Mylan-Valsartan HCTZ Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) is indicated for the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.

MYLAN-VALSARTAN HCTZ is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

Patients should be titrated on individual drugs. If the fixed combination represents the dose and dosing frequency determined by this titration, the use of MYLAN-VALSARTAN HCTZ may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary it is advisable to use the individual drugs.

Geriatrics (> 65 years of age):

No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out and appropriate caution is recommended.

Pediatrics (< 18 years of age):

The safety and efficacy of valsartan and hydrochlorothiazide tablets in children and adolescents (below the age of 18 years) have not been established and use in this age group is not recommended.

CONTRAINDICATIONS

• MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) 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).
• Because of the hydrochlorothiazide component, it is also contraindicated in patients with anuria, severe progressive renal disease and if increasing azotemia and oliguria occur during treatment.
• Patients who are hypersensitive to other sulfonamide-derived drugs.
• MYLAN-VALSARTAN HCTZ is also contraindicated in pregnant and nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Thiazide diuretics are contraindicated in patients with hyponatremia, hypercalcemia, symptomatic hyperuricemia, and conditions involving enhanced potassium loss.
• Concomitant use of angiotensin receptor antagonists (ARBs) - including 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

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. MYLAN-VALSARTAN HCTZ should be immediately discontinued in patients who develop angioedema, and MYLAN-VALSARTAN HCTZ should not be re-administered.

If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, MYLAN-VALSARTAN HCTZ 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 MYLAN-VALSARTAN HCTZ (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions).

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 when treated with vasodilators, because they do not develop as much after load reduction.

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 MYLAN-VALSARTAN HCTZ in combination with aliskiren-containing drugs is contraindicated in these patients. Co-administration of ARBs, including MYLAN-VALSARTAN HCTZ, 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.

Endocrine and Metabolism

Serum electrolyte changes

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) should be used with caution. Thiazide diuretics can precipitate new onset hypokalemia or exacerbate preexisting hypokalemia. Thiazide diuretics are contraindicated in patients with conditions involving enhanced potassium loss (refractory hypokalemia), for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.

Thiazide diuretics can precipitate new onset hyponatremia and hypochloremic alkalosis or exacerbate pre-existing hyponatremia. Hyponatremia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended. Patients receiving thiazides should be carefully observed for clinical signs of fluid and electrolyte imbalance (hyponatremia, hypochloremic alkalosis and hypokalemia). Periodic determinations of serum electrolytes to detect possible electrolyte disturbance should be performed at appropriate intervals. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Other metabolic disturbances

Like other diuretics, hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Thiazides are contraindicated in patients with symptomatic hyperuricemia.

Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, it should not be used (see Contraindications) in patients with hypercalcemia.

Pathological changes in the parathyroid gland of patients with hypercalcemia and

hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic clarification is necessary and thiazides should be discontinued.

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

Interference with adequate oral electrolyte intake will also contribute to hypokalemia.

Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).

Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances, when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Increases in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy, including hydrochlorothiazide.

Hepatic/Biliary/Pancreatic

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

In general, no dosage adjustment is needed in patients with mild to moderate liver disease. Due to the hydrochlorothiazide component, MYLAN-VALSARTAN HCTZ should not be used (not recommended) in patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION, Hepatic impairment). However, care should be exercised in patients with liver disease, especially in those patients with biliary obstructive disorders, as the major portion of valsartan is eliminated in the bile. No information is available in patients with severe liver disease (see ACTION AND CLINICAL PHARMACOLOGY-Pharmacokinetics).

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

Ophthalmologic

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute-angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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).

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 valsartan and hydrochlorothiazide tablets 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.

No dosage adjustment is required for patients with mild to moderate renal impairment (GFR ≥30 mL/min). Because of the hydrochlorothiazide component, MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) should not be used in patients with severe renal impairment (GFR<30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease (see CONTRAINDICATIONS). They are ineffective as monotherapy in severe renal impairment (GFR<30 mL/min) (see DOSAGE AND ADMINISTRATION, renal impairment, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Azotemia

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued (see CONTRAINDICATIONS).

Patients with renal impairment

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).

Sensitivity/Resistance

Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.

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, MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) 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, hyperkalaemia).

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 ARBs 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.

Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics, including hydrochlorothiazide in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse experiences which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

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. Thiazides appear in human milk. 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 (< 18 years of age): The safety and efficacy of valsartan and hydrochlorothiazide tablets in children and adolescents (below the age of 18 years) have not been established and use in this age group is not recommended.

Geriatrics (> 65 years of age): No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out and appropriate caution is recommended.

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.

Valsartan and hydrochlorothiazide tablets have been evaluated for safety in more than 7616 patients treated for essential hypertension. Of these, 4372 were treated with valsartan and hydrochlorothiazide tablets in controlled clinical trials with a mean exposure of 8 weeks.

In controlled clinical trials, discontinuation due to Adverse Experiences (AEs) occurred in 2.3 % and 3.1 % of patients treated with valsartan and hydrochlorothiazide tablets and placebo, respectively. The most common AEs resulting in discontinuation of therapy with valsartan and hydrochlorothiazide tablets were dizziness and headache.

The most common serious AEs with valsartan and hydrochlorothiazide tablets were myocardial infarction and chest pain.

The following table is based on double-blind, active or placebo-controlled trials in patients treated with valsartan and hydrochlorothiazide tablets at doses of 80 mg/12.5 mg, 80 mg/25 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg, valsartan at doses of 80 mg, 160 mg, and 320 mg, and HCT at doses of 12.5 mg and 25 mg (see CLINICAL TRIALS). The table includes all AEs with an incidence of 1% or greater in either the valsartan and hydrochlorothiazide tablets, valsartan monotherapy, HCT monotherapy, or placebo group, irrespective of causal relationship to study drug.

Table 1 - Occurrence of adverse events during double-blind controlled trials in patients treated with valsartan and hydrochlorothiazide tablets at doses of 80 mg/12.5 mg, 80 mg/25 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg.

Evaluation of the AEs in the total active-, or placebo-controlled safety population, showed that the most common events, regardless of relationship to treatment in patients treated with valsartan

320 mg/HCTZ were, dizziness, nasopharyngitis, headache and fatigue. The incidence of hypotension was 0.7% in patients treated with valsartan 320mg/HCTZ.

The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide:

Very common: mainly at higher doses, hypokalemia, blood lipids increased (total cholesterol and triglycerides).

Common: Hyponatremia, hypomagnesemia, hyperuricemia, urticaria and other forms of rash, decreased appetite, mild nausea and vomiting, orthostatic hypotension, which may be aggravated by alcohol, anaesthetics or sedatives, and impotence.

Rare: Hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic state, photosensitivity reaction, abdominal discomfort, constipation, diarrhoea, cholestasis or jaundice, arrhythmias, headache, dizziness, sleep disorders, depression, paresthesia, visual impairment, thrombocytopenia, sometimes with purpura.

Very rare: Hypochloremic alkalosis, vasculitis necrotising, toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow failure, haemolytic anaemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary oedema.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Body as a whole: arthritis, asthenia, hypersensitivity, influenza, contusion, insomnia, peripheral oedema, pyrexia, sprains and strains

Cardiovascular: angina pectoris, hypotension, myocardial infarction, palpitations, tachycardia, ventricular systoles

Digestive: motion sickness, stomach discomfort

Ear and Labyrinth: ear pain

Gastrointestinal: abdominal pain, dry mouth, dyspepsia, flatulence, gastritis, toothache, vomiting

Muscoskeletal and connective tissue: arthralgia, myalgia, muscle strain

Metabolic and Nutritional: diabetes mellitus, gout, hypokalaemia, hyperuricaemia

Nervous system/Psychiatric: anxiety, somnolence

Renal and urinary system: micturition frequency, urinary tract infection, pollakiuria

Respiratory, thoracic, mediastinal: bronchitis, chest discomfort/pain, dyspnea pharyngolaryngeal pain, sinus congestion, sinusitis

Reproductive: erectile dysfunction

Skin and subcutaneous tissue: rash

Special senses: blurred vision, conjunctivitis, vertigo, tinnitus, visual disturbance

Other: viral infection

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Findings:

Potassium: In the double-blind, active or placebo-controlled trials potassium decrease of >20% was observed most frequently with HCTZ 25mg (9.7%), followed by HCTZ 12.5mg (6.3%), valsartan/HCTZ 320/25 mg (4.5%), valsartan 320/12.5 mg (3.8%), and valsartan 320mg (2.0%) compared to placebo (3.1%). Also some patients showed serum potassium increase >20 % but no dose relationship could be demonstrated.

