Mizart Plus 40 mg/5 mg/80 mg/10 mg Film-Coated Tablets

Replacement therapy: Treatment of essential hypertension in patients who have been stabilised on the two- component medicines used at the same dose. Add-on therapy: MIZART PLUS is indicated in patients whose blood pressure is not adequately controlled on amlodipine monotherapy.

Posology: MIZART PLUS should be taken once daily.
Replacement therapy: Patients taking telmisartan and amlodipine as separate tablets can instead take MIZART PLUS containing the same component doses in one tablet once daily. Add on therapy: MIZART PLUS may be administered in patients whose blood pressure is not adequately controlled with amlodipine alone. The usual starting dose of MIZART PLUS is 40/5 mg once daily. If additional blood pressure lowering is needed after at least 2 weeks of therapy, the dose may be titrated up to a maximum of 80/10 mg once daily.
Special Populations
Renal impairment: No dosage adjustment is required for patients with mild to moderate renal impairment (see section 4.4). Amlodipine and telmisartan are not dialysable. Hepatic impairment: In patients with mild to moderate hepatic impairment. MIZART PLUS should be administered with caution. For telmisartan the dose should not exceed 40/5 mg or 40/10 mg once daily. Elderly: No dose adjustment is necessary for elderly patients. Children and adolescents: MIZART PLUS is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.
Method of administration
Oral use. MIZART PLUS may be taken with or without food.

• Known hypersensitivity to telmisartan, amlodipine or to any of the excipients of MIZART PLUS (see section 6.1).
• Hypersensitivity to dihydropyridine derivatives.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs) These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.4).
• Porphyria.
• Lithium therapy: Concomitant administration with MIZART PLUS may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of MIZART PLUS with aliskiren-containing medicines is contraindicated (see section 4.4).
• Biliary obstructive disorders.
• Severe hepatic impairment.
• Cardiogenic shock.
• Concomitant use of fluoroquinolones with Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor blockers (ARBs) is contraindicated in patients with moderate to severe renal impairment (creatinine clearance u2264 30 ml/min) and in elderly patients.

Pregnancy
Should a woman become pregnant while receiving MIZART PLUS, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure). Dual blockade of RAAS through the combined use of MIZART PLUS and aliskiren is therefore contraindicated (see section 4.3). MIZART PLUS should not be used concomitantly with aliskiren (see section 4.3).
Hepatic impairment: Telmisartan (ingredient of MIZART PLUS) is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Amlodipineu2019s half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. MIZART PLUS should therefore be used with caution in patients with mild to moderate impairment of liver function and should not be used in patients with severe liver impairment (see section 4.3).
Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicines that affect the renin- angiotensin-aldosterone system (see section 4.3).
Renal impairment and kidney transplant: When MIZART PLUS is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of MIZART PLUS in patients with a recent kidney transplant. Telmisartan and amlodipine are not dialysable.
Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of MIZART PLUS.
Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with MIZART PLUS, that affects this system, has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.
Concomitant use of fluoroquinolones: Concomitant use of fluoroquinolones and Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor blockers (ARBs) may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or Angiotensin-converting enzymes (ACE) inhibitors/Angiotensin receptor blockers (ARBs) whether used separately and/or concomitantly.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through inhibition of the renin-angiotensin-system. Therefore, the use of MIZART PLUS is not recommended.
Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy: MIZART PLUS is contraindicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy.
Unstable angina pectoris, acute myocardial infarction: There are no data to support the use of MIZART PLUS in unstable angina pectoris and during or within one month of a myocardial infarction.
Heart failure: In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema.
Hyperkalaemia: During treatment with MIZART PLUS hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended. Based on experience with the use of medicines that affect the renin-angiotensin- system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicines that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co- administered cautiously with MIZART PLUS.
Diabetes mellitus: In diabetic patients with an additional cardiovascular risk, i.e. patients with diabetes mellitus and coexistent coronary artery disease (CAD), the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treated with blood pressure lowering agents such as ARBs or ACE-inhibitors. In patients with diabetes mellitus CAD may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should undergo appropriate diagnostic evaluation, e.g. exercise stress testing, to detect and to treat CAD accordingly before initiating treatment with MIZART PLUS.
Other: Excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease may result in a myocardial infarction or stroke.
Excipient: MIZART PLUS contains mannitol and may have a laxative effect.

