Tensitev 40/5; 40/10; 80/5; 80/10mg 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: TENSITEV is indicated in patients whose blood pressure is not adequately controlled on amlodipine monotherapy.

TENSITEV should be taken once daily.

Replacement Therapy: Patients taking telmisartan and amlodipine as separate tablets can instead take TENSITEV containing the same component doses in one tablet once daily.

Add on therapy: TENSITEV may be administered in patients whose blood pressure is not adequately controlled with amlodipine alone. The usual starting dose of TENSITEV 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 TENSITEV should be administered with caution. For telmisartan the dose should not exceed 40 mg once daily (i.e. TENSITEV 40/5 mg or 40/10 mg). Elderly: No dose adjustment is necessary for elderly patients. Normal amlodipine dosage regimens are recommended in the elderly but increase of dosage should take place with care (see sections 4.4 and 5.2). Paediatric population: Children and adolescents: TENSITEV is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Method of administration: Tablet for oral administration. TENSITEV may be taken with or without food.

• Hypersensitivity to telmisartan, amlodipine, dihydropyridine derivatives, or to any of the ingredients of TENSITEV listed in section 6.1
• 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
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5)
• Porphyria
• Lithium therapy: Concomitant administration with TENSITEV may lead to toxic blood concentrations of lithium (see section 4.5)
• Pregnancy and lactation (see section 4.6)
• The concomitant use of TENSITEV with aliskiren-containing products is contraindicated (see sections 4.4 and 4.5)
• Biliary obstructive disorders
• Severe hepatic impairment
• Severe hypotension
• Shock (including cardiogenic shock)
• Haemodynamically unstable heart failure after acute myocardial infarction
• Concomitant use of fluoroquinolones with ACE inhibitors/renin-angiotensin blockers such as TENSITEV is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30 mL/min) and in elderly patients.
• Obstruction of the outflow tract of the left ventricle (e.g high grade aortic stenosis).

Should a woman become pregnant while receiving TENSITEV, 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 ACE-inhibitors, angiotensin II receptor blockers (ARBs) 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 TENSITEV and aliskiren is therefore contraindicated (see section 4.3).

TENSITEV should not be used concomitantly with aliskiren (see section 4.3).

Pregnancy: TENSITEV should not be initiated during pregnancy (see section 4.3). 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 TENSITEV should be stopped immediately, and if appropriate, alternative therapy should be started (see section 4.6).

Hepatic impairment: Telmisartan as contained in TENSITEV is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. The half-life of amlodipine as contained in TENSITEV is prolonged in patients with impaired liver function and dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range (i.e. TENSITEV 40/5 or 80/5) and caution should be used, both on initial treatment and when increasing the dose.

TENSITEV 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 TENSITEV 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 TENSITEV 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 TENSITEV.

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 TENSITEV, 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 ACE inhibitors/angiotensin receptor blockers such as TENSITEV 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 ACE inhibitors/angiotensin receptor blockers (i.e., TENSITEV) 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 TENSITEV is not recommended.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy: TENSITEV 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 TENSITEV in unstable angina pectoris and during or within one month of a myocardial infarction.

Patients with cardiac failure: In a long-term placebo-controlled study of amlodipine in patients with New York Heart Association (NYHA) class III and IV heart failure of non-ischaemic aetiology; amlodipine as contained in TENSITEV, was associated with increased reports of pulmonary oedema. Therefore, patients with heart failure should be treated with caution.

Calcium channel blockers, including amlodipine as contained in TENSITEV, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Hyperkalaemia: During treatment with TENSITEV 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 TENSITEV.

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 medicines such as ARBs or ACE-inhibitors such as TENSITEV. 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 TENSITEV.

Elderly patients: The increase of the amlodipine dose as contained in TENSITEV should take place with care in the elderly patients (see sections 4.2 and 5.2).

Other: Excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease may result in a myocardial infarction or stroke.

Sodium: Each tablet contains less than 1 mmol sodium (23 mg) per tablet, essentially u2018sodium - freeu2019.

No interactions between the two components of the fixed dose combinations have been observed in clinical studies.

Interactions linked to the combination: No interaction studies have been performed with TENSITEV and other medicines.

Other antihypertensive medicines: The blood pressure lowering effect of TENSITEV 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 TENSITEV: 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 TENSITEV: Concomitant use not recommended: Potassium sparing diuretics or potassium supplements: Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Dual blockage 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 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).

Concomitant use requiring caution: Non-steroidal anti-inflammatory medicinal products: 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. Medicines acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and telmisartan should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.

Ramipril: 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.

Fluoroquinolones: Concomitant use of fluoroquinolones and ACE inhibitors/angiotensin receptor blockers such as TENSITEV, may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Concomitant use to be taken into account: Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49 %) and in trough concentration (20 %) were observed. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

Interactions linked to the amlodipine component of TENSITEV: Concomitant use not recommended: Grapefruit and grapefruit juice: Administration of TENSITEV with grapefruit or grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.

Concomitant use requiring caution: CYP3A4 inhibitors: 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 resulting in an increased risk of hypotension. 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: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine contained in TENSITEV be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Concomitant use to be taken into account: Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of TENSITEV in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Ciclosporin: No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0 % - 40 %) of ciclosporin were observed. Consideration should be given for monitoring ciclosporin levels in renal transplant patients on TENSITEV, and ciclosporin dose reductions should be made as necessary.

Mechanistic target of rapamycin (mTOR) inhibitors: mTOR inhibitors such as sirolimus, temsirolimus and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, TENSITEV may increase exposure of mTOR inhibitors.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with simvastatin 80 mg resulted in an increase in exposure to simvastatin up to 77 % compared to simvastatin alone. Therefore, limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

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

TENSITEV should not be used during pregnancy and lactation (see section 4.3). Effects related to the mono components are described below.

Women of Childbearing Potential: Women of childbearing age should ensure effective contraception.

Pregnancy: Telmisartan: Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed TENSITEV should be discontinued. Medicines affecting the renin-angiotensin system, such as TENSITEV, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. Should exposure to TENSITEV have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken TENSITEV 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.

Breastfeeding: TENSITEV is contraindicated during lactation since it is not known whether telmisartan is excreted in human milk. Animal studies have shown excretion of telmisartan in breastmilk. Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 to 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in breastfed infants, TENSITEV 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.

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 (see section 4.8). 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.

Summary of the safety profile: The most frequent adverse reactions include dizziness and peripheral oedema. Serious syncope may occur less frequently.

Tabulated summary of adverse reactions: The following side effects derived from the use of the TENSITEV (telmisartan and amlodipine combination) or the use of the monocomponents (telmisartan or amlodipine) in clinical trials or from post-marketing experience are shown in the table below classified by MedDRA System organ class and MedDRA Preferred terms.

Symptoms: There is no experience of overdose with TENSITEV. Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdosage were hypotension, tachycardia; bradycardia might also occur. 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 may occur.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 to 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Therapy: Supportive treatment should be instituted. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine are not removed by haemodialysis.