INDICATIONS AND CLINICAL USE

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.

Chronic Heart Failure

Diovan can be used in patients with chronic heart failure who have been shown to be intolerant to an angiotensin converting enzyme inhibitor. There is no evidence that Diovan provides added benefits when it is used with ACE inhibitors (See Clinical Trials).

Geriatrics (> 65 years of age)

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

Pediatrics (< 18 years of age)

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

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

When used in pregnancy Angiotensin II receptor (AT1) Antagonist can cause injury to or even death of the developing fetus (see WARNINGS AND PRECAUTIONS - Special Populations - Pregnant Women). When pregnancy is detected, DIOVAN should be discontinued as soon as possible.

Hypotension

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). In patients with heart failure, a greater incidence of hypotension has been reported. Monitoring and dose adjustment should be considered.

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.

On average, patients with mild to moderate chronic liver disease have twice the exposure to valsartan of healthy volunteers as measured by AUC and Cmax. Care should be exercised in administering DIOVAN to these patients (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). Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium.These effects are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of DIOVAN * may be required. In the Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACE inhibitors, treatment was discontinued for elevations in creatinine or potassium in a total of 1.0% on valsartan vs. 0.2% on placebo. Use of valsartan should include appropriate assessment of renal function.

Pregnant Women:

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.

Nursing Women:

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.

Pediatrics:

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

Geriatrics (> 65 years of age): In controlled clinical trials no overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

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.

Hypertension

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. The following table 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 - Hypertension

: Occurrence of adverse events during double-blind controlled trials in patients treated with DIOVAN monotherapy at doses of 80 to 160 mg/day

	DIOVAN N = 2827 %	Placebo N = 1007 %
Central Nervous System
Headache	8.5	13.6
Dizziness	2.8	3.9
Respiratory system
Upper Respiratory Tract Infection	2.9	2.3
Coughing	2.7	1.3
Rhinitis	1.8	2.0
Sinusitis	1.5	1.7
Pharyngitis	1.3	0.7
Bronchitis	1.1	1.3
Digestive system
Diarrhea	2.5	1.6
Abdominal Pain	1.3	0.9
Nausea	1.5	2.2
Dyspepsia	1.1	1.8
Musculoskeletal system
Arthralgia	1.3	0.9
Back Pain	2.2	1.5
Body as a whole
Fatigue	1.9	1.3
Other
Viral Infection	3.1	2.6

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.

Following Myocardial Infarction

The following table 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 - Following Myocardial Infarction

: Selected serious adverse events by treatment (safety population)

Valsartan Valsartan + Captopril

Captopril

n = 4885 (%)

n = 4862 (%)

n = 4879 (%)

Hypotension [1] 2.8 3.3 2.0

Syncope 0.7 0.6 0.6

Dizziness 0.4 0.4 0.3

Renal causes [2] 3.1 3.0 2.0

Hyperkalaemia 0.4 0.6 0.4

Atrial fibrillation 1.0 0.7 0.8

Cough 0.3 0.5 0.4

Taste disturbances [3] 0.1 0.4 0.3

[1] This term includes SAEs related to hypotension, orthostatic hypotension

[2] This term includes SAEs related to acute renal failure, chronic renal failure, blood creatinine increased [3] 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.

Heart Failure

The adverse experience profile of valsartan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients for the doses of valsartan used in the Valsartan Heart Failure Trial.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Findings

These laboratory findings pertain to trials in hypertension, except as otherwise indicated. Hyperkalemia: In hypertensive patients, 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. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of valsartan-treated patients compared to 5.1% of placebo-treated patients.

Creatinine

: 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 heart failure patients, increases in serum creatinine greater than 50% were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients.

Blood Urea Nitrogen (BUN):

In heart failure trials, increases in blood urea nitrogen (BUN) greater than 50% were observed in 16.6% of patients treated with valsartan as compared to 6.3% of patients treated with placebo.

Hemoglobin and Hematocrit

: 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.

Uric Acid: 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

: 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.

Post-Market Adverse Drug Reactions

Other adverse reactions reported rarely in post-marketing use include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), renal impairment (very rare), 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.

DRUG INTERACTIONS

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.

DOSAGE AND ADMINISTRATION

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 (see PHARMACOLOGY - Following Myocardial Infarction).

