CO-TAREG Valsartan / Hydrochlorothiazide 80mg / 12.5mg Film-Coated Tablet 1's
RXDRUG-DRP-6644-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Treatment of essential hypertension in adults.
Valsartan/hydrochlorothiazide fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy.
Valsartan/hydrochlorothiazide fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy.
Dosage/Direction for Use
The recommended dose of valsartan/hydrochlorothiazide is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, up-titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events.
When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed.
The clinical response to valsartan/hydrochlorothiazide should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of valsartan/hydrochlorothiazide 320 mg/25 mg.
The antihypertensive effect is substantially present within 2 weeks.
In most patients, maximal effects are observed within 4 weeks. However, in some patients 4-8 weeks treatment may be required. This should be taken into account during dose titration.
If no relevant additional effect is seen with valsartan/hydrochlorothiazide 320 mg/25 mg after 8 weeks, treatment with an additional or alternative antihypertensive medicinal product should be considered. (See Pharmacology: Pharmacodynamics under Actions.)
Special Populations: Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min). Due to the hydrochlorothiazide component, valsartan/hydrochlorothiazide is contraindicated in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Hepatic Impairment: In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see Precautions). Valsartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Elderly: No dose adjustment is required in elderly patients.
Pediatric Patients: Valsartan/hydrochlorothiazide is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Administration: Valsartan/hydrochlorothiazide can be taken with or without food and should be administered with water.
When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed.
The clinical response to valsartan/hydrochlorothiazide should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of valsartan/hydrochlorothiazide 320 mg/25 mg.
The antihypertensive effect is substantially present within 2 weeks.
In most patients, maximal effects are observed within 4 weeks. However, in some patients 4-8 weeks treatment may be required. This should be taken into account during dose titration.
If no relevant additional effect is seen with valsartan/hydrochlorothiazide 320 mg/25 mg after 8 weeks, treatment with an additional or alternative antihypertensive medicinal product should be considered. (See Pharmacology: Pharmacodynamics under Actions.)
Special Populations: Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min). Due to the hydrochlorothiazide component, valsartan/hydrochlorothiazide is contraindicated in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Hepatic Impairment: In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see Precautions). Valsartan/hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Elderly: No dose adjustment is required in elderly patients.
Pediatric Patients: Valsartan/hydrochlorothiazide is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Administration: Valsartan/hydrochlorothiazide can be taken with or without food and should be administered with water.
Overdosage
Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be i.v. infusion of normal saline solution.
Valsartan cannot be eliminated by means of hemodialysis because of its strong plasma binding behavior, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Valsartan cannot be eliminated by means of hemodialysis because of its strong plasma binding behavior, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Administration
May be taken with or without food.
Contraindications
Known hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide derived medicinal products or to any of the excipients.
Pregnancy (see Use in Pregnancy & Lactation).
Because of hydrochlorothiazide, valsartan/hydrochlorothiazide is contraindicated in patients with anuria.
Pregnancy (see Use in Pregnancy & Lactation).
Because of hydrochlorothiazide, valsartan/hydrochlorothiazide is contraindicated in patients with anuria.
Special Precautions
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 pre-existing hypokalemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and pre-renal (cardiogenic) impairment of kidney function. If hypokalemia is accompanied by clinical signs (e.g. muscular weakness, paresis or ECG alterations) valsartan/hydrochlorothiazide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. 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 with Sodium and/or Volume-Depletion: In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with valsartan/hydrochlorothiazide. Valsartan/hydrochlorothiazide should be used only after correction of any pre-existing sodium/or volume depletion otherwise the treatment should start under close medical supervision.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an i.v. infusion of normal saline. Treatment can be continued once the blood pressure has stabilized.
Patients with Renal Artery Stenosis: Valsartan/hydrochlorothiazide should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, since blood urea and serum creatinine may increase in such patients.
