DIOVAN (valsartan) is indicated for:

• Hypertension:

  
  

  • For the treatment of mild to moderate essential hypertension.

    
    

  • DIOVAN may be administered alone, or concomitantly with thiazide diuretics.

    
    

  • The safety and efficacy of concurrent treatment with DIOVAN and angiotensin converting enzyme inhibitors have not been established.

    
    

• Following Myocardial Infarction:

  
  

  • To reduce cardiovascular mortality in clinically stable patients with signs or symptoms of left ventricular dysfunction in conjunction with acute myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate.

    
    

  • The combination of valsartan and an angiotensin-converting enzyme inhibitor (ACEI) has not been shown to result in clinically relevant improvement in cardiovascular outcome over valsartan use alone. Accordingly, such combined use is not recommended.

    
    

No overall difference in efficacy or safety observed versus younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The safety and effectiveness of DIOVAN in children and adolescents (below the age of 18 years) have not been established.

• DIOVAN (valsartan) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container (see Dosage Forms, Composition and Packaging).

  
  

Occasionally, symptomatic hypotension has occurred after administration of valsartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

Caution should be exercised when initiating therapy after acute myocardial infarction. Patients with heart failure or those in the early post-myocardial infarction period that are given DIOVAN commonly have some reduction in blood pressure, but discontinuation of therapy is usually not necessary if patients are well screened prior to instituting treatment and found to be clinically stable. If symptomatic hypotension does occur, consideration should be given to dosage reduction (see Dosage and Administration, Following Myocardial Infarction). In patients treated following myocardial infarction, the recommended regimen of valsartan has been observed to result in a greater incidence of hypotension as a serious adverse event than the conventional dosage regimen of captopril in this indication (see Adverse Reactions, Following Myocardial Infarction).

There is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction.

In general, no dosage adjustment is needed in patients with mild to moderate liver disease. However, care should be exercised in patients with liver disease, especially in those patients with biliary obstructive disorders, as the majority of valsartan is eliminated in the bile. No information is available in patients with severe liver disease (see Action and Clinical Pharmacology, Pharmacokinetics).

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Following myocardial infarction, major renal dysfunction was observed to occur more frequently with valsartan than with captopril monotherapy (see Adverse Reactions, Following Myocardial Infarction). The role of modestly lower blood pressure that may occur with valsartan compared to captopril monotherapy is not known.

The incidence of clinically relevant hyperkalemia has also been observed to be increased with valsartan (see Adverse Reactions, Laboratory Findings). Patients exposed to potassium-sparing diuretics and/or potassium supplements were more likely to develop hyperkalemia. Accordingly, their use should be carefully monitored or avoided (see Drug Interactions, Agents Increasing Serum Potassium).

Use of valsartan should include appropriate assessment of renal function.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, DIOVAN should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.

Mothers whose embryos and fetuses are exposed to an angiotensin II AT₁ receptor blocker only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of valsartan as soon as possible.

Rarely (probably less than one in every thousand pregnancies), no alternative to angiotensin II AT₁ receptor blocker will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess intra-amniotic environment.

If oligohydramnios is observed, valsartan should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II AT₁ receptor blocker should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for impaired renal function. Valsartan is not removed from plasma by dialysis.

Animal Data: No teratogenic effects were observed when valsartan was administered orally to pregnant mice and rats at 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 orally with valsartan at 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 associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day.

It is not known whether valsartan is excreted in human milk but it was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of DIOVAN in children and adolescents (below the age of 18 years) have not been established.

Of the 2542 patients receiving DIOVAN monotherapy in placebo-controlled clinical trials, 31% were 65 years and older. No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

DIOVAN has been evaluated for safety in over 4300 patients treated for hypertension, including more than 600 treated for over 6 months and more than 330 for over 1 year. Of these, 3634 were treated with valsartan monotherapy in controlled clinical trials.

In controlled clinical trials, discontinuation due to AEs occurred in 3.1% and 4.0% of patients treated with DIOVAN monotherapy and placebo, respectively.

The following potentially serious adverse reactions have been reported rarely with valsartan in controlled clinical trials: syncope, hypotension.

Table 1 is based on double-blind controlled trials in patients treated with DIOVAN monotherapy at doses of 80 to 160 mg/day. The table includes all AEs with an incidence of 1% or greater in the DIOVAN treatment group, irrespective of causal relationship to study drug. No AE appeared to have an incidence related to dose. Therefore, AEs are grouped irrespective of dose.