The recommended starting dose of DIOVAN is 40 mg twice daily. Titration every two weeks to 80 mg and 160 mg twice daily should be done to the highest dose tolerated by the patient. Consideration should be given to reduce the dose of concomitant diuretics. The maximum recommended dose is 160 mg twice daily.

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.

OVERDOSAGE

Limited data are available in regard to overdosage with DIOVAN * (valsartan) 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. For the management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

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).

Since its pharmacokinetics are linear in the 80 to 320 mg dose range, valsartan does not accumulate appreciably in plasma following repeated administration. The DIOVAN tablet and capsule dosage forms were found to be bioequivalent in a two-treatment, three period, repeated measure, randomized cross-over study conducted in 40 healthy volunteers and comparing the 320 mg tablet formulation to 2 X 160 mg capsule. The median Tmax values were similar and the mean Cmax values were nearly identical (2.75h versus 3.00 h and 6.162 mg/dL versus 6.164 mg/dL, respectively for the tablet and capsule). The AUC0-[?] was of 42.68 h *mg/L for the tablet and 39.829 h *mg/L for the capsule.

Absorption:

The mean absolute bioavailability of valsartan is about 23%, but with high variability. Peak plasma concentration is reached 2 to 4 hours after dosing. Giving DIOVAN with food reduces the area under the valsartan plasma concentration curve (AUC) by 48%. After about 8 hours however, plasma valsartan concentrations are similar in the fed and fasted state.

Distribution:

Valsartan is 94-97% bound to serum protein, mainly serum albumin. Steady-state volume of distribution is about 17 L, indicating that valsartan does not distribute into tissues extensively.

Metabolism: Following intravenous administration, valsartan shows bi-exponential decay kinetics (t1/2a <1 hour and t1/2b between 5-9 hours). Plasma clearance is relatively slow (about 2 L/hr) when compared with hepatic blood flow (about 30 L/hr). Valsartan biotransformation does not seem to involve the cytochrome P-450 system. The enzyme(s) responsible for valsartan metabolism have not been identified. Excretion: Following administration of an oral solution of 14C labelled valsartan, 83% of absorbed valsartan is excreted in the feces and 13% in the urine, mainly as unchanged compound.

Pediatrics:

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

Geriatrics: Exposure to valsartan is about 50% higher as measured by AUC and Cmax and the half life is longer in elderly subjects than in young subjects. However, this difference has not been shown to have any clinical significance.

Gender:

Hepatic Insufficiency: On average, patients with mild to moderate chronic liver disease have twice the exposure to valsartan of healthy volunteers as measured by AUC and Cmax (see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Renal Insufficiency: Renal clearance accounts for only 30% of total plasma clearance. There is no apparent correlation between renal function and exposure to valsartan, as measured by AUC and Cmax, in patients with different degrees of renal impairment. In patients with renal failure undergoing hemodialysis, limited information showed that exposure to valsartan is comparable to that in patients with creatinine clearance > 10 mL/min.

STORAGE AND STABILITY

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability

DIOVAN * (valsartan) 40 mg tablets are supplied in bottles of 30 and 100 tablets and in cartons containing 2 blister strips of 14 tablets. Since the 40 mg tablets are scored on one side, these may be used to initiate therapy following myocardial infarction (see DOSAGE AND ADMINISTRATION, Following Myocardial Infarction).

DIOVAN * (valsartan) 80 mg tablets are supplied in bottles of 30 and 100 tablets and in cartons containing 2 blister strips of 14 tablets.

DIOVAN * (valsartan) 160 mg tablets are supplied in bottles of 30 and 100 tablets and in cartons containing 2 blister strips of 14 tablets.

DIOVAN * (valsartan) 320 mg tablets are supplied in bottles of 30 and 100 tablets and in cartons containing 2 blister strips of 14 tablets.

Composition

DIOVAN tablets, 40 mg are yellow, ovaloid, scored on one side, slightly convex, with bevelled edges, debossed on one side with DO and with NVR on the other side. Each tablet contains 40 mg of valsartan and the following non-medicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The coating contains: hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

DIOVAN tablets, 80 mg are pale red, round shaped tablets with bevelled edges, debossed with DV on one side and NVR on the other. Each tablet contains 80 mg of valsartan and the following non-medicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The coating contains: hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, and titanium dioxide.