Patients with Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (GFR ≥30 mL/min). Due to the hydrochlorothiazide component use valsartan/hydrochlorothiazide with caution in severe renal impairment (GFR <30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease. They are ineffective as monotherapy in severe renal impairment (GFR <30 mL/min) but may be useful, when used with due caution in combination with loop diuretics even in patients with GFR <30 mL/min (see Pharmacology: Pharmacokinetics under Action and Dosage & Administration).
Patients with Hepatic Impairment: In patients with mild to moderate hepatic impairment no dosage adjustment is required. Valsartan/hydrochlorothiazide should be used with particular caution in patients with biliary obstructive disorders and in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharnyx, 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/hydrochlorothiazide should be immediately discontinued in patients who develop angioedema, and valsartan/hydrochlorothiazide should not be re-administered.
Systemic Lupus Erythematosus: Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other Metabolic Disturbances: Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
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 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 be used with caution in patients with hypercalcemia. Marked hypercalcemia unresponsive to thiazide withdrawal or ≥12 mg/dL may be evidence of an underlying thiazide independent hypercalcemic process.
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.
General: Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Acute Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, has been associated with 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 week of a 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 treatment 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.
Patients with Heart Failure/Post-Myocardial Infarction: In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Effects on Ability to Drive and Use Machines: Not applicable.
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 with Sodium and/or Volume-Depletion: In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with valsartan/hydrochlorothiazide. Valsartan/hydrochlorothiazide should be used only after correction of any pre-existing sodium/or volume depletion otherwise the treatment should start under close medical supervision.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an i.v. infusion of normal saline. Treatment can be continued once the blood pressure has stabilized.
Patients with Renal Artery Stenosis: Valsartan/hydrochlorothiazide should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney, since blood urea and serum creatinine may increase in such patients.
Patients with Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (GFR ≥30 mL/min). Due to the hydrochlorothiazide component use valsartan/hydrochlorothiazide with caution in severe renal impairment (GFR <30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease. They are ineffective as monotherapy in severe renal impairment (GFR <30 mL/min) but may be useful, when used with due caution in combination with loop diuretics even in patients with GFR <30 mL/min (see Pharmacology: Pharmacokinetics under Action and Dosage & Administration).
Patients with Hepatic Impairment: In patients with mild to moderate hepatic impairment no dosage adjustment is required. Valsartan/hydrochlorothiazide should be used with particular caution in patients with biliary obstructive disorders and in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharnyx, 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/hydrochlorothiazide should be immediately discontinued in patients who develop angioedema, and valsartan/hydrochlorothiazide should not be re-administered.
Systemic Lupus Erythematosus: Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other Metabolic Disturbances: Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
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 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 be used with caution in patients with hypercalcemia. Marked hypercalcemia unresponsive to thiazide withdrawal or ≥12 mg/dL may be evidence of an underlying thiazide independent hypercalcemic process.
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.
General: Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Acute Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, has been associated with 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 week of a 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 treatment 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.
Patients with Heart Failure/Post-Myocardial Infarction: In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
Effects on Ability to Drive and Use Machines: Not applicable.
Use In Pregnancy & Lactation
Use in Pregnancy: As for any drug that also acts directly on the RAAS, valsartan/hydrochlorothiazide should not be used during pregnancy (see Contraindications). Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to angiotensin converting enzyme (ACE) inhibitors (a specific class of drugs acting on the renin-angiotensin-aldosterone-system-RAAS) given to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
If pregnancy is detected during therapy, valsartan/hydrochlorothiazide should be discontinued as soon as possible (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Women of Child-Bearing Potential: As for any drug that also acts directly on the RAAS, valsartan/hydrochlorothiazide should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
Fertility: There is no information on the effects of valsartan or hydrochlorothiazide on human fertility. Studies in rats did not show any effects of valsartan or hydrochlorothiazide on fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Lactation: It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use valsartan/hydrochlorothiazide in breast-feeding mothers.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
If pregnancy is detected during therapy, valsartan/hydrochlorothiazide should be discontinued as soon as possible (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Women of Child-Bearing Potential: As for any drug that also acts directly on the RAAS, valsartan/hydrochlorothiazide should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
Fertility: There is no information on the effects of valsartan or hydrochlorothiazide on human fertility. Studies in rats did not show any effects of valsartan or hydrochlorothiazide on fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Lactation: It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use valsartan/hydrochlorothiazide in breast-feeding mothers.