Table 1: DIOVAN

Hypertension: Occurrence of Adverse Events During Double-Blind Controlled Trials in Patients Treated with Diovan Monotherapy at Doses of 80 to 160 mg/day

In a study conducted with patients taking DIOVAN at starting doses of 20 mg to 320 mg, an increased incidence of dizziness was observed with DIOVAN 320 mg (9%) compared to DIOVAN 20 to 160 mg (2 to 4%). In another study where patients were up-titrated to the 320 mg dose of DIOVAN, the incidence of dizziness was comparable to the 160 mg dose (1%).

In double-blind controlled trials, the following adverse events were reported with DIOVAN at an occurrence rate of less than 1% regardless of drug relationship: orthostatic effects, chest pain, palpitations, myalgia, asthenia, somnolence, vertigo, impotence, epistaxis, fibrosing alveolitis (one case), allergic reactions, urticaria, pruritus and rash.

Table 2 shows the frequency of selected serious adverse events (≥0.4% in any treatment group) for the valsartan, valsartan+captopril, and captopril treatment groups in a large, randomized double-blind trial. Serious adverse events related to the disease under study have not been included in this table.

Table 2: DIOVAN

Following Myocardial Infarction: Selected Serious Adverse Events by Treatment (Safety Population)

	Valsartan n=4885 (%)	Valsartan+ Captopril n=4862 (%)	Captopril n=4879 (%)
Hypotensiona	2.8	3.3	2.0
Syncope	0.7	0.6	0.6
Dizziness	0.4	0.4	0.3
Renal causesb	3.1	3.0	2.0
Hyperkalemia	0.4	0.6	0.4
Atrial fibrillation	1.0	0.7	0.8
Cough	0.3	0.5	0.4
Taste disturbancesc	0.1	0.4	0.3

^a. This term includes SAEs related to hypotension, orthostatic hypotension.
^b. This term includes SAEs related to acute renal failure, chronic renal failure, blood creatinine increased.
^c. This term includes ageusia, dysgeusia, hypogeusia.

Major renal dysfunction was observed in 3.8%, 3.7%, and 2.6% of patients in the valsartan, valsartan+captopril, and captopril treatment groups, respectively. Major renal dysfunction was defined as death from a renal cause, a serious adverse event suggestive of renal failure, and temporary or permanent discontinuation of study drug for a renal cause.

These laboratory findings pertain to trials in hypertension, except as otherwise indicated.

Greater than 20% increases in serum potassium were observed in 5.0% of valsartan-treated patients compared to 3.0% of placebo-treated patients. Hyperkalemia as an adverse event occurred in 2.3%, 2.4%, and 1.5% of post-myocardial infarction patients treated with valsartan, valsartan+captopril, and captopril, respectively.

Minor elevations in creatinine occurred in 1.1% of patients treated with valsartan and 0.8% of patients given placebo in controlled clinical trials in hypertensive patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients, 4.8% of valsartan+captopril-treated patients, and 3.4% of captopril-treated patients.

In controlled clinical trials, greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of patients treated with valsartan compared with 0.1% and 0.1% of patients given placebo. One valsartan patient discontinued treatment for microcytic anemia.

In placebo-controlled trials, elevations of uric acid levels (baseline versus terminal lab) occurred in 2.6% of patients receiving valsartan monotherapy, 8.2% receiving valsartan and hydrochlorothiazide, 6.0% receiving hydrochlorothiazide alone and 2.3% receiving placebo.

Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

In controlled clinical trials, thrombocytopenia was observed in 0.1% of patients.

Other adverse reactions reported rarely in post-marketing use include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), photosensitivity, increase in blood pressure and taste disorders.

Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction in blood pressure after initiation of therapy with DIOVAN. The possibility of symptomatic hypotension with the use of DIOVAN can be minimized by discontinuing the diuretic prior to initiation of treatment (see Warnings and Precautions, Cardiovascular, Hypotension). No drug interaction of clinical significance has been identified with thiazide diuretics.

Since DIOVAN decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.

As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.

Co-administration of valsartan and warfarin over 3 days did not affect the bioavailability of valsartan. Co-administration had no effect on activated partial thromboplastin time (APTT) and resulted in a 12% increase in prothrombin time (PT).

A single dose of digoxin administered with a single dose of valsartan did not result in a clinically significant interaction. No steady state data are available.

See Action and Clinical Pharmacology, Pharmacokinetics, Absorption.

