Exforge HCT · 4.1 Therapeutic indications · 1

HOS-095412 · has-adverse-reaction-information · PDF-Seite 13

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. 13  Summary of the safety profile 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. Tabulated list of adverse reactions 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 Adverse reactions Frequency System Organ Exforge Amlodipine Valsartan HCT Class HCT Neoplasms Non-melanoma skin cancer -- -- -- Not benign, (Basal cell carcinoma and known malignant and Squamous cell carcinoma) unspecified (incl cysts and polyps) Blood and Agranulocytosis, bone -- -- -- Very rare lymphatic system marrow failure disorders Haemoglobin and

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HOS-095408 · has-contraindication-information · PDF-Seite 4

− Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the excipients listed in section 6.1. − 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 Exforge HCT with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1). − 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.

HOS-095407 · has-indication-information · PDF-Seite 3

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.

HOS-095410 · has-interaction-information · PDF-Seite 8

No formal interaction studies with other medicinal products have been 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. 8 Concomitant use not recommended Exforge Known interactions Effect of the interaction with other medicinal products HCT with the following individual agents component Valsartan Lithium Reversible increases in serum lithium concentrations and and toxicity have been reported during concomitant HCT 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 If a medicinal product that affects potassium levels is diuretics, potassium considered necessary in combination with valsartan, supplements, salt frequent monitoring of potassium plasma levels is advised. substitutes containing potassium and other substances that may increase potassium levels Amlodipine Grapefruit or grapefruit Administration of amlodipine with grapefruit or grapefruit juice 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 Known interactions Effect of the interaction with other medicinal products HCT with the following individual agents component

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HOS-095411 · has-pregnancy-information · PDF-Seite 12

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). 12 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

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HOS-095409 · has-warning-information · PDF-Seite 4

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. 4 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 patien

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