Creatinine/Blood urea nitrogen (BUN)/Uric acid: Minor elevations in creatinine and BUN occurred in 1.9% and 14.7%, respectively, of patients treated with valsartan and hydrochlorothiazide tablets and 0.4% and 6.3%, respectively, of patients given placebo in controlled clinical trials. Uric acid increase of > 50% was observed most frequently with valsartan/HCTZ 320/25mg (5.5%), followed by valsartan/HCTZ 320/12.5mg (2.8%), HCTZ 25mg (2.0%), valsartan 320mg (1.7%), and HCTZ 12.5mg (0.8%) compared to placebo (1.6%).

Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of patients treated with valsartan and hydrochlorothiazide tablets compared with 0.0% of patients given placebo.

Neutropenia: Neutropenia was observed in 0.1% of patients treated with valsartan and hydrochlorothiazide tablets and 0.4% of patients treated with placebo.

Post-Market Adverse Drug Reactions

Other adverse reactions reported rarely in post-marketing use of valsartan alone include: anaphylaxis (very rarely), angioedema (involving swelling of the face, lips and/or tongue), dermatitis bullous (frequency unknown), photosensitivity, increase in blood pressure and taste disorders. Very rare cases of impaired renal function have also been reported.

The following adverse drug reactions have also been identified based on post-marketing experiences. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies. Therefore, the frequency assigned is “not known”: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma.

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

Cases of syncope were reported with valsartan and hydrochlorothiazide tablets. It is unknown whether these effects were causally related to the therapy.

Cases of dehydration, dizziness postural, hypoesthesia, prutitus and rhinitis, leucopenia, abdominal pain upper, bronchitis acute, epistaxis, gastroenteritis, hyperhidrosis, neck pain, otitis media, paraesthesia, ligament sprain, hypersensitivity/allergic reactions including serum sickness, non-cardiogenic pulmonary oedema and libido decreased have also been reported.

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

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.

DRUG INTERACTIONS

Drug-Drug Interactions

Table 2 – Established or Potential Drug-Drug Interactions for Valsartan

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Table 3 – Established or Potential Drug-Drug Interactions for Hydrochlorothiazide

Legend: C = Case Study; RCS = Retrospective Cohort Study; CT = Clinical Trial; T = Theoretical

Drug-Food Interactions

MYLAN-VALSARTAN HCTZ may be administered with or without food, however it should be taken consistently with respect to food intake (see DOSAGE AND ADMINISTRATION).

DOSAGE AND ADMINISTRATION

Dosing Considerations

Dosage must be individualized. The fixed combination is not for initial therapy. The dose of MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) should be determined by the titration of the individual components.

Hepatic Impairment

No initial dosage adjustment in valsartan is required in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, MYLAN-VALSARTAN HCTZ is not recommended in patients with severe hepatic impairment (see Warnings and Precautions). Because thiazide diuretics may precipitate hepatic coma, care should be exercised when administering a fixed combination product containing hydrochlorothiazide (see WARNINGS AND PRECAUTIONS). Due to the valsartan component, MYLAN-VALSARTAN HCTZ should be used with particular caution in patients with biliary obstructive disorders (see Contraindications and Warnings and Precautions).

Renal Impairment

No dosage adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) ≥30 mL/min). Due to the hydrochlorothiazide component, MYLAN-VALSARTAN HCTZ is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) and with anuria (see Contraindications) and should be used with caution in patients with severe renal impairment (GFR <30 mL/min) (see Warnings and precautions for use and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Elderly

No dosage adjustment is usually necessary however see WARNINGS AND PRECAUTIONS.

Recommended Dose and Dosage Adjustment

Once the patient has been stabilized on the individual components as described below, MYLAN-VALSARTAN HCTZ, 80mg/12.5mg, 160mg/12.5mg, 160 mg/25, 320mg/12.5mg, or 320mg/25mg once daily may be substituted if the doses on which the patient was stabilized are the same as those in the fixed combination (see INDICATIONS AND CLINICAL USE and WARNINGS AND PRECAUTIONS).