DIOVAN tablets, 160 mg are grey orange, ovaloid shaped tablets with bevelled edges, debossed with DX on one side and NVR on the other. Each tablet contains 160 mg of valsartan and the following non- medicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The coating contains: hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

DIOVAN tablets, 320 mg are dark grey-violet, ovaloid with bevelled edges, slightly convex, debossed with DXL on one side and NVR on the other. Each tablet contains 320 mg of valsartan and the following non-medicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The coating contains: hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

PHARMACEUTICAL INFORMATION

Drug Substance

Chemical name: (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl}-valine Molecular formula and molecular mass: C24H29N5O3 / 435.5

CLINICAL TRIALS

Study demographics and trial design

Study results

Description: Fine white to practically white, practically odourless powder. Solubility:
Melting Range: 105 - 110OC with decomposition. pKa Values:
pK a -Values	Solvent	Temp. ( O C)	Assignment
4.73 3.90	water water	22 22	tetrazole group carboxylic group

In a 6-week controlled study of the incidence of cough in hypertensive patients with a history of cough during ACE inhibitor therapy, the incidence of cough reported in patients receiving DIOVAN (valsartan) was significantly less than in patients rechallenged with an ACE inhibitor. In addition, an overall analysis of double-blind clinical trials in 4,565 patients revealed that the incidence of spontaneously reported cough was 2.7% in patients treated with DIOVAN 80 and 160 mg (n=2827), compared to 1.3% in patients treated with placebo (n=1007), whereas the incidence of cough with ACE inhibitors (n=731) was 12.6%. The antihypertensive effects of DIOVAN were demonstrated principally in 9 placebo-controlled, 4- to 12- week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115 mmHg. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison of response by gender, age, and race. Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to two years. The antihypertensive effect is independent of age, gender or race. Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure. The 9 studies of valsartan monotherapy included over 2,800 patients randomized to various doses of valsartan and about 1,100 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6- 9/3-5 mmHg at 80-160 mg and 8-9/4-7 mmHg at 320 mg. In another study, patients randomized to valsartan 320 mg once daily had an incremental blood pressure reduction of 2.6/1.2 mmHg lower than did patients randomized to valsartan 160 mg once daily. Patients with an inadequate response to valsartan 80 mg once daily were titrated to either valsartan 160 mg once daily or valsartan 80 mg twice daily, which resulted in a comparable response in both groups. In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once- daily enalapril 20 mg or once-daily lisinopril 10 mg. There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs or symptoms of congestive heart failure and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction <= 40% by radionuclide ventriculography or <= 35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 mg twice daily to highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor captopril (titrated from 6.25 mg three times daily to highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The mean treatment duration was two years. The mean daily dose of DIOVAN in the monotherapy group was 217 mg, while that of captopril in the monotherapy group was 104 mg, and that of valsartan 103 mg and captopril 93 mg when used in combination. Baseline therapy included acetylsalicylic acid (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%), and statins (34%). The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. The primary endpoint was time to all-cause mortality. All-cause mortality was similar in the valsartan (19.9%), captopril (19.5%), and valsartan + captopril (19.3%) groups. Note that combining valsartan with captopril did not add further benefit over captopril alone. The hazard ratio for all-cause mortality for valsartan versus captopril was 1.00 (97.5% CI, 0.90 to 1.11; p=0.98), and for valsartan + captopril versus captopril was 0.98 (97.5% CI, 0.89 to 1.09; p=0.73), when adjusted for age and prior MI. Further, there was no difference in all-cause mortality or cardiovascular mortality between study treatment groups when beta-blockers were administered concomitantly with valsartan, captopril, or the combination of valsartan with captopril. Irrespective of study drug treatment, mortality was about 70% higher in patients not treated with a beta-blocker, suggesting that the known beta-blocker benefit in this population was maintained in this trial.

