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Patients with sodium- and/or volume depletion: Excessive hypotension, including orthostatic hypotension was seen in 1.7% of patients treated with the maximum dose (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.
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. Use only after correction of any pre-existing sodium and/or volume depletion otherwise the treatment should start under close medical supervision.
If excessive hypotension, 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 blood pressure has been stabilized.
Patients with renal impairment: Due to the hydrochlorothiazide component, use with caution in patients with severe renal impairment (GFR < 30 mL/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease. Thiazides diuretics 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 PRECAUTIONS and also PHARMACOLOGY under ACTIONS). No dosage adjustment is required for patients with mild to moderate renal impairment.
The use of ARBs - including valsartan- or of ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR < 30 mL/min) (see Dual blockade of the RAS under INTERACTIONS).
Patients with renal artery stenosis: Use with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis, stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.
Patients with kidney transplantation: There is no experience with the use in patients with recent kidney transplantation.
Patients with hepatic impairment: Valsartan is mostly eliminated unchanged via the bile whereas amlodipine is extensively metabolized by the liver. Due to the valsartan, hydrochlorothiazide and amlodipine components, particular caution should be exercised when administering to patients with hepatic impairment or biliary obstructive disorders. (See DOSAGE & ADMINISTRATION and also PHARMACOLOGY under ACTIONS.)
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. Use should be immediately discontinued in patients who develop angioedema, and it should not be re-administered.
Patients with heart failure/post-myocardial Infarction: In general, calcium channel blockers including amlodipine should be used with caution in patients with serious congestive heart failure (New York Heart Association (NYHA) functional class III-IV).
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.
Patients with acute myocardial infarction: Worsening angina pectoris and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.
Patients with aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with all other vasodilators, special caution is required when using amlodipine in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
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.) could lead to hyperkalaemia and 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 prerenal (cardiogenic) impairment of kidney function. If hypokalemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), treatment 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.
Amlodipine-Valsartan-Hydrochlorothiazide: In the controlled trial of Amlodipine/Valsartan/HCTZ (Exforge HCT) in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose (10/320/25 mg) was 9.9% compared to 24.5% with HCTZ/amlodipine (25/10 mg), 6.6% with valsartan/HCTZ (320/25 mg), and 2.7% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the Amlodipine/Valsartan/HCTZ and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% compared to 0.2-0.7% with the dual therapies.
In the controlled trial of Amlodipine/Valsartan/HCTZ (Exforge HCT), the opposite effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
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 as well as 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 weeks 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.
Dual Blockade of the Renin-Angiotensin System (RAS): Caution is required while co-administering ARBs, including valsartan, with other agents blocking the RAS such as ACEIs or aliskiren (see Dual blockade of the RAS under INTERACTIONS).
Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on Danish National cancer registry. The risk for NMSC appears to increase with long-term use (see PHARMACOLOGY under ACTIONS). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and adequate protection when exposed to sunlight should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined, potentially including histological examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have previously experienced NMSC (see ADVERSE REACTIONS).
