Diovan hct tablet, film coated

Recent major changes section

Indications and Usage: Benefits of lowering blood pressure ( 1)12/2011

Warnings and Precautions: Acute Angle-Closure Glaucoma ( 5.9)2/2011

Warning: avoid use in pregnancy

When pregnancy is detected, discontinue Diovan HCT ® as soon as possible. Drugs that act directly on the renin- angiotensin system can cause injury and even death to the developing fetus . [ see Warnings and Precautions (5.1) ]

WARNING: AVOID USE IN PREGNANCY

See full prescribing information for complete boxed warning.

When pregnancy is detected , discontinue D iovan HCT as soon as possible. D rugs that act directly on the renin- angiotensin system can cause injury and even death to the developing fetus. ( 5.1)

1 indications and usage

DiovanHCT (valsartan and hydrochlorothiazide, USP) is 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 Diovan HCT.

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 Programs 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 (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.

DiovanHCT may be used in patients whose blood pressure is not adequately controlled on monotherapy.

DiovanHCT may be used as initial therapy inpatients who are likely to need multiple drugs to achieve blood pressure goals.

The choice of DiovanHCT 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 patients 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 DiovanHCT compared to valsartan or hydrochlorothiazide monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with DiovanHCT 320/25mg, 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.

Figure 1: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8
Figure 1 : Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8
Figure 2: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8
Figure 2 : Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8
Figure 3: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8
Figure 3 : Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8
Figure 4: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8
Figure 4 : Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

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 Diovan HCT rises to about 84% (systolic) or 80% (diastolic). The likelihood of achieving these goals on placebo is about 23% (systolic) or 36% (diastolic).

DiovanHCT is the combination tablet of valsartan (Diovan), an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ), a diuretic. DiovanHCT is 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.

2 d osage and administration

General considerations:
  • Maximum effects within 2 to 4 weeks after dose change ( 2.1)
  • Renal impairment: Not recommended for patients with severe renal impairment (creatinine clearance 30mL/min)( 2.1, 5.8)
  • DiovanHCT may be administered with or without food.
Hypertension
  • Add- on t herapyOR Initial therapy: Initiate with 160/12.5mg. Titrate upwards as needed to a maximum dose of 320/25mg. One tablet daily ( 2.2, 2.4)
  • Replacement therapy: may be substituted for titrated components ( 2.3)

2.1 general considerations

The side effects of valsartan are generally rare and appear independent of dose.Those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter [ see Adverse Reactions (6)].

Dose once-daily. Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose.

DiovanHCT may be administered with or without food.

DiovanHCT may be administered with other antihypertensive agents.

Elderly patients : No initial dosage adjustment is required for elderly patients.

Renal impairment :The usual regimens of therapy with DiovanHCT may be followed as long as the patients creatinine clearance is >30mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so DiovanHCT is not recommended.

Hepatic impairment :Care should be exercised with dosing of DiovanHCT in patients with hepatic impairment. Start with a low dose and titrate slowly in patients with hepatic impairment [ s ee Warnings and Precautions (5.3)] .

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 DiovanHCT.

A patient who experiences dose-limiting adverse reactions on either component alone may be switched to Diovan HCT containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to Diovan HCT 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 of320/25 mg.

2.3 replacement therapy

DiovanHCT may be substituted for the titrated components.

2.4 initial therapy

The usual starting dose is DiovanHCT 160/12.5mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320/25mg tablet once daily as needed to control blood pressure [ see Clinical Studies(14.2)]. DiovanHCT is not recommended as initial therapy in patients with intravascular volume depletion [ see Warnings and Precautions (5.2)].