Adverse Reactions
Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual post-marketing reports are presented as follows according to system organ class. Adverse reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/hydrochlorothiazide.
Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Frequency of Adverse Drug Reactions with Valsartan/Hydrochlorothiazide: Metabolism and Nutrition Disorders: Uncommon: Dehydration.
Nervous System Disorders: Very Rare: Dizziness. Uncommon: Paresthesia. Not Known: Syncope.
Eye Disorders: Uncommon: Vision blurred.
Ear and Labyrinth Disorders: Uncommon: Tinnitus.
Vascular Disorders: Uncommon: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough. Not Known: Non cardiogenic pulmonary edema.
Gastrointestinal Disorders: Very Rare: Diarrhea.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Myalgia. Very Rare: Arthralgia.
Renal and Urinary Disorders: Not Known: Impaired renal function.
General Disorders and Administration Site Conditions: Uncommon: Fatigue.
Investigations: Not Known: Serum uric acid increased, serum bilirubin and serum creatinine increased, hypokalemia, hyponatremia, elevation of blood urea, nitrogen, neutropenia.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their casual association with the study drug: Abdominal pain, abdominal pain upper, anxiety, arthritis, asthenia, back pain, bronchitis, bronchitis acute, chest pain, dizziness postural, dyspepsia, dyspnea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhydrosis, hypoesthesia, influenza, insomnia, ligament sprain, muscle spasms, muscle strain, nasal congestion, nasopharyngitis, nausea, neck pain, edema, edema peripheral, otitis media, pain in extremity, palpitations, pharyngolaryngeal pain, pollakiuria, pyrexia, sinusitis, sinus congestion, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, vision disturbance.
Additional Information on the Individual Components: Adverse reactions previously reported with one of the individual components may be potential undesirable effects with valsartan/hydrochlorothiazide as well, even if not observed in clinical trials or during post-marketing period.
Frequency of Adverse Drug Reactions with Valsartan: Blood and Lymphatic System Disorders: Not Known: Decrease in hemoglobin, decrease in hematocrit, thrombocytopenia.
Immune System Disorders: Not Known: Other hypersensitivity/allergic reactions including serum sickness.
Metabolism and Nutrition Disorders: Not Known: Increase of serum potassium.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
Vascular Disorders: Not Known: Vasculitis.
Gastrointestinal Disorders: Uncommon: Abdominal pain.
Hepatobiliary Disorders: Not Known: Elevation of liver function values.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioedema, rash, pruritus.
Renal and Urinary Disorders: Not Known: Renal failure.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their casual association with the study drug: Arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, libido decrease, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Frequency of Adverse Reactions with Hydrochlorothiazide: Metabolism and Nutrition Disorders: Very Common: Mainly at higher doses, blood lipid increased. Common: Hypomagnesemia, and hyperuricemia. Rare: Hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic state. Very Rare: Hypochloremic alkalosis.
Skin and Subcutaneous Tissue Disorders: Common: Urticaria and other forms of rash. Rare: Photosensitivity reaction. Very Rare: Necrotizing vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus. Not Known: Erythema multiforme.
Gastrointestinal Disorders: Common: Decreased appetite, mild nausea and vomiting. Rare: Abdominal discomfort, constipation and diarrhea. Very Rare: Pancreatitis.
Hepatobiliary Disorders: Rare: Cholestasis or jaundice.
Vascular Disorders: Common: Orthostatic hypotension, which may be aggravated by alcohol, anesthetics or sedatives.
Cardiac Disorders: Rare: Arrhythmias.
