We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we'll assume that you are happy to receive all cookies on the medicines.ie website. Find out more

Novartis Ireland Limited

Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4,
Telephone: +353 1 2601255
Fax: +353 1 2601263
Medical Information e-mail: medinfo.dublin@novartis.com


Summary of Product Characteristics last updated on medicines.ie: 20/05/2014
SPC Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets



Go to top of the page
1. NAME OF THE MEDICINAL PRODUCT

Exforge HCT 5 mg/160 mg/12.5 mg film-coated tablets


Go to top of the page
2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan, and 12.5 mg of hydrochlorothiazide.

For a full list of excipients, see section 6.1.


Go to top of the page
3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

White, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VCL” on the other side.


Go to top of the page
4. CLINICAL PARTICULARS

Go to top of the page
4.1 Therapeutic indications

Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of amlodipine, valsartan and hydrochlorothiazide (HCT), taken either as three single-component formulations or as a dual-component and a single-component formulation.


Go to top of the page
4.2 Posology and method of administration

Posology

The recommended dose of Exforge HCT is one tablet per day, to be taken preferably in the morning.

Before switching to Exforge HCT patients should be controlled on stable doses of the monocomponents taken at the same time. The dose of Exforge HCT should be based on the doses of the individual components of the combination at the time of switching.

The maximum recommended dose of Exforge HCT is 10 mg/320 mg/25 mg.

Special populations

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Exforge HCT is contraindicated for use in patients with anuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).

The concomitant use of Exforge HCT with aliskiren is contraindicated in patients with renal impairment (GFR <60 ml/min/1.73 m2) (see section 4.3).

Diabetes mellitus

The concomitant use of Exforge HCT with aliskiren is contraindicated in patients with diabetes mellitus (see section 4.3).

Hepatic impairment

Due to the valsartan component, Exforge HCT is contraindicated in patients with severe hepatic impairment (see section 4.3). 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 sections 4.3, 4.4 and 5.2). Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment.

Heart failure and coronary artery disease

There is limited experience with the use of Exforge HCT, particulary at the maximum dose, in patients with heart failure and coronary artery disease. 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.

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.

Paediatric population

There is no relevant use of Exforge HCT in the paediatric population (patients below age 18 years) for the indication of essential hypertension.

Method of administration

Exforge HCT can be taken with or without food. The tablets should be swallowed whole with some water, at the same time of the day and preferably in the morning.


Go to top of the page
4.3 Contraindications

− Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the excipients.

− Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

− Hepatic impairment, biliary cirrhosis or cholestasis.

− Severe renal impairment (GFR <30 ml/min/1.73 m2), anuria and patients undergoing dialysis.

− Concomitant use of angiotensin receptor antagonists (ARB) - including valsartan - or of angiotensin converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.4 and 4.5).

− Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

− Severe hypotension.

− Shock (including cardiogenic shock).

− Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis).

− Haemodynamically unstable heart failure after acute myocardial infarction.


Go to top of the page
4.4 Special warnings and precautions for use

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 section 4.3).

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 sections 4.3 and 4.5).

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 sections 4.2, 4.3 and 5.2).

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.

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 sections 4.3 and 4.6).

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 section 4.8). 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.

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.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The concomitant use of ARBs, including valsartan, with other agents acting on the RAAS is associated with an increased incidence of hypotension, hyperkalaemia, and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Exforge HCT and other agents that affect the RAAS.

Caution is required when co-administering ARBs - including valsartan - with other agents blocking the RAAS such as ACE inhibitors or aliskiren (see section 4.5).

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 sections 4.3 and 4.5).


Go to top of the page
4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies with other medicinal products were performed with Exforge HCT. Thus, only information on interactions with other medicinal products that are known for the individual active substances is provided in this section.

However, it is important to take into account that Exforge HCT may increase the hypotensive effect of other antihypertensive agents.

Concomitant use not recommended

Exforge HCT individual component

Known interactions with the following agents

Effect of the interaction with other medicinal products

Valsartan and HCT

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists including valsartan or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Exforge HCT. Therefore careful monitoring of serum lithium concentrations is recommended during concomitant use.

Valsartan

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels

If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, frequent monitoring of potassium plasma levels is advised.