3 dosage forms and strengths

80/12.5mg tablets, imprinted CG/HGH (Side 1/Side 2)

160/12.5mg tablets, imprinted CG/HHH

160/25mg tablets, imprinted NVR/HXH

320/12.5mg tablets, imprinted NVR/HIL

320/25mg tablets, imprinted NVR/CTI

Tablets (valsartan/HCTZ mg): 80/12.5, 160/12.5, 160/25, 320/12.5, 320/25

4 contraindications

DiovanHCT (valsartan and hydrochlorothiazide, USP) is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Anuria; Hypersensitivity to any sulfonamide-derived drugs

5 warnings and precautions

  • Avoid fetal or neonatal exposure ( 5.1)
  • Symptomatic hypotension withvolume- and/or salt-depletion.Correct volume-depletion prior to administration. Not recommended as initial therapy in volume-depleted patients ( 2.4, 5.2)
  • Use with caution in patients with impaired hepatic ( 5.3) or renal ( 5.8) function
  • Observe for signs of fluid or electrolyte imbalance ( 5.7)
  • Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus ( 5.5)
  • Hydrochlorothiazide has been associated with acute angle-closure glaucoma ( 5.9)

5.1 fetal/neonatal morbidity and mortality

DiovanHCT can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus .

Drugs that act on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death [ 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 DiovanHCT 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 DiovanHCT, 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 i mpaired hepatic function

Hydrochlorothiazide :Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Valsartan :As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering Diovan (valsartan) to these patients.

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

Hydrochlorothiazide :Lithium generally should not be given with thiazides [ see Drug Interactions (7)].

5.7 serum electrolytes

Valsartan Hydrochlorothiazide :In the controlled trials of various doses of the combination of valsartan and hydrochlorothiazide the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5mEq/L) was 3.0%; the incidence of hyperkalemia (serum potassium >5.7mEq/L) was 0.4%.

In controlled clinical trials of DiovanHCT (valsartan and hydrochlorothiazide, USP), the average change in serum potassium was near zero in subjects who received DiovanHCT 160/12.5mg, 320/12.5mg or 320/25mg, but the average subject who received DiovanHCT 80/12.5mg, 80/25mg or 160/25mg experienced a mild reduction in serum potassium.

In clinical trials, the opposite effects of valsartan (80, 160 or 320mg) and hydrochlorothiazide (12.5mg) on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Hydrochlorothiazide :All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

5.8 impaired renal function

Valsartan :As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Diovan ®.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide :Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

5.9 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.

6 adverse reactions

The most common reasons for discontinuation of therapy with DiovanHCT were headache and dizziness. The only adverse experience that occurred in 2% of patients treated with DiovanHCT and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%)( 6.1)



To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 clinical trials experience

Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Hypertension

DiovanHCT (valsartan and hydrochlorothiazide, USP) has been evaluated for safety in more than 5,700 patients, including over 990 treated for over 6 months, and over 370 for over 1 year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with DiovanHCT was comparable to placebo.

The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of valsartan-hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with DiovanHCT were headache and dizziness.

The only adversereaction that occurred in controlled clinical trials in at least 2% of patients treated with DiovanHCT and at a higher incidence in valsartan-hydrochlorothiazide (n=4372) than placebo (n=262) patients was nasopharyngitis (2.4% vs. 1.9%).

Dose-related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a dose-related increase in the incidence of dizziness was observed in patients treated with DiovanHCT.

Other adverse reactions that have been reported with valsartan-hydrochlorothiazide (>0.2% of valsartan-hydrochlorothiazide patients in controlled clinical trials) without regard to causality, are listed below:

Cardiovascular :Palpitations and tachycardia

Ear and L abyrinth :Tinnitus and vertigo

Gastrointestinal :Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, abdominal pain upper, and vomiting

General and A dministration S ite C onditions :Asthenia, chest pain, fatigue, peripheral edema and pyrexia

Infections and I nfestations :Bronchitis, bronchitis acute, influenza, gastroenteritis, sinusitis, upper respiratory tract infection and urinary tract infection

Investigations :Blood urea increased

Musculoskeletal :Arthralgia, back pain, muscle cramps, myalgia, and pain in extremity

Nervous S ystem :Dizziness postural, paresthesia, and somnolence

Psychiatric :Anxiety and insomnia

Renal and U rinary :Pollakiuria

Reproductive S ystem :Erectile dysfunction

Respiratory, T horacic and M ediastinal :Dyspnea, cough, nasal congestion, pharyngolaryngeal pain and sinus congestion

Skin and S ubcutaneous T issue :Hyperhidrosis and rash

Vascular :Hypotension

Other reported reactions seen less frequently in clinical trials included abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope, and viral infection.

