Act Valsartan Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ACT VALSARTAN (valsartan) is indicated for:

• Hypertension
• For the treatment of mild to moderate essential hypertension.
• ACT VALSARTAN may be administered alone, or concomitantly with thiazide diuretics.
• The safety and efficacy of concurrent treatment with valsartan and angiotensin converting enzyme inhibitors have not been established.

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 valsartan in children and adolescents (below the age of 18 years) have not been established.

CONTRAINDICATIONS

• ACT 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).
• ACT VALSARTAN is contraindicated in pregnant and nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Concomitant use of angiotensin receptor antagonists (ARBs) - including ACT VALSARTAN - or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR <60ml/min/1.73m²) is contraindicated (see WARNINGS AND PRECAUTION, General, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal and DRUG INTERACTIONS, Drug-Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren).

WARNINGS AND PRECAUTIONS

Cardiovascular

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.

Valvular Stenosis

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.

General

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan: some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should be immediately discontinued in patients who develop angioedema, and valsartan should not be re-administered.

If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, valsartan should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS - Post Marketing Adverse Drug Reactions).

Patients with a known hypersensitivity (anaphylaxis) or angioedema to ARBs should not be treated with valsartan (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions).

Dual Blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin receptor antagonists (ARBs), including valsartan, or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR<60ml/min/1.73m²). Therefore, the use of valsartan in combination with aliskiren-containing drugs is contraindicated in these patients. Co-administration of ARBs, including valsartan, with other agents blocking the RAS such as ACEIs or aliskiren-containing drugs is not recommended in any patient, as adverse outcomes cannot be excluded.

Hepatic/Biliary/Pancreatic

On average, patients with mild to moderate chronic liver disease have twice the exposure to valsartan of healthy volunteers as measured by AUC and C_max. Care should be exercised in administering valsartan to these patients (see ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics).

Renal

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.

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.

The use of ARBs – including valsartan – or of ACEIs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR <60ml/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs).

Special Populations

Pregnant Women: Drugs that act directly on the renin-angiotensin-aldosterone- system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, valsartan should be discontinued as soon as possible.

The use of ARB is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARB, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

The use of ARBS during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.

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; however, limited experience with those procedures has not been associated with significant clinical benefit. 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 significant levels have been found 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 valsartan 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

Valsartan 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 valsartan 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 valsartan monotherapy at doses of 80 to 160 mg/day. The table includes all AEs with an incidence of 1% or greater in the valsartan 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 valsartan monotherapy at doses of 80 to 160 mg/day

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

In double-blind controlled trials, the following adverse events were reported with valsartan 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.

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 in post-marketing use include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), dermatitis bullous (unknown frequency), renal impairment (very rare), photosensitivity, increase in blood pressure and taste disorders.

The following serious adverse events, irrespective of causality and with unknown frequency, have been reported from clinical studies or post-marketing experiences: Toxic epidermal necrolysis (TEN), Stevens-Johnsons syndrome (SJS), erythema multiforme (EM), toxic skin eruption, skin necrosis, exfoliative rash, pemphigus and pemphigoid.

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

The following other adverse drug reactions with unknown frequency have been reported from clinical studies or post-marketing experiences: Hypersensitivity including serum sickness, vasculitis, insomnia and libido decrease.

Hepato-biliary disorder: Hepatic enzyme increased including blood bilirubin increased.

DRUG INTERACTIONS

Drug-Drug Interactions

Diuretics

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 valsartan. The possibility of symptomatic hypotension with the use of valsartan 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.

Agents Increasing Serum Potassium

Since valsartan 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 monitoring of serum potassium.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further with ACT VALSARTAN.

Lithium Salts

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.

Warfarin

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).

Digoxin

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.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs)

Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function including possible acute renal failure. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment and periodically in patients on valsartan who are taking NSAIDs concomitantly.