Nervous System Disorders: Rare: Headache, dizziness, sleep disorders, depression and paresthesia.
Eye Disorders: Rare: Visual impairment particularly in the first few weeks of treatment. Not Known: Acute angle-closure glaucoma.
Blood and Lymphatic System Disorders: Rare: Thrombocytopenia sometimes with purpura. Very Rare: Leucopenia, agranulocytosis, bone marrow failure and hemolytic anaemia. Not Known: Aplastic anemia.
Reproductive System and Breast Disorders: Common: Impotence.
Immune System Disorders: Very Rare: Hypersensitivity reactions - respiratory distress including pneumonitis and pulmonary edema.
Renal and Urinary Disorders: Not Known: Acute renal failure, renal disorder.
General Disorders and Administration Site Conditions: Not Known: Pyrexia, asthenia.
Musculoskeletal and Connective Tissue Disorders: Not Known: Muscle spasms.
Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Frequency of Adverse Drug Reactions with Valsartan/Hydrochlorothiazide: Metabolism and Nutrition Disorders: Uncommon: Dehydration.
Nervous System Disorders: Very Rare: Dizziness. Uncommon: Paresthesia. Not Known: Syncope.
Eye Disorders: Uncommon: Vision blurred.
Ear and Labyrinth Disorders: Uncommon: Tinnitus.
Vascular Disorders: Uncommon: Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough. Not Known: Non cardiogenic pulmonary edema.
Gastrointestinal Disorders: Very Rare: Diarrhea.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Myalgia. Very Rare: Arthralgia.
Renal and Urinary Disorders: Not Known: Impaired renal function.
General Disorders and Administration Site Conditions: Uncommon: Fatigue.
Investigations: Not Known: Serum uric acid increased, serum bilirubin and serum creatinine increased, hypokalemia, hyponatremia, elevation of blood urea, nitrogen, neutropenia.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their casual association with the study drug: Abdominal pain, abdominal pain upper, anxiety, arthritis, asthenia, back pain, bronchitis, bronchitis acute, chest pain, dizziness postural, dyspepsia, dyspnea, dry mouth, epistaxis, erectile dysfunction, gastroenteritis, headache, hyperhydrosis, hypoesthesia, influenza, insomnia, ligament sprain, muscle spasms, muscle strain, nasal congestion, nasopharyngitis, nausea, neck pain, edema, edema peripheral, otitis media, pain in extremity, palpitations, pharyngolaryngeal pain, pollakiuria, pyrexia, sinusitis, sinus congestion, somnolence, tachycardia, upper respiratory tract infections, urinary tract infections, vertigo, viral infections, vision disturbance.
Additional Information on the Individual Components: Adverse reactions previously reported with one of the individual components may be potential undesirable effects with valsartan/hydrochlorothiazide as well, even if not observed in clinical trials or during post-marketing period.
Frequency of Adverse Drug Reactions with Valsartan: Blood and Lymphatic System Disorders: Not Known: Decrease in hemoglobin, decrease in hematocrit, thrombocytopenia.
Immune System Disorders: Not Known: Other hypersensitivity/allergic reactions including serum sickness.
Metabolism and Nutrition Disorders: Not Known: Increase of serum potassium.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
Vascular Disorders: Not Known: Vasculitis.
Gastrointestinal Disorders: Uncommon: Abdominal pain.
Hepatobiliary Disorders: Not Known: Elevation of liver function values.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioedema, rash, pruritus.
Renal and Urinary Disorders: Not Known: Renal failure.
The following events have also been observed during clinical trials in hypertensive patients irrespective of their casual association with the study drug: Arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, libido decrease, nausea, edema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Frequency of Adverse Reactions with Hydrochlorothiazide: Metabolism and Nutrition Disorders: Very Common: Mainly at higher doses, blood lipid increased. Common: Hypomagnesemia, and hyperuricemia. Rare: Hypercalcemia, hyperglycemia, glycosuria and worsening of diabetic metabolic state. Very Rare: Hypochloremic alkalosis.