Valsartan :In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide, or lisinopril were 20%, 19%, 69% respectively (p <0.001).

Other reported reactions seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.

Hydrochlorothiazide :Other adverse reactions that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Body As A Whole :weakness;

Digestive :pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation;

Hematologic :aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia;

Hypersensitivity :purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions;

Metabolic :hyperglycemia, glycosuria, hyperuricemia;

Musculoskeletal :muscle spasm;

Nervous System/Psychiatric :restlessness;

Renal :renal failure, renal dysfunction, interstitial nephritis;

Skin :erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis;

Special Senses :transient blurred vision, xanthopsia.

Initial T herapy- Hypertension

In a clinical study in patients with severe hypertension (diastolic blood pressure 110mmHg and systolic blood pressure 140mmHg), the overall pattern of adverse reactions reported through six weeks of follow-up was similar in patients treated with DiovanHCT as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with DiovanHCT (force-titrated to 320/25mg) and valsartan (force-titrated to 320mg), dizziness was observed in6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving DiovanHCT and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with DiovanHCT as initial therapy in patients with severe hypertension were similar to those reported with DiovanHCT in patients with less severe hypertension [ see Clinical Studies (14.2) and Drug Interactions (7.3)].

6.2 postmarketing experience

The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazidepostmarketing experience:

Hypersensitivity :There are rare reports of angioedema;

Digestive :Elevated liver enzymes and very rare reports of hepatitis;

Renal :Impaired renal function;

Clinical Laboratory Tests :Hyperkalemia;

Dermatologic :Alopecia;

Vascular:Vasculitis;

Nervous System:Syncope.

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 drug interactions

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 vitrometabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of the low extent of metabolism [see Clinical Pharmacology (12.3)].

Transporters:The results from an in vitrostudy with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration 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, co-administration 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.

Hydrochlorothiazide :When administered concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, Barbiturates, or N arcotics- Potentiation of orthostatic hypotension may occur.

Antidiabetic D rugs(oral agents and insulin) - Dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive D rugs- Additive effect or potentiation.

Cholestyramine and Colestipol R esins- Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43% respectively.

Corticosteroids, ACTH- Intensified electrolyte depletion, particularly hypokalemia.

Pressor A mines(e.g., norepinephrine) - Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, N ondepolarizing(e.g., tubocurarine) - Possible increased responsiveness to the muscle relaxant.

Lithium- Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with DiovanHCT.

Non steroidal A nti -inflammatory Drugs- In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when DiovanHCT and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

CarbamazepineMay lead to symptomatic hyponatremia.

Hydrochlorothiazide ( 7):

  • Alcohol, barbiturates, narcotics: Potentiation of orthostatic hypotension
  • Antidiabetic drugs: Dosage adjustment of antidiabetic may be required
  • Cholestyramine and colestipol: Reduced absorption of thiazides
  • Corticosteroids, Adrenocorticotrophic Hormone (ACTH): Hypokalemia, electrolyte depletion
  • Lithium: Reduced renal clearance and high risk of lithium toxicity when used with diuretics. Should not be given with diuretics.
  • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Can reduce diuretic, natriuretic and antihypertensive effects of diuretics. Observe patient closely.

7.3 clinical laboratory test findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of DiovanHCT.

Creatinine /Blood Urea N itrogen (BUN) :Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking DiovanHCT and 0.4% and 6% respectively, given placebo in controlled clinical trials.

Hemoglobin and Hematocrit :Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of DiovanHCT patients, compared with 0.0% in placebo-treated patients.

Liver Function Tests :Occasional elevations (greater than 150%) of liver chemistries occurred in DiovanHCT-treated patients.

Neutropenia :Neutropenia was observed in 0.1% of patients treated with DiovanHCT and 0.4% of patients treated with placebo.

Serum Electrolytes :[ see W arnings and Precautions ( 5.7)].