A study called Val-HeFT (valsartan in heart failure trial) was carried out in 5,010 patients, predominantly NYHA Class II (62%) and III (36%), male (80%), white (90%) with heart failure primarily due to coronary heart disease (57%) or idiopathic origin (31%) and left ventricular ejection fraction less than 40%. Forty seven percent of the patients were 65 years or older. Patients were randomized double-blindly to valsartan 160 mg (target dose) or placebo twice daily. The double-blind therapy was given in addition to what treating physicians considered adequate treatment: diuretic (86%), digoxin (67%), beta-blocker (35%: carvedilol 15%, metoprolol 12%) and ACE inhibitor 93%. Blood pressure was on average 3/2 mmHg lower in the valsartan group at the end of the trial (average 2 years). The trial was designed with two co-primary endpoints: (1) mortality from any cause and (2) the combined endpoint of all cause mortality and morbidity which was defined as cardiac arrest with resuscitation, hospitalization for worsening heart failure, or intravenous administration of inotropic or vasodilator drugs for 4 hours or longer without hospitalization. It can be seen in Figure 2 and Table 3 there was no significant difference in mortality (the first primary endpoint) between the two groups of patients. The second co-primary endpoint was statistically significant in favour of valsartan (Table 3). The predominant benefit on the combined endpoint was largely due to a lower incidence of hospitalization for worsening heart failure with valsartan compared to placebo (p=0.001).

The 98% confidence interval (CI) was calculated for the mortality end point (death from any cause), and the 97.5% confidence interval was calculated for the combined mortality-morbidity end point.

The results obtained from patients on different background therapies are given in Figure 3. The benefits of valsartan were most apparent in patients not receiving either an ACE inhibitor or a beta blocker. However, risk ratios favoring placebo were observed for those patients treated with the triple combination of a beta blocker, an ACE inhibitor and an ARB (angiotensin II receptor blocker), valsartan. These data, however, were obtained from post hoc analyses and could have occurred by chance. Further studies such as VALIANT, where mortality was not increased in these patients, have reduced the concerns regarding the triple combination.

Relative Risks and 95% Confidence Intervals for the Combined End Point (Death from Any Cause, Cardiac Arrest with Resuscitation, Hospitalization for Worsening Heart Failure, or Therapy with Intravenous Inotropes or Vasodilators)

According to the Background Therapy at Base Line, as Calculated by Means of a Cox Regression Model.

The results of another subgroup in patients not treated with an ACE inhibitor are provided in the following Figure 4 and Table 4. These results suggest that valsartan may be beneficial in patients who are not treated with an ACE inhibitor but remain to be confirmed by results from trials specifically designed to support this suggestion. Figure 4 Kaplan-Meier curves for mortality in the valsartan (dotted line) and placebo (solid line) groups without angiotensin-converting enzyme (ACE) inhibitor background therapy (p = 0.017 by log-rank test)+.

Clinical Events in Patients Not Treated with Angiotensin-Converting Enzyme Inhibitors:

A) Mortality and Morbidity End Points and B) Total Investigator- Assessed Hospital Admissions+

Risk ratio (RR) and 95% confidence interval (CI) obtained using Cox regression, adjusting for New York Heart Association (NYHA) class, left ventricular ejection fraction baseline beta-blocker usage, etiology, and age group.

P Based on the Cochran-Mantel-Haenzel test for the number of hospital admissions stratified by beta-blocker usage and NYHA class, using modified ridit scores.

+ By chi-square test. H Persistent standing systolic blood pressure < 80 mm Hg or symptoms of hypotension.

The most common adverse events regardless of causality were for valsartan and placebo, respectively, dizziness (24% and 19%), and hypotension (15% and 6%). The mean increase in serum creatinine was significantly higher in the valsartan-treated patients (0.18 +- 0.02 vs. 0.10 +- 0.02 mg/dL, p=0.009).