Amlodipine

Grapefruit or grapefruit juice

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

Caution required with concomitant use

Exforge HCT individual component

Known interactions with the following agents

Effect of the interaction with other medicinal products

Amlodipine

CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir)

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum [St. John's wort])

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Simvastatin

Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Valsartan and HCT

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetylsalicylic acid (>3 g/day), and non-selective NSAIDs

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Exforge HCT and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Valsartan

Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)

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

HCT

Alcohol, barbiturates or narcotics

Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.

Anticholinergic agents and other medicinal products affecting gastric motility

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, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.

Antidiabetic agents (e.g. insulin and oral antidiabetic agents)

Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.

Metformin

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.

Ciclosporin

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Cytotoxic agents

Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.

Iodine contrasting agents

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be re-hydrated before the administration.

Ion exchange resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimise the interaction.

Medicinal products affecting serum potassium level

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives or antiarrhythmics. If these medicinal products are to be prescribed with the amlodipine /valsartan /hydrochlorothiazide combination, monitoring of potassium plasma levels is advised.

Medicinal products affecting serum sodium level

The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicinal products.

Medicinal products that could induce torsades de pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)

Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary.

Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Non-depolarising skeletal muscle relaxants (e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.

Other anti-hypertensive drugs

Thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors [DRIs]).

Pressor amines (e.g. noradrenaline, adrenaline)

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.

Vitamin D and calcium salts

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

No interaction

Exforge HCT individual component

Known interactions with the following agents

Effect of the interaction with other medicinal products

Valsartan

Others

(cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide)

In monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.

Some of these substances could interact with the hydrochlorothiazide component of Exforge HCT (see interactions related to HCT).

Amlodipine

Others

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

The concomitant use of ARBs - including valsartan - or of ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.3 and 4.4).


Go to top of the page
4.6 Pregnancy and lactation

Pregnancy

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. 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.

Exposure to AIIRAs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience on the use of Exforge HCT in pregnant women. Based on the existing data with the components, the use of Exforge HCT is not recommended during first trimester and contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Breast-feeding

No information is available regarding the use of valsartan and/or amlodipine during breast-feeding. Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production. The use of Exforge HCT during breast-feeding is not recommended. If Exforge HCT is used during breast-feeding, doses should be kept as low as possible. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

There are no clinical studies on fertility with Exforge HCT.

Valsartan

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).


Go to top of the page
4.7 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.


Go to top of the page
4.8 Undesirable effects

The safety profile of Exforge HCT presented below is based on clinical studies performed with Exforge HCT and the known safety profile of the individual components amlodipine, valsartan and hydrochlorothiazide.

Information on Exforge HCT

The safety of Exforge HCT has been evaluated at its maximum dose of 10 mg/320 mg/25 mg in one controlled short-term (8 weeks) clinical study with 2,271 patients, 582 of whom received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse reactions were generally mild and transient in nature and only infrequently required discontinuation of therapy. In this active controlled clinical trial, the most common reasons for discontinuation of therapy with Exforge HCT were dizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse reactions were observed with triple therapy treatment compared to the known effects of the monotherapy or dual therapy components.

In the 8-week controlled clinical study, changes in laboratory parameters observed with the combination of Exforge HCT were minor and consistent with the pharmacological mechanism of action of the monotherapy agents. The presence of valsartan in the triple combination attenuated the hypokalaemic effect of hydrochlorothiazide.

The following adverse reactions, listed by MedDRA System Organ Class and frequency, concern Exforge HCT (amlodipine/valsartan/HCT) and amlodipine, valsartan and HCT individually.

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).

MedDRA System Organ Class

Adverse reactions

Frequency

 

 

 

Exforge HCT

Amlodipine

Valsartan

HCT

Blood and lymphatic system disorders

Agranulocytosis, bone marrow depression

--

--

--

Very rare

Decrease in haemoglobin and in haematocrit

--

--

Not known

--

Haemolytic anaemia

--

--

--

Very rare

Leukopenia

--

Very rare

--

Very rare

Neutropenia

--

--

Not known

--

Thrombocytopenia, sometimes with purpura

--

Very rare

Not known

Rare

Aplastic anaemia

--

--

--

Not known

Immune system disorders

Hypersensitivity

--

Very rare

Not known

Very rare

Metabolism and nutrition disorders

Anorexia

Uncommon

--

--

--

Hypercalcaemia

Uncommon

--

--

Rare

Hyperglycaemia

--

Very rare

--

Rare

Hyperlipidaemia

Uncommon

--

--

--

Hyperuricaemia

Uncommon

--

--

Common

Hypochloraemic alkalosis

--

--

--

Very rare

Hypokalaemia

Common

--

--

Very common

Hypomagnesaemia

--

--

--

Common

Hyponatraemia

Uncommon

--

--

Common

Worsening of diabetic metabolic state

--

--

--

Rare

Psychiatric disorders

Depression

--

Uncommon

--

Rare

Insomnia/sleep disturbances

Uncommon

Uncommon

--

Rare

Mood swings

--

Uncommon

--

 