8 use in specific populations

Nursing Mothers :Nursing or drug should be discontinued ( 8.3)


8.1 pregnancy

Pregnancy Category D [ see Warnings and Precautions (5.1)]

DiovanHCT, like other drugs that act on the renin-angiotensin system, can cause fetal and neonatal morbidity and death when used during the second or third trimester of pregnancy. DiovanHCT can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Angiotensin II receptor antagonists, like valsartan, and angiotensin-converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin system. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios was also reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also reported, although it is not clear whether these occurrences were due to exposure to the drug. In a retrospective study, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin system, was associated with a potential risk of birth defects.

When pregnancy occurs in a patient using DiovanHCT, the physician should discontinue DiovanHCT treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to DiovanHCT (first trimester only or later). If exposure occurs beyond the first trimester, an ultrasound examination should be done.

In rare cases when another antihypertensive agent can not be used to treat the pregnant patient, serial ultrasound examinations should be performed to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, and/or contraction stress tests may be appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions about continuing or discontinuing DiovanHCT treatment and about pregnancy management should be made by the patient, her physician, and experts in the management of high-risk pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in uteroexposure to DiovanHCT should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension and/or support decreased renal function.

Healthcare professionals who prescribe drugs acting directly on the renin-angiotensin system should counsel women of childbearing potential about the risks of these agents during pregnancy. [ see Nonclin i cal Toxicology (13)] .

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 DiovanHCT, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 pediatric use

Safety and effectiveness of DiovanHCT in pediatric patients have not been established.

8.5 geriatric use

In the controlled clinical trials of DiovanHCT, 764 (17.5%) of patients treated with valsartan-hydrochlorothiazide were 65years and 118 (2.7%) were 75years. No overall difference in the efficacy or safety of valsartan-hydrochlorothiazide was observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 overdosage

Valsartan 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 762mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238mg/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 amg/m 2basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide and a 60-kg patient.)

Valsartan :Valsartan was without grossly observable adverse effects at single oral doses up to 2000mg/kg in rats and up to 1000mg/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/m 2basis). (Calculations assume an oral dose of 320mg/day and a 60-kg patient.)

Hydrochlorothiazide :The oral LD 50of hydrochlorothiazide is greater than 10g/kg in both mice and rats, which represents 2027 and 4054 times, respectively, the maximum recommended human dose on amg/m 2basis. (Calculations assume an oral dose of 25mg/day and a 60-kg patient.)

11 description

DiovanHCT (valsartan and hydrochlorothiazide, USP) is a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB) acting on the AT 1receptor subtype, and hydrochlorothiazide, a diuretic.

Valsartan, a nonpeptide molecule, is chemically described as N-(1-oxopentyl)- N-[[2-(1 H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-L-Valine. Its empirical formula is C 24H 29N 5O 3, its molecular weight is 435.5, and its structural formula is

Valsartan structural formula

Valsartan 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 empirical formula is C 7H 8ClN 3O 4S 2, its molecular weight is 297.73, and its structural formula is

Hydrochlorothiazide structural formula

DiovanHCT tablets are formulated for oral administration to contain valsartan and hydrochlorothiazide, USP 80/12.5mg, 160/12.5mg, 160/25mg, 320/12.5mg and 320/25mg. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

12 clinical pharmacology

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 1receptor 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 2receptor found in many tissues, but AT 2is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT 1receptor than for the AT 2receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT 1receptor 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.

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.

12.2 pharmacodynamics

Valsartan :Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24hours. No information on the effect of larger doses is available.

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; very little effect on serum potassium was observed.

In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.

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

Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

12.3 pharmacokinetics

Valsartan :Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C max) by about 50%. AUC and C maxvalues of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.

Hydrochlorothiazide :Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours.

Geriatric :Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary [ see Dosage and Administration (2. 1 )].

Gender :Pharmacokinetics of valsartan does not differ significantly between males and females.

Race :Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency :There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan [ see Dosage and Administration (2. 1)].

In a study of patients with impaired renal function (mean creatinine clearance of 19mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.

Hepatic Insufficiency :On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex,and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease [ see Dosage and Administration (2. 1)].

