The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Sodium- and/or volume-depleted patients: Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of Exforge HCT (10 mg/320 mg/25 mg) compared to 1.8% of valsartan/hydrochlorothiazide (320 mg/25 mg) patients, 0.4% of amlodipine/valsartan (10 mg/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.
In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment with Exforge HCT. Exforge HCT should be used only after correction of any pre-existing sodium and/or volume depletion.
If excessive hypotension occurs with Exforge HCT, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
Serum electrolyte changes: Amlodipine/valsartan/hydrochlorothiazide: In the controlled trial of Exforge HCT, the counteracting 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.
Periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals to detect possible electrolyte imbalance, especially in patients with other risk factors such as impaired renal function, treatment with other medicinal products or history of prior electrolyte imbalances.
Valsartan: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Hydrochlorothiazide: Treatment with Exforge HCT should only start after correction of hypokalaemia and any coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. 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 hypokalaemia develops during hydrochlorothiazide therapy, Exforge HCT should be discontinued until stable correction of the potassium balance.
Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during Exforge HCT therapy, the treatment should be discontinued until normalisation of natraemia.
All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.
Renal impairment: Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Exforge HCT is used in patients with renal impairment periodic monitoring of serum electrolytes (including potassium), creatinine and uric acid serum levels is recommended. Exforge HCT is contraindicated in patients with severe renal impairment, anuria or undergoing dialysis (see Contraindications).
No dosage adjustment of Exforge HCT is required for patients with mild to moderate renal impairment (GFR ≥30 ml/min/1.73 m2).
The concomitant use of ARBs-including valsartan-or of ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR <60 ml/min/1.73 m2) (see Contraindications and Interactions).
Renal artery stenosis: Exforge HCT 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.
Kidney transplantation: To date there is no experience of the safe use of Exforge HCT in patients who have had a recent kidney transplantation.
Hepatic impairment: Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan, and therefore, Exforge HCT is not suitable in this group of patients (see Dosage & Administration, Contraindications and Pharmacology: Pharmacokinetics 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 medicinal products including ACE inhibitors. Exforge HCT should be discontinued immediately in patients who develop angioedema and should not be re-administered.
Heart failure and coronary artery disease/post-myocardial infarction: As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of Exforge HCT, 10 mg/320 mg/25 mg, since available data in these patient populations is limited.
Aortic and mitral valve stenosis: As with all other vasodilators, special caution is indicated in patients with mitral stenosis or significant aortic stenosis that is not high grade.
Primary hyperaldosteronism: Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is not activated. Therefore, Exforge HCT is not recommended in this population.
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, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Due to the hydrochlorothiazide component, Exforge HCT is contraindicated in symptomatic hyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.
Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Exforge HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Exforge HCT should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Photosensitivity: Cases of photosensitivity reactions have been reported with thiazide diuretics (see Adverse Reactions). If photosensitivity reaction occurs during treatment with Exforge HCT, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Acute angle-closure glaucoma: Hydrochlorothiazide, a sulphonamide, 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 a week of treatment 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 sulphonamide or penicillin allergy.
General: Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.
Caution is required when co-administering ARBs-including valsartan-with other agents blocking the RAAS such as ACE inhibitors or aliskiren (see Interactions).
The concomitant use of ARBs-including valsartan-or of ACE inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) is contraindicated (see Contraindications and Interactions).
Elderly (age 65 years or over): Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of Exforge HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited.
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see Contraindications and Use in Pregnancy & Lactation).
Effects on ability to drive and use machines: Patients taking Exforge HCT and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.
Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.