The maximum recommended dose is 320 mg valsartan and 25 mg hydrochlorothiazide and the titration will be based on physician’s judgment according to severity of hypertension and other associated risk factors.

MYLAN-VALSARTAN HCTZ may be administered with or without food, however it should be taken consistently with respect to food intake.

Valsartan monotherapy

The recommended starting dose of 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.

Diuretic-Treated Patients

In patients receiving diuretics, 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 MYLAN-VALSARTAN HCTZ to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). If this is not possible because of the patient’s condition, MYLAN-VALSARTAN HCTZ 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.

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

No specific information is available on the treatment of overdosage with valsartan and hydrochlorothiazide tablets. Treatment is symptomatic and supportive.

Valsartan

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

Valsartan is not removed from the plasma by dialysis.

Hydrochlorothiazide

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

ACTION AND CLINICAL PHARMACOLOGY

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) combines the actions of valsartan, an orally active angiotensin II AT₁ receptor blocker, and that of a diuretic, hydrochlorothiazide.

Mechanism of Action

Valsartan

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.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, therefore co-administration of an angiotensin II AT₁ Receptor Blocker tends to reverse the potassium loss associated with thiazide diuretics.

Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure.

Pharmacodynamics

Valsartan

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 heart 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).

Hydrochlorothiazide

Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6-12 hours.

Valsartan-Hydrochlorothiazide

The components of valsartan and hydrochlorothiazide tablets have been shown to have additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component used alone.

The antihypertensive effect of valsartan and hydrochlorothiazide tablets is sustained for a 24-hour period. In clinical studies of at least one year duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of valsartan and hydrochlorothiazide tablets had no clinically significant effect on heart rate.

Pharmacokinetics

Valsartan

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

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.

Distribution: Valsartan is 94-97% bound to serum protein, mainly serum albumin. The steady-state volume of distribution of valsartan after intravenous administration is about 17 L, indicating that valsartan is not distributed 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 labeled 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.

Hydrochlorothiazide

Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (T_max about 2 h).The increase in mean AUC is linear and dose proportional in the therapeutic range. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of hydrochlorothiazide is 70 % after oral administration.

Distribution: The distribution and elimination kinetics have generally been described as a bi-exponential decay function. The apparent volume of distribution is 4-8 L/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

Metabolism: Hydrochlorothiazide is eliminated predominantly as unchanged drug.

Excretion: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95 % of the absorbed dose being excreted as unchanged compound in the urine.

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

Valsartan-Hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined used of valsartan and hydrochlorothiazide.

Special Populations and Conditions

Pediatrics: The pharmacokinetics of valsartan have not been investigated in patients <18 years of age.

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).

MYLAN-VALSARTAN HCTZ should be used with particular caution in patients with biliary obstructive disorders. Because of hydrochlorothiazide, MYLAN-VALSARTAN HCTZ is not recommended in patients with severe hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic).

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.

In the patients with moderate to severe renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased by 2.27 fold and 8.46 fold respectively and the mean cumulative urinary excretion rate is reduced by 35% as compared to baseline 51% of the oral dose.

As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide. Therefore, MYLAN-VALSARTAN HCTZ is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Valsartan is not removed from plasma by dialysis.

STORAGE AND STABILITY

Store at controlled room temperature (15°C to 30°C). Protect from moisture.

SPECIAL HANDLING INSTRUCTIONS

Not applicable.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) tablets, 80mg/12.5mg are supplied in cartons containing 3 blister strips of 10 tablets and HDPE bottles containing 100 and 500 tablets.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) tablets, 160mg/12.5mg are supplied in cartons containing 3 blister strips of 10 tablets and HDPE bottles containing 100 and 500 tablets.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) tablets, 160mg/25mg are supplied in cartons containing 3 blister strips of 10 tablets and HDPE bottles containing 100 and 500 tablets.

MYLAN-VALSARTAN HCT (valsartan and hydrochlorothiazide) tablets, 320mg/12.5mg are supplied in cartons containing 3 blister strips of 10 tablets and HDPE bottles containing 100 tablets.

MYLAN-VALSARTAN HCT (valsartan and hydrochlorothiazide) tablets, 320mg/25mg are supplied in cartons containing 3 blister strips of 10 tablets and HDPE bottles containing 100 tablets.