Skin and Subcutaneous Tissue Disorders: Common: Urticaria and other forms of rash. Rare: Photosensitivity reaction. Very Rare: Necrotizing vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus. Not Known: Erythema multiforme.
Gastrointestinal Disorders: Common: Decreased appetite, mild nausea and vomiting. Rare: Abdominal discomfort, constipation and diarrhea. Very Rare: Pancreatitis.
Hepatobiliary Disorders: Rare: Cholestasis or jaundice.
Vascular Disorders: Common: Orthostatic hypotension, which may be aggravated by alcohol, anesthetics or sedatives.
Cardiac Disorders: Rare: Arrhythmias.
Nervous System Disorders: Rare: Headache, dizziness, sleep disorders, depression and paresthesia.
Eye Disorders: Rare: Visual impairment particularly in the first few weeks of treatment. Not Known: Acute angle-closure glaucoma.
Blood and Lymphatic System Disorders: Rare: Thrombocytopenia sometimes with purpura. Very Rare: Leucopenia, agranulocytosis, bone marrow failure and hemolytic anaemia. Not Known: Aplastic anemia.
Reproductive System and Breast Disorders: Common: Impotence.
Immune System Disorders: Very Rare: Hypersensitivity reactions - respiratory distress including pneumonitis and pulmonary edema.
Renal and Urinary Disorders: Not Known: Acute renal failure, renal disorder.
General Disorders and Administration Site Conditions: Not Known: Pyrexia, asthenia.
Musculoskeletal and Connective Tissue Disorders: Not Known: Muscle spasms.
Drug Interactions
Valsartan: Potassium: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may alter potassium levels (heparin, etc.) should be used with caution and with frequent monitoring of potassium.
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 have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Transporters: 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, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: Cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Hydrochlorothiazide: The following potential drug interactions may occur due to the thiazide component of valsartan/hydrochlorothiazide: Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazides. There is no experience with concomitant use of valsartan and lithium. Therefore, monitoring of serum lithium concentrations is recommended during concurrent use.
Other Antihypertensive Drugs: Thiazides potentiate the antihypertensive action of other antihypertensive drugs [e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (ARBs) and direct renin inhibitors (DRIs)].
Skeletal Muscle Relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.
Medicinal Products Affecting Serum Potassium Level: The hypokalemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics (see Precautions).
Medicinal Products Affecting Serum Sodium Level: The hyponatremic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs (see Precautions).
Antidiabetic Agents: Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and of oral antidiabetic agents.
Digitalis Glycosides: Thiazide-induced hypokalemia or hypomagnesemia may occur as unwanted effects, favoring the onset of digitalis-induced cardiac arrhythmias (see Precautions).
NSAIDs and COX-2 Selective Inhibitors: Concomitant administration of NSAIDs (e.g. salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of valsartan/hydrochlorothiazide. Concurrent hypovolemia may induce acute renal failure.
Allopurinol: Coadministration of thiazide diuretics (including hydrochlorothiazide) may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine: Coadministration of thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine.
Antineoplastic Agents (e.g. Cyclophosphamide, Methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Anticholinergic Agents: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.
Ion Exchange Resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimize the interaction.
Vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricemia and gout-type complications.
Calcium Salts: Concomitant use of thiazide type diuretics may lead to hypercalcemia by increasing tubular calcium reabsorption.
Diazoxide: Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.
Methyldopa: There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Alcohol, Barbiturates or Narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.
Pressor Amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
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 have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Transporters: 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, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
In monotherapy with valsartan, no drug interactions of clinical significance have been found with the following drugs: Cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
Hydrochlorothiazide: The following potential drug interactions may occur due to the thiazide component of valsartan/hydrochlorothiazide: Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazides. There is no experience with concomitant use of valsartan and lithium. Therefore, monitoring of serum lithium concentrations is recommended during concurrent use.