Distribution

Valsartan :The steady state volume of distribution of valsartan after intravenous administration is small (17L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

Hydrochlorothiazide :Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism

Valsartan :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 co-administered drugs are unlikely because of the low extent of metabolism.

Hydrochlorothiazide :Is not metabolized.

Excretion

Valsartan :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.

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

Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24hours. The elimination half-life is between 5.8 and 18.9hours.

13 nonclinical toxicology

13.1 carcinogenesis, mutagenesis, impairment of fertility

Valsartan- Hydrochlorothiazide :No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. However, these studies have been conducted for valsartan as well as hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide.

Valsartan :There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2years at doses up to 160 and 200mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6times, respectively, the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 320mg/day and a 60-kg patient.)

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E. coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200mg/kg/day. This dose is about 6times the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 320mg/day and a 60-kg patient.)

Hydrochlorothiazide :Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600mg/kg/day) or in male and female rats (at doses of up to approximately 100mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300mcgm/mL, and in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4mg/kg, respectively, prior to mating and throughout gestation.These doses of hydrochlorothiazide in mice and rats represent 19 and 1.5times, respectively, the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 25mg/day and a 60-kg patient.)

13.3 developmental toxicity studies

Valsartan-Hydrochlorothiazide :There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100 and 10mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31 and 3mg/kg/day. These non-teratogenic doses in mice, rats and rabbits, respectively, represent 9, 3.5 and 0.5 times the maximum recommended human dose (MRHD) of valsartan and 38, 13 and 2 times the MRHD of hydrochlorothiazide on a mg/m 2basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide and a 60-kg patient.)

Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of 200 and 10mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 63 and 3mg/kg/day. Fetotoxicity in rats was considered to be related to decreased fetal weights and included fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Fetotoxicity in rabbits included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses and decreased number of live fetuses. The no observed adverse effect doses in mice, rats and rabbits for valsartan were 600, 100 and 3mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 188, 31 and 1mg/kg/day. These no adverse effect doses in mice, rats and rabbits, respectively, represent 9, 3 and 0.18 times the MRHD of valsartan and 38, 13 and 0.5 times the MRHD of hydrochlorothiazide on a mg/m 2basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide and a 60-kg patient.)

Valsartan :No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6 and 0.1 times, respectively, the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Hydrochlorothiazide :Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats represent 608 and 405 times, respectively, the maximum recommended human dose on a mg/m 2basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

14 clinical studies

14.1 hypertension

Valsartan- Hydrochlorothiazide :In controlled clinical trials including over 7600 patients, 4372 patients were exposed to valsartan (80, 160 and 320mg) and concomitant hydrochlorothiazide (12.5 and 25mg). Two factorial trials compared various combinations of 80/12.5mg, 80/25mg, 160/12.5mg, 160/25mg, 320/12.5mg and 320/25mg 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 14-21/8-11mmHg at 80/12.5mg to 320/25mg, compared to 7-10/4-5mmHg for valsartan 80mg to 320mg and 5-11/2-5mmHg for hydrochlorothiazide 12.5mg to 25mg, alone.

Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80mg to valsartan 320mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4-12/2-5mmHg.

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 two 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 Diovan HCT 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 7placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160mg/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 2hours, and maximum reduction of blood pressure is achieved within 6hours. The antihypertensive effect persists for 24hours after dosing, but there is a decrease from peak effect at lower doses (40mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160mg), 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 4weeks. 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 angiotensinII 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 Diovan 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 7 studies of valsartan monotherapy included over 2000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5mmHg at 80-160mg and 9/6mmHg at 320mg.

Patients with an inadequate response to 80mg once daily were titrated to either 160mg once daily or 80mg twice daily, which resulted in a comparable response in both groups.

In another 4-week study, 1876 patients randomized to valsartan 320mg once daily had an incremental blood pressure reduction 3/1mmHg lower than did 1900 patients randomized to valsartan 160mg once daily.