Composition

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) Tablet, 80mg/12.5mg

Each pink, oval biconvex film-coated tablet debossed with VH1 on one side of the tablet and M on the other side contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, sodium dodesyl sulphate, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The coating contains hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol 8000, talc and titanium dioxide.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) Tablet, 160mg/12.5mg

Each reddish, oval biconvex film-coated tablet debossed with VH2 on one side of the tablet and M on the other side contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: colloidal silicon dioxide, sodium dodesyl sulphate, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The coating contains hypromellose, iron oxide red, polyethylene glycol 400, talc and titanium dioxide.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) Tablet, 160mg/25mg

Each brown, oval biconvex film-coated tablet debossed with VH3 on one side of the tablet and M on the other side contains 160 mg of valsartan and 25 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, sodium dodesyl sulphate, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The coating contains hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol 8000, talc and titanium dioxide.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) Tablet, 320mg/12.5mg

Each pink, oval biconvex film-coated tablet debossed with VH4 on one side of the tablet and M on the other side contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, sodium dodesyl sulphate, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The coating contains hypromellose, iron oxide black, iron oxide red, polyethylene glycol 4000, talc and titanium dioxide.

MYLAN-VALSARTAN HCTZ (valsartan and hydrochlorothiazide) Tablet, 320mg/25mg

Each yellow, oval biconvex film-coated tablet debossed with VH5 on one side of the tablet and M on the other side contains 320 mg of valsartan and 25 mg of hydrochlorothiazide as the active ingredients. Each tablet contains the following non-medicinal ingredients: Colloidal silicon dioxide, sodium dodesyl sulphate, crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch. The coating contains hypromellose, iron oxide yellow, polyethylene glycol 8000, talc and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

CLINICAL TRIALS

Comparative Bioavailability Studies

A double blind, balanced, randomized, two-treatment, two-sequence, two-period, single-dose, crossover, oral bioequivalence study of Mylan-Valsartan HCTZ 320 mg/25 mg (Mylan Pharmaceuticals ULC) and ^Pr Diovan HCT^® (Valsartan and Hydrochlorothiazide) 320 mg/25 mg (Novartis Pharmaceuticals Canada Inc.) was performed in 52 normal, healthy, adult, Asian male volunteers under fasting conditions.

A summary of the results is presented in the following tables.

VALSARTAN

*Mylan-Valsartan-Hydrochlorothiazide manufactured for Mylan Pharmaceuticals ULC, Toronto, Canada.

^† Diovan HCT (Manufactured by Novartis Pharmaceuticals Canada Inc. 385 Bouchard, Dorval (Quebec) H9S 1A9) was purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV%) only.

HYDROCHLOROTHIAZIDE

*Mylan-Valsartan-Hydrochlorothiazide manufactured for Mylan Pharmaceuticals ULC, Toronto, Canada.

^† Diovan HCT (manufactured by Novartis Pharmaceuticals Canada Inc. 385 Bouchard, Dorval (Quebec) H9S 1A9) was purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV%) only.

In controlled clinical trials including over 7600 patients with essential hypertension, 4372 patients were exposed to valsartan (80, 160 and 320 mg) and concomitant hydrochlorothiazide (12.5 and 25 mg). Two randomized, double-blind factorial trials compared various combinations of 80/12.5 mg, 80/25 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7-10/4-5 mmHg for valsartan 80 mg to 320 mg and 5-11/2-5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg, alone.

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

The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.

In one year open label follow up study (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide was maintained. The antihypertensive effect was independent of age or gender. The overall response to the combination was similar for black and non-black patients.

There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.

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.

TOXICOLOGY

Acute Toxicity

Valsartan

Valsartan and hydrochlorothiazide

Long-Term Toxicity

Valsartan

In toxicity studies conducted in several animal species, the main preclinical safety findings involving the kidney and related effects, are attributed to the pharmacological action of the compound.

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.

NOEL No observable effect level.

NOAEL No observable adverse effect level.