Other Antihypertensive Drugs: Thiazides potentiate the antihypertensive action of other antihypertensive drugs [e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers (ARBs) and direct renin inhibitors (DRIs)].
Skeletal Muscle Relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.
Medicinal Products Affecting Serum Potassium Level: The hypokalemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives or antiarrhythmics (see Precautions).
Medicinal Products Affecting Serum Sodium Level: The hyponatremic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs (see Precautions).
Antidiabetic Agents: Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and of oral antidiabetic agents.
Digitalis Glycosides: Thiazide-induced hypokalemia or hypomagnesemia may occur as unwanted effects, favoring the onset of digitalis-induced cardiac arrhythmias (see Precautions).
NSAIDs and COX-2 Selective Inhibitors: Concomitant administration of NSAIDs (e.g. salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component of valsartan/hydrochlorothiazide. Concurrent hypovolemia may induce acute renal failure.
Allopurinol: Coadministration of thiazide diuretics (including hydrochlorothiazide) may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine: Coadministration of thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine.
Antineoplastic Agents (e.g. Cyclophosphamide, Methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Anticholinergic Agents: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.
Ion Exchange Resins: Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimize the interaction.
Vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricemia and gout-type complications.
Calcium Salts: Concomitant use of thiazide type diuretics may lead to hypercalcemia by increasing tubular calcium reabsorption.
Diazoxide: Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.
Methyldopa: There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Alcohol, Barbiturates or Narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.
Pressor Amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C. Keep in the original package (to protect from moisture).
Action
Pharmacotherapeutic Group: Angiotensin II antagonists and diuretics, valsartan and diuretics.
Pharmacodynamics: Valsartan/Hydrochlorothiazide: In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan 160 mg (37%).
In a double-blind randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo (29%) and hydrochlorothiazide (41%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a significantly greater percentage of patients responded (BP <140/90 mmHg) or SBP reduction ≥20 mmHg or DBP reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/12.5 mg (50%) compared to hydrochlorothiazide 25 mg (25%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 160/25 mg (14.6/11.9 mmHg) and valsartan/hydrochlorothiazide 160/12.5 mg (12.4/10.4 mmHg) compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the 160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (68%) and 160/12.5 mg (62%) compared to valsartan 160 mg (49%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (81%) and valsartan/hydrochlorothiazide 160/12.5 mg (76%) compared to placebo (29%) and the respective monotherapies, i.e, hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and valsartan 160 mg (59%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 320 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 320/25 mg (15.4/10.4 mmHg) and valsartan/hydrochlorothiazide 320/12.5 mg (13.6/9.7 mmHg) compared to valsartan 320 mg (6.1/5.8 mmHg).
The difference in systolic BP reduction between the 320/25 mg and 320/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (75%) and 320/12.5 mg (69%) compared to valsartan 320 mg (53%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 320/12.5 mg (21.7/15.0 mmHg) and 320/25 mg (24.7/16.6 mmHg) compared to placebo (7.0/5.9 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (11.1/9.0 mmHg), hydrochlorothiazide 25 mg (14.5/10.8 mmHg) and valsartan 320 mg (13.7/11.3 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (85%) and 320/12.5 mg (83%) compared to placebo (45%) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (60%), hydrochlorothiazide 25 mg (66%), and valsartan 320 mg (69%).
Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan.
Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Valsartan: Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the ATII receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following ATII receptor blockade with valsartan may stimulate the unblocked ATII receptor, which appears to counterbalance the effect of the ATII receptor. Valsartan does not exhibit any partial agonist activity at the ATII receptor and has much (about 20,000-fold) greater affinity for the ATII receptor than for the ATII receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In an experienced cough compared to 68.5% of those treated with an ACE inhibitor (P<0.05).
Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction on blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80 160 mg/od) versus amlodipine (5 10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 μmol/L). At 24 weeks, UAE was reduced (p<0.001) by 42% (-24.2 μg/min; 95% CI: -40.4 to -19.1) with valsartan and approximately 3% (-1.7 μg/min; 95% CI: -5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 μg/min; 20 700 μg/min) and preserved renal function (mean serum creatinine=80 μmol/L). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), and by 44% with valsartan 320 mg (95% CI: 31 to 54%). It was concluded that 160 320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.
Hydrochlorothiazide: The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: Directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide.
Pharmacokinetics: 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 use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear anti-hypertensive effect, greater than that obtained with either active substance given alone, or placebo.
Valsartan: Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t½ <1 h and t½ about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Hydrochlorothiazide: Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (t½ about 2 h), with similar absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-80% after oral administration.
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 minimal clinical importance. The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.
Distribution: The distribution and elimination kinetics have generally been described by 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 1.8 times the level in plasma.
Elimination: For hydrochlorothiazide, >95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule. The terminal half-life is 6-15 h.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Renal Impairment: At the recommended dose of Valsartan Hydrochlorothiazide Sandoz no dose adjustment is required for patients with a creatinine clearance of 30-70 mL/min.
In patients with severe renal impairment (creatinine clearance <30 mL/min) and patients undergoing dialysis no data are available for Valsartan Hydrochlorothiazide Sandoz. Valsartan is highly bound to plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see Contraindications).
Hepatic Impairment: In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction, exposure to valsartan was increased approximately 2-fold compared with healthy volunteers.
There is no data available on the use of valsartan in patients with severe hepatic dysfunction (see Contraindications). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Toxicology: Preclinical Safety Data: The potential toxicity of the valsartan-hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man.
The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in marmoset, respectively, represent 0.3 and 1.2 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume on oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
High doses of the valsartan-hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, hemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent arterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.
The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans.
The valsartan-hydrochlorothiazide combination was not tested for mutagenicity, chromosomal breakage or carcinogenicity, since there is no evidence of interaction between the two substances. However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced no evidence of mutagenicity, chromosomal breakage or carcinogenicity.
In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see Use in Pregnancy & Lactation). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed.
Pharmacodynamics: Valsartan/Hydrochlorothiazide: In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (14.9/11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2/2.9 mmHg) and hydrochlorothiazide 25 mg (6.8/5.7 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (9.8/8.2 mmHg) compared to valsartan 80 mg (3.9/5.1 mmHg) and valsartan 160 mg (6.5/6.2 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan 160 mg (37%).
In a double-blind randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to placebo (1.9/4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg) and valsartan 80 mg (8.8/8.6 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo (29%) and hydrochlorothiazide (41%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (12.4/7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6/2.1 mmHg). In addition, a significantly greater percentage of patients responded (BP <140/90 mmHg) or SBP reduction ≥20 mmHg or DBP reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/12.5 mg (50%) compared to hydrochlorothiazide 25 mg (25%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 160 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 160/25 mg (14.6/11.9 mmHg) and valsartan/hydrochlorothiazide 160/12.5 mg (12.4/10.4 mmHg) compared to valsartan 160 mg (8.7/8.8 mmHg). The difference in BP reductions between the 160/25 mg and 160/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (68%) and 160/12.5 mg (62%) compared to valsartan 160 mg (49%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 160/12.5 mg (17.8/13.5 mmHg) and 160/25 mg (22.5/15.3 mmHg) compared to placebo (1.9/4.1 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (7.3/7.2 mmHg), hydrochlorothiazide 25 mg (12.7/9.3 mmHg) and valsartan 160 mg (12.1/9.4 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 160/25 mg (81%) and valsartan/hydrochlorothiazide 160/12.5 mg (76%) compared to placebo (29%) and the respective monotherapies, i.e, hydrochlorothiazide 12.5 mg (41%), hydrochlorothiazide 25 mg (54%), and valsartan 160 mg (59%).
In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 320 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 320/25 mg (15.4/10.4 mmHg) and valsartan/hydrochlorothiazide 320/12.5 mg (13.6/9.7 mmHg) compared to valsartan 320 mg (6.1/5.8 mmHg).