Comparative Bioavailability Studies

DETAILED PHARMACOLOGY

Pharmacodynamics

The in vitro data support that valsartan is a specific antagonist of the AT1 sub-type receptor, that valsartan does not react at other receptor sites and has an affinity for the receptor that is similar in the rat, marmoset and human; whereas the affinity of valsartan for the AT1 sub-type receptor in the dog is significantly smaller. This is further reinforced by data from in vivo studies and the literature. From animal and human studies, there is also no evidence that AT1 receptor blockade by valsartan together with the resulting Ang II increase causes any arrhythmogenic effects. Vascular reactivity in the rat to exogenous Ang II is attenuated by sodium restriction and increased during sodium loading. These effects are opposite to those exhibited by the adrenal glomerulosa where sensitivity to Ang II increases during sodium restriction. This phenomenon is the consequence of changes in circulating Ang II levels linked to the altered sodium balance. As expected, in rats, after treatment with valsartan, there is a high level of circulating Ang II, so a down regulation of the receptor could therefore be expected which would reduce the efficacy of valsartan, but vascular receptor density and therefore vascular reactivity in the liver does not decrease after chronic treatment. So valsartan, should not produce internalisation of the Ang II receptor and hence, tolerance. With the increase in circulating Ang II, there is the possibility of some effects through stimulation of the AT2 receptor. The role of the AT2 receptor is currently unknown. No untoward effects were noted in preclinical or clinical studies that might suggest an AT2 receptor mediated action. The correlation between plasma levels and pharmacological response is not very clear. A similar effect is also seen in the clinic where there is also not a very clear relationship between plasma levels and blood pressure reduction. The variability of the plasma levels is most likely due to the variability in absorption which is pH dependent and thus there will be a limited window of absorption in the alimentary tract. However the critical factor in the relationship between plasma drug levels and effect is that once the AT1 receptors are blocked, increasing plasma concentrations produce very little further action. Therefore this individual variability is not of major importance.

Pharmacokinetics

Results from the absorption, distribution, metabolism and excretion studies show a fairly similar pattern for the rat, marmoset and human though the volume of distribution is greater in the two former species. In the rat the distribution is rapid and valsartan is found mainly in the blood, plasma, liver, lung and renal cortex. In all 3 species the extent of protein binding is comprised between 94% and 97% and the metabolism is fairly low (> 10%) with excretion mainly via the bile. The vast majority of the dose is cleared within 24 hours and there does not appear to be any accumulation on repeated dosing. It does not cross the blood/brain barrier or transfer into the foetus.

MICROBIOLOGY

TOXICOLOGY

In toxicity studies conducted in several animal species, there was no evidence of systemic or target organ toxicity, apart from fetotoxicity. Offsprings from rats treated at 600 mg/kg during the last trimester and lactation showed a slightly reduced survival rate and a slight delay in developmental milestones. The main preclinical safety findings involving the kidney and related effects are attributed to the pharmacological action of the compound. There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Acute Toxicity

Long-Term Toxicity

Reproduction and Teratology

Segment III

Mutagenicity

There is no evidence of compound-related mutagenicity and clastogenicity in a battery of mutagenicity studies covering various end points.

* * S typhimurium - TA98, TA100, TA 1537 E coli - WP2uvrA * * * S typhimurium - TA98, TA100, TA1535, TA 1537 E coli - WP2uvrA

Carcinogenicity

REFERENCES

Pfeffer MA, McMurray JJV, Velazquez EJ, et al. The VALsartan In Acute myocardial iNfarcTion trial (VALIANT). N Engl J Med. 349(20): 1893-1906, 2003.

This leaflet is part III of a three-part "Product Monograph" published when DIOVAN * was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about DIOVAN *. Contact your doctor or pharmacist if you have any questions about the drug.

DIOVAN * is used to lower blood pressure or to treat people after a heart attack (myocardial infarction) when the use of an

DIOVAN * is also used in patients with chronic heart failure, when they are unable to tolerate the standard treatment with medications called ACE inhibitors. There is no evidence that DIOVAN * provides added benefit when it is used with ACE inhibitors.

High blood pressure increases the workload of the heart and arteries. If this condition continues for a long time, damage to the blood vessels of the brain, heart, and kidneys can occur, and may eventually result in a stroke, heart failure or kidney failure. High blood pressure also increases the risk of heart attacks. Reducing your blood pressure decreases your risk of developing these illnesses.

receptor blocker, which help to control high blood pressure or other heart-related problems. Angiotensin II is a natural hormone produced in the body to keep blood pressure at normal levels. One function of angiotensin II is to increase blood pressure, usually when it becomes too low. DIOVAN * works by blocking the effect of angiotensin II. As a result, blood pressure is lowered.

DIOVAN * is not recommended for children and adolescents (below the age of 18 years).