No initial dosage adjustment is required in patients with mild to moderate liver disease. Care should be exercised in patients with liver disease (see Action and Clinical Pharmacology, Pharmacokinetics, and Warnings and Precautions, Hepatic/Biliary/Pancreatic).

No initial dosage adjustment is required for patients with renal impairment including those patients requiring hemodialysis. Appropriate monitoring of these patients is however recommended (see Action and Clinical Pharmacology, Pharmacokinetics, and Warnings and Precautions, Renal).

No dosage adjustment is usually necessary (see Warnings and Precautions, Special Populations, Geriatrics).

In patients receiving diuretics, DIOVAN therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional anti-hypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of DIOVAN to reduce the likelihood of hypotension (see Warnings and Precautions, Hypotension, and Drug Interactions, Diuretics). If this is not possible because of the patient's condition, DIOVAN should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors (see Warnings and Precautions, Hypotension). The dosage of antihypertensive agents used with DIOVAN may need to be adjusted.

The recommended initial dose of DIOVAN is 80 mg once daily. The antihypertensive effect is present within 2 weeks and maximal reduction is usually attained within 4 weeks following initiation of therapy. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to a maximum of 320 mg or a thiazide diuretic added.

It is not recommended to prescribe the maximum dose of 320 mg without prior up-titration.

DIOVAN should be administered consistently with or without food (see Action and Clinical Pharmacology, Pharmacokinetics).

DIOVAN may be initiated as early as 12 hours after a myocardial infarction in clinically stable patients. In order to diminish the risk of hypotension, the recommended starting dose is 20 mg twice daily. Thereafter, patients may be uptitrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated. If symptomatic hypotension or renal dysfunction occurs, consideration should be given to dosage reduction. DIOVAN should be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin and statins, as indicated.

Concomitant use of beta-blockers is to be encouraged with DIOVAN in this clinical setting, if indicated, since further substantial relative risk reduction may be expected with such use over that of valsartan alone.

Patients should try to take their dose at the same time each day, preferably in the morning. However, if they have forgotten to take the dose during the day, they should carry on with the next dose at the usual time. They should not double doses.

Limited data are available in regard to overdosage with DIOVAN (valsartan) in humans. The most likely manifestations of overdosage would be hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock, and/or tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted.

Valsartan is not removed from the plasma by dialysis.

DIOVAN (valsartan) is an orally active angiotensin II AT₁ receptor blocker.

Valsartan acts selectively on AT₁, the receptor subtype that mediates the known cardiovascular actions of angiotensin II, the primary vaso-active hormone of the renin-angiotensin-system. The AT₂ receptor subtype, found in tissues such as brain, endometrium, myometrium and fetal kidney and adrenals, plays no known role in cardiovascular homeostasis to date. Valsartan does not exhibit any partial AT₁ receptor agonist activity and has essentially no activity at the AT₂ receptor. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The primary metabolite, valeryl 4-hydroxy valsartan, is essentially inactive.

Angiotensin II has a wide variety of physiological effects; many are either directly or indirectly involved in blood pressure regulation. A potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and aldosterone secretion.

Blockade of angiotensin II AT₁ receptors results in two- to three-fold increase in plasma renin and angiotensin II plasma concentrations in hypertensive patients. Long-term effects of increased AT₂ receptor stimulation by angiotensin II are unknown.

Valsartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin.

Administration of valsartan to patients with type II diabetes and microalbuminuria has resulted in significant reduction of urinary albumin excretion.

Valsartan inhibits the pressor effect of an angiotensin II infusion. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours.

After a single oral dose, the antihypertensive activity of valsartan has an onset within approximately 2 hours and peaks within 4-6 hours in most patients.

The anti-hypertensive effect of valsartan persists for 24 hours after dosing. Trough/peak ratio ranges from 0.54 to 0.76. DIOVAN reduces blood pressure in hypertensive patients without affecting pulse rate.

During repeated dosing, the maximum blood pressure reduction with any dose is generally attained within 4 weeks, and is sustained during long-term therapy. Combinations with hydrochlorothiazide produce additional reduction in blood pressure.

There is no apparent rebound effect after abrupt withdrawal of valsartan therapy.

Although data available to date indicate a similar pharmacodynamic effect of valsartan in black and white hypertensive patients, this should be viewed with caution since antihypertensive drugs that affect the renin-angiotensin system, such as ACE inhibitors and angiotensin II AT₁ receptor blockers, have generally been found to be less effective in low-renin hypertensives (frequently blacks).