The difference in systolic BP reduction between the 320/25 mg and 320/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (75%) and 320/12.5 mg (69%) compared to valsartan 320 mg (53%).
In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 320/12.5 mg (21.7/15.0 mmHg) and 320/25 mg (24.7/16.6 mmHg) compared to placebo (7.0/5.9 mmHg) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (11.1/9.0 mmHg), hydrochlorothiazide 25 mg (14.5/10.8 mmHg) and valsartan 320 mg (13.7/11.3 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (85%) and 320/12.5 mg (83%) compared to placebo (45%) and the respective monotherapies, i.e., hydrochlorothiazide 12.5 mg (60%), hydrochlorothiazide 25 mg (66%), and valsartan 320 mg (69%).
Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan.
Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Valsartan: Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the ATII receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following ATII receptor blockade with valsartan may stimulate the unblocked ATII receptor, which appears to counterbalance the effect of the ATII receptor. Valsartan does not exhibit any partial agonist activity at the ATII receptor and has much (about 20,000-fold) greater affinity for the ATII receptor than for the ATII receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In an experienced cough compared to 68.5% of those treated with an ACE inhibitor (P<0.05).
Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction on blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80 160 mg/od) versus amlodipine (5 10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 μmol/L). At 24 weeks, UAE was reduced (p<0.001) by 42% (-24.2 μg/min; 95% CI: -40.4 to -19.1) with valsartan and approximately 3% (-1.7 μg/min; 95% CI: -5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 μg/min; 20 700 μg/min) and preserved renal function (mean serum creatinine=80 μmol/L). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), and by 44% with valsartan 320 mg (95% CI: 31 to 54%). It was concluded that 160 320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.
Hydrochlorothiazide: The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: Directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide.
Pharmacokinetics: 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 use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear anti-hypertensive effect, greater than that obtained with either active substance given alone, or placebo.
Valsartan: Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t½ <1 h and t½ about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Hydrochlorothiazide: Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (t½ about 2 h), with similar absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-80% after oral administration.
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 minimal clinical importance. The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.
Distribution: The distribution and elimination kinetics have generally been described by 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 1.8 times the level in plasma.
Elimination: For hydrochlorothiazide, >95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule. The terminal half-life is 6-15 h.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Renal Impairment: At the recommended dose of Valsartan Hydrochlorothiazide Sandoz no dose adjustment is required for patients with a creatinine clearance of 30-70 mL/min.
In patients with severe renal impairment (creatinine clearance <30 mL/min) and patients undergoing dialysis no data are available for Valsartan Hydrochlorothiazide Sandoz. Valsartan is highly bound to plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see Contraindications).
Hepatic Impairment: In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction, exposure to valsartan was increased approximately 2-fold compared with healthy volunteers.
There is no data available on the use of valsartan in patients with severe hepatic dysfunction (see Contraindications). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
Toxicology: Preclinical Safety Data: The potential toxicity of the valsartan-hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man.
The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in marmoset, respectively, represent 0.3 and 1.2 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume on oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
High doses of the valsartan-hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, hemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent arterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m basis (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.
The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans.
The valsartan-hydrochlorothiazide combination was not tested for mutagenicity, chromosomal breakage or carcinogenicity, since there is no evidence of interaction between the two substances. However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced no evidence of mutagenicity, chromosomal breakage or carcinogenicity.
In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see Use in Pregnancy & Lactation). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbits. In embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed.
MedsGo Class
Angiotensin II Antagonists / Diuretics
Features
Brand
Co-Tareg
Full Details
Dosage Strength
80mg / 12.5mg
Drug Ingredients
- Hydrochlorothiazide
- Valsartan
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Valsartan / Hydrochlorothiazide
Dosage Form
Film-Coated Tablet
Registration Number
DRP-6644
Drug Classification
Prescription Drug (RX)
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