40 mg tablets: Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

80 mg tablets: Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, and titanium dioxide.

160 mg tablets: Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose., hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

320 mg tablets: Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose., hydroxypropyl methylcellulose, polyethylene glycol, black iron oxide, red iron oxide, yellow iron oxide, and titanium dioxide.

If you are on a special diet, or if you are allergic to any substance, ask your doctor or pharmacist whether any of these ingredients may cause a problem.

DIOVAN * is available in four tablet strengths containing valsartan 40 mg, 80 mg, 160 mg and 320 mg.

DIOVAN * 40mg is a divisible film-coated tablet. The 20 mg dose may be obtained by dividing a 40 mg tablet in half at the break line.

DIOVAN * should not be used during pregnancy. If you discover that you are pregnant while taking DIOVAN *, stop the medication and contact your physician as soon as possible.

Similar medicines were associated with serious harm to fetuses when they were taken after the first three months of pregnancy. (It is not known if they are harmful during the first three months). It is therefore important to tell your doctor immediately if you think you may have become pregnant, or planning to become pregnant. Your doctor will discuss with you the potential risk of taking DIOVAN during pregnancy.

Although it is not known whether DIOVAN * can pass into human breast milk, this does happen in animals. Therefore do not breast- feed during treatment. Tell your doctor if you are breast-feeding, so that other treatment options can be tried.

Like many other medicines used to treat high blood pressure, DIOVAN * may rarely cause dizziness and affect your concentration. So before you drive a vehicle, use machinery, or do other things that need concentration, make sure you know how you react to the effects of DIOVAN *.

As with other medicines, interactions with other drugs are possible. Therefore, do not take any other medicines unless you have discussed the matter with your physician or your pharmacist.

Before taking DIOVAN * make sure your doctor knows about all the medications you are taking, including those not prescribed by your doctor. It may be necessary to change the dose, take other precautions, or perhaps stop one of the medicines. This applies to both prescription and non-prescription medicines.

Patients who have high blood pressure often do not notice any signs or symptoms of this condition. So even though you are feeling well, your health may be getting worse. This makes it all the more important for you to continue your treatment program and to keep your appointments with your doctor.

Remember that this medicine does not cure your high blood pressure; it only may help to control it. Therefore, if you want to lower your blood pressure and keep it down, you must continue to take DIOVAN * as directed.

It is very important that you take this medicine exactly as your doctor tells you in order to get the best results and reduce the

80 mg tablet once a day. In some cases, your doctor may increase the dose to 160 mg and then eventually to 320 mg or prescribe it together with another medicine (e.g., a diuretic).

heart attack, usually at a low dose of 20 mg twice daily in order to minimise side effects including hypotension (low blood pressure). Your doctor may increase this dose gradually over several weeks to a maximum of 160 mg twice daily.

Treatment is generally started at a dose of 40 mg twice daily in order to minimize side effects including low blood pressure. Your

doctor may increase this dose gradually over several weeks to a maximum of 160 mg twice daily.

Swallow DIOVAN * tablets with a glass of water. You can take DIOVAN * with or without food, but it should be taken the same way each day and at the same time.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Try to take your dose at the same time each day, preferably in the morning. However, if you have forgotten to take your dose

during the day, carry on with the next one at the usual time. Do not take a double dose to make up for the forgotten tablet.

If your doctor has prescribed DIOVAN * for you following a heart attack, it is important to continue to take it even if you feel well, so

Like all medicines, DIOVAN * may cause unwanted reactions, so- called side effects. Most patients do not experience side effects from DIOVAN *. Examples of occasional side effects include:

This is not a complete list of side effects. For any unexpected effects while taking DIOVAN *, contact your doctor or pharmacist.

Do not take DIOVAN * past the expiry date shown on the pack. Store your DIOVAN * tablets in a dry place at room temperature

This medicine has been prescribed to you for your current medical problem only. Do not give it to other people.

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax 866-678-6789 By email: CanadaVigilance @hc-sc.gc.ca

NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

Please consult your doctor or pharmacist with any questions or concerns you may have regarding your individual condition.