In controlled trials, the antihypertensive effect of once daily valsartan 80mg was similar to that of once daily enalapril 20mg or once daily lisinopril 10mg.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

14.2 initial t herapy - hypertension

The safety and efficacy of DiovanHCT as initial therapy for patients with severe hypertension (defined as a sitting diastolic blood pressure 110mmHg and systolic blood pressure 140mmHg off all antihypertensive therapy) was studied in a 6-week multicenter, randomized, double-blind study. Patients were randomized to either DiovanHCT (valsartan and hydrochlorothiazide 160/12.5mg once daily) or to valsartan (160mg once daily) and followed for blood pressure response. Patients were force-titrated at 2-week intervals. Patients on combination therapy were subsequently titrated to 160/25mg followed by 320/25mg valsartan/hydrochlorothiazide. Patients on monotherapy were subsequently titrated to 320mg valsartan followed by a titration to 320mg 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 168/112mmHg. The mean age was 52 years. After 4 weeks of therapy, reductions in systolic and diastolic blood pressure were 9/5mmHg greater in the group treated with DiovanHCT compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race or age.

16 how supplied/storage and handling

DiovanHCT (valsartan and hydrochlorothiazide, USP) is available as non-scored tablets containing valsartan/hydrochlorothiazide 80/12.5mg, 160/12.5mg, 160/25mg, 320/12.5mg and 320/25mg. Strengths are available as follows.

80/12.5 mg Tablet- Light orange, ovaloid with slightly convex faces debossed CG on one side and HGH on the other side.

Bottles of 10
NDC 54868-4425-1
Bottles of 90
NDC 54868-4425-3

160/12.5 mg Tablet- Dark red, ovaloid with slightly convex faces debossed CG on one side and HHH on the other side.

Bottles of 30
NDC 54868-4428-0
Bottles of 60
NDC 54868-4428-2
Bottles of 90
NDC 54868-4428-3

160/25 mg Tablet- Brown orange, ovaloid with slightly convex faces debossed NVR on one side and HXH on the other side.

Bottles of 30
NDC 54868-5323-0
Bottles of 90
NDC 54868-5323-1

320/12.5 mg Tablet- Pink, ovaloid with beveled edge, debossed NVR on one side and HIL on the other side.

Bottles of 30
NDC 54868-5780-0
Bottles of 90
NDC 54868-5780-1

320/25 mg Tablet- Yellow, ovaloid with beveled edge, debossed NVR on one side and CTI on the other side.

Bottles of 30
NDC 54868-5607-0
Bottles of 90
NDC 54868-5607-1

Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in tight container (USP).

17 patient counseling information

Information for Patients

Pregnancy :Female patients of childbearing age should be told that use of drugs like DiovanHCTthat act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including: low blood pressure, poor development of skull bones, kidney failure and death. Discuss other treatment options with female patients planning to become pregnant.Women using DiovanHCT who become pregnant should notify their physician as soon as possible.

Symptomatic Hypotension :A patient receiving DiovanHCT 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, DiovanHCT 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 DiovanHCT should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Spl patient package insert section

FDA-Approved Patient Labeling

PATIENT INFORMATION

DIOVAN HCT (DYE -o -van HCT)

(valsartan and hydrochlorothiazide)

Tablets

Read the Patient Information that comes with DIOVANHCT 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 DIOVANHCT, ask your doctor or pharmacist.

What is the most important information I should know about DIOVAN HCT?
If you become pregnant, stop taking DIOVAN HCT and call your doctor right away. DIOVAN HCT can harm an unborn baby causing injury and even death.If you plan to become pregnant, talk to your doctor about other treatment options to lower your high blood pressure before taking DIOVANHCT.

What is DIOVAN HCT?

DIOVANHCT contains two prescription medicines:

  1. valsartan, an angiotensin receptor blocker (ARB)
  2. hydrochlorothiazide (HCTZ), a water pill (diuretic)

DIOVANHCT 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.

DIOVANHCT has not been studied in children under 18 years of age.

Who should not take DIOVAN HCT?

Do not take DIOVAN HCT if you:

  • are allergic to any of the ingredients in DIOVANHCT.See the end of this leaflet for a complete list of ingredients in DIOVANHCT.
  • make less urine due to kidney problems
  • are allergic to medicines that contain sulfonamides.

What should I tell my doctor before taking DIOVAN HCT?