Transporters of OATP1B1 and/or MPR2

The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

Dual blockade of the Renin-Angiotensin- System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs. See WARNINGS AND PRECAUTIONS, General, Dual Blockade of the Renin-Angiotensin System (RAS).

Drug-Food Interactions

See ACTION AND CLINICAL PHARMACOLOGY - Pharmacokinetics - Absorption

DOSAGE AND ADMINISTRATION

Dosing Considerations

Hepatic Impairment

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).

Renal Impairment

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).

Elderly

No dosage adjustment is usually necessary (see WARNINGS AND PRECAUTIONS – Special Populations – Geriatrics).

Concomitant Diuretic Therapy

In patients receiving diuretics, ACT VALSARTAN 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 ACT Valsartan 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, ACT VALSARTAN 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.

Recommended Dose and Dosage Adjustment

Hypertension

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 ACT VALSARTAN may need to be adjusted.

The recommended initial dose of ACT VALSARTAN 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.

ACT VALSARTAN should be administered consistently with or without food (See ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics).

Missed Dose

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 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

Mechanism of Action

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.

Pharmacodynamics

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. Valsartan 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).

Pharmacokinetics

Since its pharmacokinetics are linear in the 80 to 320 mg dose range, valsartan does not accumulate appreciably in plasma following repeated administration.

The valsartan 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 T_max values were similar and the mean C_max 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 AUC_0→∞ was of 42.68 h•mg/L for the tablet and 39.829 h•mg/L for the capsule.

Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2 – 4 hours. The mean absolute bioavailability of valsartan is about 23%, but with high variability. Giving valsartan 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. These food effect data were obtained with the capsule formulation of valsartan. The effect of food on the tablet formulation of valsartan remains unknown thus far.

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

Metabolism: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive. 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 intravenous administration, valsartan shows bi-exponential decay kinetics (t_1/2α<1 hour and t_1/2β between 5-9 hours). Following administration of an oral solution of ¹⁴C labelled valsartan, 83% of absorbed valsartan is primarily excreted in the feces and 13% in the urine, mainly as unchanged compound. Following intravenous administration, plasma clearance of valsartan is about 2 L/h. The half-life of valsartan is 6 hours.

Special Populations and Conditions

Pediatrics: The safety and effectiveness of valsartan 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 C_max 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: Plasma concentrations are similar in males and females.

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 C_max (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 C_max, 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

Store ACT VALSARTAN Tablets at room temperature (15°C-30 C). Protect from heat and moisture.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

ACT VALSARTAN tablets are formulated for oral administration and are available as 40 mg, 80 mg, 160 mg and 320 mg tablets with the following descriptions:

ACT VALSARTAN 40 mg tablets are yellow, film-coated, oval-shaped, biconvex tablet with “V” bisect “S on one side and “ ” on the other side.

ACT VALSARTAN 80 mg tablets are pink, film-coated, round, biconvex tablet with “VS” over “80” on one side and “ ” on the other side.

ACT VALSARTAN 160 mg tablets are orange, film-coated, oval-shaped, biconvex tablet with “VS 160” on one side and “ ” on the other side.

ACT VALSARTAN 320 mg tablets are dark grey-violet, film-coated, oval-shaped, biconvex tablet with “VS 320” on one side and “ ” on the other side.

Composition

ACT VALSARTAN 40 mg Tablets

Each tablet contains 40 mg of valsartan as the active ingredient and the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone and sodium dodecyl sulphate. In addition, the tablet film coating contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and iron oxide yellow.

ACT VALSARTAN 80 mg Tablets

Each tablet contains 80 mg of valsartan as the active ingredient and the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone and sodium dodecyl sulphate. In addition, the tablet film coating contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, iron oxide red, FD&C Yellow #6, and FD&C Blue #2.

ACT VALSARTAN 160 mg Tablets

Each tablet contains 160 mg of valsartan as the active ingredient and the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone and sodium dodecyl sulphate. In addition, the tablet film coating contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, iron oxide yellow, and FD&C Yellow #6.