This document plus the full product monograph, prepared for health professionals can be found at:

This leaflet was prepared by Novartis Pharmaceuticals Canada Inc. Last revised: August 14, 2008

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	40 mg, 80 mg, 160 mg and 320 mg tablets	Colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose For a complete listing see Dosage Forms, Composition and Packaging section.

Solvent	Temp. ( O C)	Resulting pH	Solubility (g/L)
Water	25	3.8	0.18
water	37	3.8	0.21
0.1 N HCl	22	1.12	0.084
0.01 N HCl	37	1.0	0.10
0.067 M phosphate buffer, pH = 5.2	22	4.41	0.64
0.067 M phosphate buffer, pH = 8.0	22	5.29	16.8
chloroform	27	-	56 - 61
ethanol 96%	26	-	> 300
methanol p.a.	26	-	> 500

Event	Valsartan Group (N = 2511)	Placebo Group (N = 2499)	Relative Risk (CI) +	P Value +
no. with event (%)
Death from any cause (during entire	495 (19.7)	484 (19.4)	1.02 (0.88 -	0.80
trial)	723 (28.8)	801 (32.1)	1.18)	0.009
Combined end point	356 (14.2)	315 (12.6)	0.87 (0.77 -
Death from any cause (at first	346 (13.8)	455 (18.2)	0.97)
event)	16 (0.6)	26 (1.0)
Hospitalization for heart failure	5 (0.2)	5 (0.2)
Cardiac arrest with resuscitation
Intravenous therapy

A	Valsartan Group (n = 185)	Placebo Group (n = 181)	RR +	95% CI +	p Value +
Primary end points All-cause mortality Mortality/morbidity Secondary mortality/morbidity end points (first occurrence) Cardiovascular deaths Nonfatal morbid event Sudden death with resuscitation Therapy for HF Hospital admission for HF	32 (17.3%) 46 (24.9%) 29 (15.7%) 24 (13.0%) 1 (0.5%) 0 24 (13.0%)	49 (27.1%) 77 (42.5%) 40 (22.1%) 49 (27.1%) 2 (1.1%) 1 (0.6%) 48(26.5%)	0.67 0.56 0.76 0.46 0.46 --- 0.47	0.42-1.06 0.39-0.81 0.46-1.24 0.28-0.76 0.04-5.25 --- 0.29-0.78	0.017 ++ < 0.001 ++ 0.074 < 0.001 ++ 0.529 --- < 0.001 ++
B	Valsartan	Placebo	Diff. SS	% Diff.	p Value P
Hospitalization cause	199	262	-63	-24.0	0.260
All-cause	199	262	-63	-24.0	0.260
HF	51	117	-66	-56.4	0.010 ++
Non-HF	148	145	3	2.1	0.567

	Valsartan (n = 185)	Placebo (n= 181)	Total (n = 366)	p Value +
Adverse events	18 (9.7%)	23 (12.7%)	41 (11.2%)	0.367
Life-threatening laboratory abnormalities	1 (0.5%)	1 (0.06%)	2 (0.05%)	0.988
Hypotension H	1 (0.5%)	1 (0.06%)	2 (0.05%)	0.988
Other	12 (6.5%)	20 (11.1%)	32 (8.7%)	0.122
Total	32 (17.3%)	45 (24.9%)	77 (21.0%)	0.076

Species	Route	Duration	Dose mg/kg	Major findings
Rat	Gavage	Acute	100	No adverse findings.
Rat	Gavage	Acute	1000, 2000	2000 mg/kg: Diarrhea, white substance (similar to test substance) in feces. Approximate LD 50 >2000 mg/kg.
Marmoset	Gavage	Acute	600, 1000	No effect 600 mg/kg. 1000 mg/kg: Vomiting, white substance (similar to test substance) in vomitus. Approximate LD 50 >1000 mg/kg.

Species	Route	Duration of dosing	Dose mg/kg	Major findings
Rat	Gavage	M - 90 days F - day 14 to 19 or 14 to +20	10, 50, 200	\| in field motor actvity at 200 mg/kg in F; no effect on fertility, reproductive performance in F o & F 1 and on F 1 development. No effect on kidney development.