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 DIOVANHCT?
  • are breast -feeding.DIOVANHCT passes into breast milk. You should choose either to take DIOVANHCT or breast-feed, but not both.
  • have liver problems
  • have kidney problems
  • have or had gallstones
  • have Lupus

Tell your doctor about all the medicines you takeincluding prescription and nonprescription medicines, vitamins and herbal supplements. Some of your other medicines and DIOVAN HCT 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
  • a salt substitute containing potassium
  • 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

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 DIOVAN HCT?

  • Take DIOVANHCT exactly as prescribed by your doctor. Your doctor may change your dose if needed.
  • Take DIOVANHCT once each day.
  • DIOVANHCT 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 DIOVANHCT, call your doctor or Poison Control Center, or go to the nearest hospital emergency room.

What should I avoid while taking DIOVAN HCT?

You should not take DIOVAN HCT during pregnancy. See What is the most important information I should know about DIOVAN HCT?

What are the possible side effects of DIOVAN HCT?

DIOVAN HCT 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 DIOVAN HCT?
  • 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.

  • Worsening liver problems .Liver problems may get worse in people who already have liver problems and take DIOVAN HCT.
  • Allergic reactions .People with and without allergy problems or asthma who take DIOVAN HCT may get allergic reactions.
  • Worsening of Lupus .Hydrochlorothiazide, one of the medicines in DIOVAN HCT 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
  • K idney 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 DIOVANHCT. 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 DIOVANHCT.
  • Skin rash.Call your doctor right away if you have an unusual skin rash.
  • Eye Problems.One of the medicines in DIOVAN HCT can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting DIOVAN HCT. 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 DIOVANHCT.

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 DIOVANHCT. 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 DIOVAN HCT?

  • Store DIOVANHCT tablets at room temperature between 59 oF to 86 oF (15 oC to 30 oC).
  • Keep DIOVANHCT in a closed container in a dry place.

Keep DIOVAN HCT and all medicines out of the reach of children.

General information about DIOVAN HCT

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use DIOVANHCT for a condition for which it was not prescribed. Do not give DIOVANHCT to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about DIOVANHCT. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DIOVANHCT that is written for health professionals. For more information about DIOVANHCT, go to www.DIOVAN.com or call 1-866-404-6359.

What are the ingredients in DIOVAN HCT?

Active ingredients: Valsartan and hydrochlorothiazide

Inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

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. DIOVANHCT 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.

Eskalith ®and Lithobid ®are registered trademarks of Noven Pharmaceuticals, Inc.

Distributed by:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis


T2012-03/T2012-04
December 2011/December 2011

Spl unclassified section

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma 74146

Ingredients and appearance - Product information

Diovan hct tablet, film coated- Valsartan and hydrochlorothiazide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-4425
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Valsartan ( UNII: 80M03YXJ7I)( Valsartan - UNII: 80M03YXJ7I ) 80 mgin 1
Hydrochlorothiazide ( UNII: 0J48LPH2TH)( Hydrochlorothiazide - UNII: 0J48LPH2TH ) 12.5 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Crospovidone ( UNII: 68401960MK)
Hypromelloses ( UNII: 3NXW29V3WO)
Ferric oxide red ( UNII: 1K09F3G675)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Color ORANGE (Light orange) Imprint Code CG;HGH
Score 1 Shape OVAL (ovaloid)
Size 10 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020818 USA

Diovan hct tablet, film coated- Valsartan and hydrochlorothiazide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-4428
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Valsartan ( UNII: 80M03YXJ7I)( Valsartan - UNII: 80M03YXJ7I ) 160 mgin 1
Hydrochlorothiazide ( UNII: 0J48LPH2TH)( Hydrochlorothiazide - UNII: 0J48LPH2TH ) 12.5 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Crospovidone ( UNII: 68401960MK)
Hypromelloses ( UNII: 3NXW29V3WO)
Ferric oxide red ( UNII: 1K09F3G675)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)
Hypromelloses ( UNII: 3NXW29V3WO)

Product Characteristics

Color RED (Dark red) Imprint Code CG;HHH
Score 1 Shape OVAL
Size 15 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020818 USA