Confusion

--

Rare

--

--

Nervous system disorders

Coordination abnormal

Uncommon

--

--

--

Dizziness

Common

Common

--

Rare

Dizziness postural, dizziness exertional

Uncommon

--

--

--

Dysgeusia

Uncommon

Uncommon

--

--

Extrapyramidal syndrome

--

Not known

--

--

Headache

Common

Common

--

Rare

Hypertonia

--

Very rare

--

--

Lethargy

Uncommon

--

--

--

Paraesthesia

Uncommon

Uncommon

--

Rare

Peripheral neuropathy, neuropathy

Uncommon

Very rare

--

--

Somnolence

Uncommon

Common

--

--

Syncope

Uncommon

Uncommon

--

--

Tremor

--

Uncommon

--

--

Hypoesthesia

--

Uncommon

--

--

Eye disorders

Acute angle-closure glaucoma

--

--

--

Not known

Visual disturbance

--

Uncommon

--

--

Visual impairment

Uncommon

Uncommon

--

Rare

Ear and labyrinth disorders

Tinnitus

--

Uncommon

--

--

Vertigo

Uncommon

--

Uncommon

--

Cardiac disorders

Palpitations

--

Common

--

--

Tachycardia

Uncommon

--

--

--

Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)

--

Very rare

--

Rare

Myocardial infarction

--

Very rare

--

--

Vascular disorders

Flushing

--

Common

--

--

Hypotension

Common

Uncommon

--

--

Orthostatic hypotension

Uncommon

--

--

Common

Phlebitis, thrombophlebitis

Uncommon

--

--

--

Vasculitis

--

Very rare

Not known

--

Respiratory, thoracic and mediastinal disorders

Cough

Uncommon

Very rare

Uncommon

--

Dyspnoea

Uncommon

Uncommon

--

--

Respiratory distress, pulmonary oedema, pneumonitis

--

--

--

Very rare

Rhinitis

--

Uncommon

--

--

Throat irritation

Uncommon

--

--

--

Gastrointestinal disorders

Abdominal discomfort, abdominal pain upper

Uncommon

Common

Uncommon

Rare

Breath odour

Uncommon

--

--

--

Change of bowel habit

--

Uncommon

--

--

Constipation

--

--

--

Rare

Decreased appetite

--

--

--

Common

Diarrhoea

Uncommon

Uncommon

--

Rare

Dry mouth

Uncommon

Uncommon

--

--

Dyspepsia

Common

Uncommon

--

--

Gastritis

--

Very rare

--

--

Gingival hyperplasia

--

Very rare

--

--

Nausea

Uncommon

Common

--

Common

Pancreatitis

--

Very rare

--

Very rare

Vomiting

Uncommon

Uncommon

--

Common

Hepatobiliary disorders

Hepatic enzyme elevation, including increase of serum bilirubin

--

Very rare**

Not known

--

Hepatitis

--

Very rare

--

--

Intrahepatic cholestasis, jaundice

--

Very rare

--

Rare

Skin and subcutaneous tissue disorders

Alopecia

--

Uncommon

--

 