Mouse	Gavage	Day 6 to 15	60, 200, 600	No embryotoxicity, fetotoxicity or teratogenicity at 600 mg/kg.
Rat	Gavage	Day 6 to 15	60, 200, 600	Reduced maternal body weight gain at 200 & 600 mg/kg and fetal weights at 600 mg/kg. No embryotoxicity, fetotoxicity or teratogenicity at 600 mg/kg.
Rabbit (range finding)	Drench	Day 6 to 18	2.5, 15, 30, 45, 50, 150	Litter losses and deaths at 15 mg/kg and above. One litter loss (1/5) at 2.5 mg/kg.
Rabbit	Gavage	Day 6 to 18 Day 7 to 19	2, 5, 10	Increased incidence of low fetal weights at 5 mg/kg. Litter loss and abortion at 5 & 10 mg/kg. No teratogenicity at 10 mg/kg.

Test	System	mg/mL or *plate	Comments
Mutagenicity	Bacteria * *	*5.0 - 5000.0	Negative
Mutagenicity	Bacteria * * *	*5000.0	Negative
Gene mutation	Chinese hamster cells (V79)	81.88 - 5550.00	Negative
Chromosome aberration	Chinese hamster cells (ovary)	81.88 - 1310.00	Negative

Test	System	mg/kg	Comments
Micro-nucleus	Rat	781.3 - 3 125.0	Negative

Mouse	Diet	2 years	10, 40, 160	Hyperplasia of gastric mucosa in males. \| body weight gain at 10 mg/kg. No carcinogenic effect
Rat	Diet	2 years	10, 50, 200	\| body weight gain, anemia, nephropathy at >= 50 mg/kg. \| urea and creatinine, \| total proteins and albumin at 200 mg/kg. No carcinogenic effect.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM
Symptom / effect		Talk with your doctor or pharmacist		Stop taking drug and call your doctor or pharmacist
Symptom / effect		Only if severe	In all cases	Stop taking drug and call your doctor or pharmacist
Common	Allergic reactions Skin rash, skin eruption or other effect on the skin or eyes			9
Uncommon	Low blood pressure (hypotension) Fainting when the blood pressure is too low			9
	Allergic reactions Swelling of the lips, face or neck, accompanied by difficulty in breathing or speaking			9
	Kidney and Liver disorder Symptoms such as nausea, vomiting dark/brown urine			9
	Muscle tenderness or weakness, generalized weakness (sign of rhabdomyoly- sis)		9
	Abdominal pain		9

(valsartan)

mg, 80 mg, 160 mg and 320 mg tablets

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3

INDICATIONS AND CLINICAL USE 3

CONTRAINDICATIONS 4

WARNINGS AND PRECAUTIONS 4

DRUG INTERACTIONS 10

DOSAGE AND ADMINISTRATION 11

OVERDOSAGE 12

ACTION AND CLINICAL PHARMACOLOGY 12

STORAGE AND STABILITY 14

SPECIAL HANDLING INSTRUCTIONS 14

DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 17

PHARMACEUTICAL INFORMATION 17

CLINICAL TRIALS 18

DETAILED PHARMACOLOGY 24

MICROBIOLOGY 24

TOXICOLOGY 24

REFERENCES 29

PART III: CONSUMER INFORMATION. 30

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Hypertension

Following Myocardial Infarction

Chronic Heart Failure

Geriatrics (> 65 years of age)

Pediatrics (< 18 years of age)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Hypotension

Pregnant Women:

Nursing Women:

Pediatrics:

Geriatrics (> 65 years of age): In controlled clinical trials no overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.

ADVERSE REACTIONS

Hypertension

Following Myocardial Infarction

Heart Failure

Laboratory Findings

DRUG INTERACTIONS

DOSAGE AND ADMINISTRATION

OVERDOSAGE

ACTION AND CLINICAL PHARMACOLOGY

Absorption:

Distribution:

Pediatrics:

Gender:

STORAGE AND STABILITY

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability

Composition

PHARMACEUTICAL INFORMATION

Drug Substance

CLINICAL TRIALS

Study demographics and trial design

Study results

Comparative Bioavailability Studies

DETAILED PHARMACOLOGY

Pharmacodynamics

Pharmacokinetics

MICROBIOLOGY

TOXICOLOGY

Acute Toxicity

Long-Term Toxicity

Reproduction and Teratology

Segment III

Mutagenicity

Carcinogenicity

REFERENCES