Diovan hct tablet, film coated- Valsartan and hydrochlorothiazide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5323
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Valsartan ( UNII: 80M03YXJ7I)( Valsartan - UNII: 80M03YXJ7I ) 160 mgin 1
Hydrochlorothiazide ( UNII: 0J48LPH2TH)( Hydrochlorothiazide - UNII: 0J48LPH2TH ) 25 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Crospovidone ( UNII: 68401960MK)
Hypromelloses ( UNII: 3NXW29V3WO)
Ferric oxide red ( UNII: 1K09F3G675)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Color BROWN (Brown orange) Imprint Code NVR;HXH
Score 1 Shape OVAL
Size 14 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020818 USA

Diovan hct tablet, film coated- Valsartan and hydrochlorothiazide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5780
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Valsartan ( UNII: 80M03YXJ7I)( Valsartan - UNII: 80M03YXJ7I ) 320 mgin 1
Hydrochlorothiazide ( UNII: 0J48LPH2TH)( Hydrochlorothiazide - UNII: 0J48LPH2TH ) 12.5 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Crospovidone ( UNII: 68401960MK)
Hypromelloses ( UNII: 3NXW29V3WO)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)
Ferric oxide red ( UNII: 1K09F3G675)

Product Characteristics

Color PINK Imprint Code NVR;HIL
Score 1 Shape OVAL
Size 18 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020818 USA

Diovan hct tablet, film coated- Valsartan and hydrochlorothiazide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 54868-5607
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Valsartan ( UNII: 80M03YXJ7I)( Valsartan - UNII: 80M03YXJ7I ) 320 mgin 1
Hydrochlorothiazide ( UNII: 0J48LPH2TH)( Hydrochlorothiazide - UNII: 0J48LPH2TH ) 25 mgin 1

Inactive Ingredients

Ingredient Name Code
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Crospovidone ( UNII: 68401960MK)
Hypromelloses ( UNII: 3NXW29V3WO)
Ferric oxide red ( UNII: 1K09F3G675)
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Color YELLOW (Yellow) Imprint Code NVR;CTI
Score 1 Shape OVAL
Size 18 mm

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020818 USA

Labeler - Physicians Total Care, Inc.( 194123980)

Establishment

Name ID/FEI Business Operations
Physicians Total Care, Inc. 194123980 relabel(), repack()

Package label.principal display panel

PRINCIPAL DISPLAY PANEL

Package Label 80 mg /12.5 mg

Rx Only

Diovan HCT®

valsartan and hydrochlorothiazide, USP

80 mg/12.5 mg

Package label.principal display panel

PRINCIPAL DISPLAY PANEL

Package Label 160 mg /12.5 mg

Rx Only

Diovan HCT®

valsartan and hydrochlorothiazide, USP

160 mg/12.5 mg per tablet


Dosage: See package insert

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

Protect from moisture.

Please see accompanying full Prescribing Information.

Keep this and all drugs out of the reach of children.

Package label.principal display panel

PRINCIPAL DISPLAY PANEL

Package Label 160 mg /25 mg

Rx Only

Diovan HCT®

valsartan and hydrochlorothiazide, USP

160 mg/25 mg per tablet


Dosage: See package insert

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

Protect from moisture.

Please see accompanying full Prescribing Information.

Keep this and all drugs out of the reach of children.

Package label.principal display panel

Package label.principal display panel

PRINCIPAL DISPLAY PANEL

Package Label 320 mg /12.5 mg

Rx Only

Diovan HCT®

valsartan and hydrochlorothiazide, USP

320 mg/12.5 mg per tablet


Dosage: See package insert

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

Protect from moisture.

Please see accompanying full Prescribing Information.

Keep this and all drugs out of the reach of children.

Package label.principal display panel

PRINCIPAL DISPLAY PANEL

Package Label 320 mg /25 mg

Rx Only

Diovan HCT®

valsartan and hydrochlorothiazide, USP

320 mg/25 mg per tablet


Dosage: See package insert

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).

Protect from moisture.

Please see accompanying full Prescribing Information.

Keep this and all drugs out of the reach of children.