Angioedema

--

Very rare

Not known

--

Dermatitis bullous

--

--

Not known

--

Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus

--

--

--

Very rare

Erythema multiforme

--

Very rare

--

Not known

Exanthema

--

Uncommon

--

--

Hyperhidrosis

Uncommon

Uncommon

--

--

Photosensitivity reaction*

--

Very rare

--

Rare

Pruritus

Uncommon

Uncommon

Not known

--

Purpura

--

Uncommon

--

Rare

Rash

--

Uncommon

Not known

Common

Skin discoloration

--

Uncommon

--

--

Urticaria and other forms of rash

--

Very rare

--

Common

Vasculitis necrotising and toxic epidermal necrolysis

--

--

--

Very rare

Exfoliative dermatitis

--

Very rare

--

--

Stevens-Johnson syndrome

--

Very rare

--

--

Quincke oedema

--

Very rare

--

--

Musculoskeletal and connective tissue disorders

Arthralgia

--

Uncommon

--

--

Back pain

Uncommon

Uncommon

--

--

Joint swelling

Uncommon

--

--

--

Muscle spasm

Uncommon

Uncommon

--

Not known

Muscular weakness

Uncommon

--

--

--

Myalgia

Uncommon

Uncommon

Not known

--

Pain in extremity

Uncommon

--

--

--

Ankle swelling

--

Common

--

--

Renal and urinary disorders

Elevation of serum creatinine

Uncommon

--

Not known

--

Micturition disorder

 

Uncommon

 

 

Nocturia

--

Uncommon

--

--

Pollakiuria

Common

Uncommon

 

 

Renal dysfunction

--

--

--

Not known

Renal failure acute

Uncommon

--

--

Not known

Renal failure and impairment

--

--

Not known

Rare

Reproductive system and breast disorders

Impotence

Uncommon

Uncommon

--

Common

Gynaecomastia

 

Uncommon

--

--

General disorders and administration site conditions

Abasia, gait disturbance

Uncommon

--

--

--

Asthenia

Uncommon

Uncommon

--

Not known

Discomfort, malaise

Uncommon

Uncommon

--

--

Fatigue

Common

Common

Uncommon

--

Non cardiac chest pain

Uncommon

Uncommon

--

--

Oedema

Common

Common

--

--

Pain

--

Uncommon

--

--

Pyrexia

--

--

--

Not known

Investigations

Lipids increased

 

--

 

Very common

Blood urea nitrogen increased

Uncommon

--

--

--

Blood uric acid increased

Uncommon

--

--

 

Glycosuria

 

 

 

Rare

Serum potassium decreased

Uncommon

--

--

--

Serum potassium increased

--

--

Not known

--

Weight increase

Uncommon

Uncommon

--

--

Weight decrease

--

Uncommon

--

--

* See section 4.4 Photosensitivity

** Mostly consistent with cholestasis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie


Go to top of the page
4.9 Overdose

Symptoms

There is no experience of overdose with Exforge HCT. The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, have been reported with amlodipine.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically significant hypotension due to Exforge HCT overdose calls for active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Amlodipine

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.

Amlodipine is unlikely to be removed by haemodialysis.

Valsartan

Valsartan is unlikely to be removed by haemodialysis.

Hydrochlorothiazide

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

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


Go to top of the page
5. PHARMACOLOGICAL PROPERTIES

Go to top of the page
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists, plain (valsartan), combinations with dihydropyridine derivatives (amlodipine) and thiazide diuretics (hydrochlorothiazide), ATC code: C09DX01 valsartan, amlodipine and hydrochlorothiazide.

Exforge HCT combines three antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines and hydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of these substances has an additive antihypertensive effect.

Amlodipine/Valsartan/Hydrochlorothiazide

Exforge HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of 2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/hydrochlorothiazide 10 mg/320 mg/25 mg, valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, or hydrochlorothiazide/amlodipine 25 mg/10 mg. At study initiation patients were assigned lower doses of their treatment combination and were titrated to their full treatment dose by week 2.

At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg with Exforge HCT, 32.0/19.7 mmHg with valsartan/hydrochlorothiazide, 33.5/21.5 mmHg with amlodipine/valsartan, and 31.5/19.5 mmHg with amlodipine/hydrochlorothiazide. The triple combination therapy was statistically superior to each of the three dual combination treatments in reduction of diastolic and systolic blood pressures. The reductions in systolic/diastolic blood pressure with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/hydrochlorothiazide, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/hydrochlorothiazide. The full blood pressure lowering effect was achieved 2 weeks after being on their maximal dose of Exforge HCT. Statistically greater proportions of patients achieved blood pressure control (<140/90 mmHg) with Exforge HCT (71%) compared to each of the three dual combination therapies (45-54%) (p<0.0001).

In a subgroup of 283 patients focusing on ambulatory blood pressure monitoring, clinically and statistically superior reductions in 24-hour systolic and diastolic blood pressures were observed with the triple combination compared to valsartan/hydrochlorothiazide, valsartan/amlodipine, and hydrochlorothiazide/amlodipine.