Valsartan and hydrochlorothiazide

The combination of valsartan/hydrochlorothiazide was evaluated for toxicity in the rat and marmoset for up to 6 months. Treatment-related findings were mainly related to the exaggerated pharmacological effects of valsartan and/or hydrochlorothiazide and consisted of reduction in red cells parameters, alterations in electrolyte and water concentrations in the body, hypertrophy of the juxtaglomerular apparatus and renal tubular changes. The marmoset was a much more sensitive species in which there was an approximate 10-fold potentiation of blood pressure reduction with the combination of valsartan and hydrochlorothiazide as compared to valsartan alone. Hydrochlorothiazide alone had no effect on the blood pressure of marmosets. This potentiation has not been seen in the human subject; the effect of valsartan and hydrochlorothiazide is additive.

NOAEL: No Observed Adverse Effect Level

NOEL: No Observed Effect Level

Reproduction and Teratology

Valsartan

In reproductive studies in rats, mice and rabbits, only minor effects were noted. In rabbits there was evidence of low fetal weights, litter loss and abortion, but no teratogenicity at 5 and 10 mg/kg. Rabbits are extremely susceptible to compounds acting on the RAAS so this finding is not unexpected. There was also a slightly reduced postnatal F1 survival and development together with reduced maternal bodyweight gain in rats at 600 mg/kg. Otherwise, there was no effect at the highest doses tested on fertility, reproductive performance in rats (200 mg/kg), embryotoxcity, fetotoxicity, teratogenicity in rats and mice (600 mg/kg).

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 offsprings from rats treated at 600 mg/kg during the last trimester and during lactation showed a slightly reduced survival rate and a slight developmental delay (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

Segment I

Segment II

1. 1. Range Finding

Segment III

+ - Number of days post-parturition

Valsartan and hydrochorothiazide

Reproductive studies with the combination of valsartan/hydrochlorothiazide were conducted in rats, mice and rabbits. In all 3 species, there was no evidence of teratogenicity. In rats, there were maternal changes, mainly decreased food consumption, bodyweight or bodyweight gain at 50:115.6 mg/kg and above and deaths at 200:62.5 mg/kg and above. Fetotoxicity was seen at 262.5 mg/kg and above. This was considered to be related to the maternal toxicity. No effects were noted in mice at 600:187.5 mg/kg. Rabbits showed similar effects to those of valsartan alone at equivalent doses.

Segment II

Mutagenicity

Valsartan

Valsartan has been tested for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.

In vitro

In-vivo

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

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

Carcinogenicity

Valsartan

REFERENCES

1. 1. Benz J, Oshrain C, et al. Valsartan, a new Angiotensin II receptor antagonist: A double-blind study comparing the incidence of cough with Lisinopril and Hydrochlorothiazide. J Clin Pharmacol 1997; 37: 101-107.
2. 2. Beerman B and Groschinsky-Grand M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol. 1977; 12: 297-303.
3. 3. Beerman B, Groschinsky-Grand M and Rosen A. Absorption, metabolism, and excretion of hydrochlorothiazide. Clin Pharmacol Ther. 1975; 19: 531-537.
4. 4. Black HR, Graff A, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: Efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J of Human Hypertension 1997; 11: 483-489.
5. 5. Bremner AD, Mehring GH and Meilenbrock S. Long-term systemic tolerability of valsartan compared with lisinopril in elderly hypertensive patients. Advances in Therapy 1997; 14 (5): 245-253, 1997.
6. 6. Bucher JR. NTP technical report on the toxicology and carcinogenesis studies of hydrochlorothiazide (CAS no. 58-93-5) in F344/N rats and B6C3F1 mice (feed studies). NTP TR 357. NIH publication No. 89-2812. July 1989. US Department of Health and Human Services.
7. 7. Holwerda NJ, Fogari R, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: Efficacy and safety compared with placebo and enalapril. J of Hypertension. 1996; 14: 1147-1151.
8. 8. 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.
9. 9. Neutel J, Weber M, et al. Valsartan, a new angiotensin II antagonist: Antihypertensive effects over 24 hours. Clin Therapeutics. 1997; 19 (3): 447-458.
10. 10. Oparil S, Dyke S, et al. The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension. Clin Therapeutics. 1996; 18 (5): 797-810.
11. 11. ^Pr DIOVAN^®-HCT, Novartis Pharmaceuticals Canada Inc., Product Monograph dated: May 12, 2015, Control No.: 181891.