ACT VALSARTAN 320 mg Tablets

Each tablet contains 320 mg of valsartan as the active ingredient and the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, povidone and sodium dodecyl sulphate. In addition, the tablet film coating contains: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, iron oxide black, iron oxide red, iron oxide yellow, FD&C Red #40, and FD&C Blue #2.

Packaging

ACT VALSARTAN 40 mg are available in HDPE bottles of 100 and 500 tablets, and in unit dose blister packs of 30 tablets (blister strip of 15 tablets).

ACT VALSARTAN 80 mg are available in HDPE bottles of 100 and 500 tablets, and in unit dose blister packs of 30 tablets (blister strip of 15 tablets).

ACT VALSARTAN 160 mg are available in HDPE bottles of 100 and 500 tablets, and in unit dose blister packs of 30 tablets (blister strip of 15 tablets).

ACT VALSARTAN 320 mg are available in HDPE bottles of 100 and 500 tablets, and in unit dose blister packs of 30 tablets (blister strip of 15 tablets).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Valsartan

Chemical name: (S)-N-valeryl-N-{[2`-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl}-valine

Molecular formula: C₂₄H₂₉N₅O₃

Molecular mass: 435.5 g/mol

Structural formula:

Physicochemical properties: Valsartan is a white to off-white powder. Valsartan is freely soluble in methanol and ethanol, sparingly soluble in ethyl acetate, slightly soluble in dichloromethane, and practically insoluble in water. Melting point: 97.5-105°C.

CLINICAL TRIALS

Comparative Bioavailability Studies

A blinded, single-dose, randomized, two-period, two-sequence, two-treatment, two-group crossover comparative bioavailability study of ACT VALSARTAN (valsartan) 320 mg tablets and Diovan^® (valsartan) 320 mg tablets by Novartis Pharmaceuticals Canada Inc., was conducted under fasting conditions with 50 healthy male volunteers. A summary of the bioavailability data from 49 subjects is presented in the table below.

Comparative Bioavailability Data for

ACT VALSARTAN 320 mg Tablets vs. Diovan^® 320 mg Tablets

* Valsartan 320 mg tablets (Actavis Pharma Company, Canada)

^† The reference product, Diovan^® 320 mg tablets (Novartis Pharmaceuticals Canada, Inc.), was purchased in Canada.

§ Expressed as the median (range) only

€ Expressed as the arithmetic mean (CV%) only

Study Demographics and Trial Design

Not Applicable

Study Results

Hypertension

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 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 valsartan 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 valsartan 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.

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

Not applicable.

TOXICOLOGY

In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. In embryofetal development studies (Segment II) in mice rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats and valsartan doses of > 200 mg/kg/days and in rabbits at doses of > 10 mg/kg/day. In a peri- and postnatal development toxicity (segment III) study, the offspring 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 (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women). 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, abnormal reproductive performance in rats or carcinogenicity in mice and rats.

Acute Toxicity

Long-Term Toxicity

NOEL No observable effect level.

NOAEL No observable adverse effect level.

Reproduction and Teratology

Segment 1

Segment II

Segment III

+ - Number of days post-parturition

Mutagenicity

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

In vitro

In vivo

** S typhimurium – TA98, TA100, TA 1537 E coli – WP2uvrA

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

Carcinogenicity

REFERENCES

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5. 5. Mallion J-M, Boutelant S, et al. Valsartan, a new angiotensin II antagonist; blood pressure reduction in essential hypertension compared with an angiotensin converting enzyme inhibitor, enalapril. J Blood Pressure Monitoring. 1997; 2 (3-4): 1-5.
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8. 8. Viberti G, Wheeldon NM et al., for the Microalbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 106: 672-678, 2002.
9. 9. Muirhead N, Feagan BF, Mahon J, et al. The effects of valsartan and captopril on reducing microalbuminuria in patients with type 2 diabetes mellitus: a placebo-controlled trial. Curr. Ther. Res. 60: 650-660, 1999.
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