Amlodipine

The amlodipine component of Exforge HCT inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and increases in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 4.9 years. The patients had at least one additional coronary heart disease risk factor, including: previous myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89-1.02] p=0.20.

Valsartan

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the receptor subtype AT1, which is responsible for the known actions of angiotensin II.

Administration of valsartan to patients with hypertension results in a drop in 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 drop in blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks.

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 European Medicines Agency has waived the obligation to submit the results of studies with Exforge HCT in all subsets of the paediatric population in essential hypertension. See section 4.2 for information on paediatric use.


Go to top of the page
5.2 Pharmacokinetic properties

Linearity

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

Following oral administration of Exforge HCT in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and hydrochlorothiazide are reached in 6-8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from Exforge HCT are the same as when administered as individual dosage forms.

Amlodipine

Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.

Distribution: Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins.

Biotransformation: Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten per cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

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 transformed 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 (t½α <1 h and t½ß 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 (Tmax about 2 hours). The increase in mean AUC is linear and dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution: The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

Biotransformation: Hydrochlorothiazide is eliminated predominantly as unchanged compound.

Elimination: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. More than 95% of the absorbed dose is being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.

Special populations

Paediatric patients (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.

Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but 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.

Since the three components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see section 4.2).

Renal impairment

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan.

Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see sections 4.2 and 4.4).

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed. Exforge HCT is contraindicated in patients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Due to the valsartan component, Exforge HCT is contraindicated in patients with hepatic impairment (see sections 4.2 and 4.3).


Go to top of the page
5.3 Preclinical safety data

Amlodipine/Valsartan/Hydrochlorothiazide

In a variety of preclinical safety studies conducted in several animal species with amlodipine, valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide (Exforge HCT), there was no evidence of systemic or target organ toxicity that would adversely affect the development of Exforge HCT for clinical use in humans.

Preclinical safety studies of up to 13 weeks in duration were conducted with amlodipine/valsartan/hydrochlorothiazide in rats. The combination resulted in expected reduction of red blood cell mass (erythrocytes, haemoglobin, haematocrit, and reticulocytes), increase in serum urea, increase in serum creatinine, increase in serum potassium, juxtaglomerular (JG) hyperplasia in the kidney and focal erosions in the glandular stomach in rats. All these changes were reversible after a 4-week recovery period and were considered to be exaggerated pharmacological effects.

The amlodipine/valsartan/hydrochlorothiazide combination was not tested for genotoxicity or carcinogenicity as there was no evidence of any interaction between these substances, which have been on the market for a long time. However, amlodipine, valsartan and hydrochlorothiazide have been tested individually for genotoxicity and carcinogenicity with negative results.

Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

* Based on patient weight of 50 kg

Valsartan

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In rats, maternally toxic doses (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 section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.


Go to top of the page
6. PHARMACEUTICAL PARTICULARS

Go to top of the page
6.1 List of excipient(s)

Tablet core

Cellulose microcrystalline

Crospovidone

Silica, colloidal anhydrous

Magnesium stearate

Coating

Hypromellose

Titanium dioxide (E171)

Macrogol 4000

Talc


Go to top of the page
6.2 Incompatibilities

Not applicable.


Go to top of the page
6.3 Shelf life

2 years


Go to top of the page
6.4 Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.


Go to top of the page
6.5 Nature and contents of container

PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.

Pack sizes: 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.

Multipacks of 280 tablets, comprising 20 cartons, each containing 14 tablets.

PVC/PVDC perforated unit dose blisters for hospital use:

Pack sizes: 56, 98 or 280 film-coated tablets

Multipacks of 280 tablets, comprising 4 cartons, each containing 70 tablets.

Not all pack sizes or strengths may be marketed.


Go to top of the page
6.6 Special precautions for disposal and other handling

No special requirements.


Go to top of the page
7. MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom


Go to top of the page
8. MARKETING AUTHORISATION NUMBER(S)

EU/1/09/569/001-012


Go to top of the page
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16 October 2009


Go to top of the page
10. DATE OF REVISION OF THE TEXT

20 March 2014

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu



Link to this document from your website:
http://www.medicines.ie/medicine/14621/SPC/Exforge+HCT+5+mg+160+mg+12.5+mg+film-coated+tablets/

Document Links

 
  Link to this page
  View all medicines
from this company
Print this page
View document history
Bookmark and Share

Active Ingredients

 
   Hydrochlorothiazide
   Valsartan
   Amlodipine besylate