclophosphamide or methotrexate certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir).
These drugs may increase the effect of valsartan.
Ask your doctor if you are not sure if you are taking one of these medicines.
Know the medicines you take.
Keep a list of your medicines with you to show to your doctor and pharmacist when a new medicine is prescribed.
Talk to your doctor or pharmacist before you start taking any new medicine.
Your doctor or pharmacist will know what medicines are safe to take together.
How should I take valsartan and hydrochlorothiazide tablets? Take valsartan and hydrochlorothiazide tablets exactly as prescribed by your doctor.
Your doctor may change your dose if needed.
Take valsartan and hydrochlorothiazide tablets once each day.
Valsartan and hydrochlorothiazide tablets can be taken with or without food.
If you miss a dose, take it as soon as you remember.
If it is close to your next dose, do not take the missed dose.
Just take the next dose at your regular time.
If you take too much valsartan and hydrochlorothiazide, call your doctor or Poison Control Center, or go to the nearest hospital emergency room.
What should I avoid while taking valsartan and hydrochlorothiazide tablets? You should not take valsartan and hydrochlorothiazide tablets during pregnancy.
See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” What are the possible side effects of valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets may cause serious side effects including: Harm to an unborn baby causing injury and even death.
See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” Low blood pressure (hypotension).
Low blood pressure is most likely to happen if you: take water pills are on a low salt diet get dialysis treatments have heart problems get sick with vomiting or diarrhea drink alcohol Lie down if you feel faint or dizzy.
Call your doctor right away.
Allergic reactions.
People with and without allergy problems or asthma who take valsartan and hydrochlorothiazide tablets may get allergic reactions.
Worsening of Lupus.
Hydrochlorothiazide, one of the medicines in valsartan and hydrochlorothiazide tablets may cause Lupus to become active or worse.
Fluid and electrolyte (salt) problems.
Tell your doctor about any of the following signs and symptoms of fluid and electrolyte problems: dry mouth thirst lack of energy (lethargic) weakness drowsiness restlessness confusion seizures muscle pain or cramps muscle fatigue very low urine output fast heartbeat nausea and vomiting Kidney problems.
Kidney problems may become worse in people that already have kidney disease.
Some people will have changes on blood tests for kidney function and may need a lower dose of valsartan and hydrochlorothiazide tablets.
Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.
If you have heart failure, your doctor should check your kidney function before prescribing valsartan and hydrochlorothiazide tablets.
Skin rash.
Call your doctor right away if you have an unusual skin rash.
Eye Problems.
One of the medicines in valsartan and hydrochlorothiazide tablets can cause eye problems that may lead to vision loss.
Symptoms of eye problems can happen within hours to weeks of starting valsartan and hydrochlorothiazide tablets.
Tell your doctor right away if you have: decrease in vision eye pain Other side effects were generally mild and brief.
They generally have not caused patients to stop taking valsartan and hydrochlorothiazide tablets.
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of valsartan and hydrochlorothiazide tablets.
For a complete list, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How do I store valsartan and hydrochlorothiazide tablets? Store valsartan and hydrochlorothiazide tablets at 20° to 25°C (68° to 77°F).
Keep valsartan and hydrochlorothiazide tablets in a closed container in a dry place.
Keep valsartan and hydrochlorothiazide tablets and all medicines out of the reach of children.
General information about valsartan and hydrochlorothiazide tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.
Do not use valsartan and hydrochlorothiazide tablets for a condition for which it was not prescribed.
Do not give valsartan and hydrochlorothiazide tablets to other people, even if they have the same symptoms you have.
It may harm them.
This leaflet summarizes the most important information about valsartan and hydrochlorothiazide tablets.
If you would like more information, talk with your doctor.
You can ask your doctor or pharmacist for information about valsartan and hydrochlorothiazide tablets that is written for health professionals.
For more information about valsartan and hydrochlorothiazide tablets, call Mylan Pharmaceuticals Inc.
at 1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in valsartan and hydrochlorothiazide tablets? Active ingredients: Valsartan and hydrochlorothiazide Inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch(corn), sodium lauryl sulfate, titanium dioxide and triacetin.
The 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg and 320 mg/12.5 mg tablets also contain red iron oxide and yellow iron oxide.
The 320 mg/25 mg tablet also contains FD&C Blue No.
2 Aluminum Lake and FD&C Yellow No.
6 Aluminum Lake.
What is high blood pressure (hypertension)? Blood pressure is the force in your blood vessels when your heart beats and when your heart rests.
You have high blood pressure when the force is too much.
Valsartan and hydrochlorothiazide tablets can help your blood vessels relax and reduce the amount of water in your body so your blood pressure is lower.
Medicines that lower blood pressure lower your risk of having a stroke or heart attack.
High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels.
If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.
* Registered trademarks are property of their respective owners.
Manufactured by: Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Mylan Institutional Inc.
Distributed by: Rockford, IL 61103 U.S.A.
S-11364 R1 9/14
DOSAGE AND ADMINISTRATION
2 Dose once daily.
Titrate as needed to a maximum dose of 320 mg/25 mg ( 2) May be used as add-on/switch therapy for patients not adequately controlled on any of the components (valsartan or HCTZ) ( 2) May be substituted for titrated components ( 2.3) 2.1 General Considerations The usual starting dose is valsartan and hydrochlorothiazide tablets 160 mg/12.5 mg once daily.
The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2)].
Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.
2.2 Add-On Therapy A patient whose blood pressure is not adequately controlled with valsartan (or another ARB) alone or hydrochlorothiazide alone may be switched to combination therapy with valsartan and hydrochlorothiazide tablets.
A patient who experiences dose-limiting adverse reactions on either component alone may be switched to valsartan and hydrochlorothiazide tablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions.
The clinical response to valsartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 320 mg/25 mg.
2.3 Replacement Therapy Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components.
2.4 Initial Therapy Valsartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2)] .
2.5 Use with Other Antihypertensive Drugs Valsartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.