No interactions between the two components of the fixed dose combinations have been observed in clinical studies.
Interactions common to the combination: No interaction studies have been performed with MIZART PLUS and other medicines.
Concomitant use to be taken into account: Other antihypertensive medicines: The blood pressure lowering effect of MIZART PLUS can be increased by concomitant use of other antihypertensive medicines.
Medicines with blood pressure lowering potential: Based on their pharmacological properties it can be expected that the following medicines may potentiate the hypotensive effects of MIZART PLUS: e.g. baclofen, amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics, or antidepressants.
Corticosteroids (systemic route): Reduction of the antihypertensive effect.
Interactions linked to the telmisartan component of MIZART PLUS: Telmisartan may increase the hypotensive effect of other antihypertensive medicines. Other interactions of clinical significance have not been identified. Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin, and amlodipine. For digoxin a 20 % increase in median plasma digoxin trough concentration has been observed (39 % in a single case); monitoring of plasma digoxin levels should be considered. In one study the co-administration of telmisartan and ramipril led to an increase of up to 2,5- fold in the AUC 0-24 and C max of ramipril and ramiprilat. The clinical relevance of this observation is not known. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin-converting enzyme (ACE) inhibitors. Increased serum levels have also been reported with telmisartan. Treatment with NSAIDs (i.e. aspirin at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and MIZART PLUS should be adequately hydrated and be monitored for renal function at the beginning of combined treatment. A reduced effect of antihypertensive medicines like MIZART PLUS by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.
Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (see sections 4.3 and 4.4).

MIZART PLUS should not be used during pregnancy and lactation. Effects related to the mono components are described below.
Pregnancy: Telmisartan: Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed, MIZART PLUS should be discontinued. Refer to sections 4.3 and 4.4. Medicines affecting the renin-angiotensin system, such as MIZART PLUS, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Women of childbearing age should ensure effective contraception. 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 MIZART PLUS should be stopped immediately, and, if appropriate, alternative therapy should be started. Should exposure to MIZART PLUS have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended. Infants whose mothers have taken MIZART PLUS should be closely observed for hypotension.
Amlodipine: The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses.
Lactation: It is not known whether telmisartan (as in MIZART PLUS) is excreted in human milk. Animal studies have shown excretion of telmisartan in breastmilk. Amlodipine has been identified in breastfed infants of treated women. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in breastfed infants, MIZART PLUS should not be used by breastfeeding mothers (see section 4.3).
Fertility: No data from controlled clinical studies with the fixed dose combination or with the individual components are available. Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted. In preclinical studies, no effects of telmisartan on male and female fertility were observed. In some patients treated by calcium channel blockers, reversible biochemical changes in the head of spermatozoa have been reported. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as syncope (fainting), somnolence, dizziness, or vertigo during treatment. Therefore, caution should be recommended when driving a vehicle or operating machinery. If patients experience these adverse effects, they should avoid potentially hazardous tasks such as driving or operating machinery.

a) Summary of adverse effects
The most frequent adverse reactions include dizziness and peripheral oedema. Serious syncope may occur less frequently.
Adverse reactions previously reported with one of the individual components (telmisartan or amlodipine) may be potential adverse reactions with MIZART PLUS as well, even if not observed in clinical trials or during the post-marketing period.
b) Tabulated summary of adverse reactions
The safety and tolerability have been evaluated in five controlled clinical studies with over 3,500 patients, over 2,500 of whom received telmisartan in combination with amlodipine. Adverse reactions have been ranked under headings of frequency using the following convention: frequent; less frequent and not known (cannot be estimated from the available data).

Symptoms
Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdose are expected to be hypotension and tachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.
Treatment
The patient should be closely monitored, and the treatment should be symptomatic and supportive. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine are not removed by haemodialysis.