TWYNSTA 80mg / 5mg tablets medication leaflet

Twynsta 80 mg/5 mg tablets

Each tablet contains 80 mg telmisartan and 5 mg amlodipine (as amlodipine besilate).

Each tablet contains 337.28 mg sorbitol (E420).

For the full list of excipients, see section 6.1.

Tablet

Blue and white oval shaped two layer tablets of approximately 16 mm length engraved with the productcode A3 and the company logo on the white layer.

Treatment of essential hypertension in adults:

Add on therapy

Twynsta 80 mg/5 mg is indicated in adults whose blood pressure is not adequately controlled on

Twynsta 40 mg/5 mg.

Replacement therapy

Adult patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of

Twynsta containing the same component doses.

The recommended dose of this medicinal product is one tablet per day.

The maximum recommended dose is one tablet 80 mg telmisartan/10 mg amlodipine per day. Thismedicinal product is indicated for long term treatment.

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailabilitymay be increased in some patients resulting in increased blood pressure lowering effects (see section 4.5).

Add on therapy

Twynsta 80 mg/5 mg may be administered in patients whose blood pressure is not adequately controlledon Twynsta 40 mg/5 mg.

Individual dose titration with the components (i.e. amlodipine and telmisartan) is recommended beforechanging to the fixed dose combination. When clinically appropriate, direct change from monotherapy tothe fixed combination may be considered.

Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such asoedema, may be switched to Twynsta 40 mg/5 mg once daily, reducing the dose of amlodipine withoutreducing the overall expected antihypertensive response.

Replacement therapy

Patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of Twynstacontaining the same component doses in one tablet once daily.

Elderly (> 65 years)

No dose adjustment is necessary for elderly patients. Little information is available in the very elderlypatients.

Normal amlodipine dose regimens are recommended in the elderly, but increase of dose should take placewith care (see section 4.4).

Limited experience is available in patients with severe renal impairment or haemodialysis. Caution isadvised when using telmisartan/amlodipine in such patients as amlodipine is not dialysable andtelmisartan is not removed from blood by haemofiltration and not dialysable (see also section 4.4).

No posology adjustment is required for patients with mild to moderate renal impairment.

Twynsta is contraindicated in patients with severe hepatic impairment (see section 4.3).

In patients with mild to moderate hepatic impairment telmisartan/amlodipine should be administered withcaution. For telmisartan the posology should not exceed 40 mg once daily (see section 4.4).

The safety and efficacy of telmisartan/amlodipine in children aged below 18 years have not beenestablished. No data are available.

Oral use.

Twynsta can be taken with or without food. It is recommended to take Twynsta with some liquid.

Twynsta should be kept in the sealed blister due to the hygroscopic property of the tablets. Tabletsshould be taken out of the blister shortly before administration (see section 6.6).

* Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipientslisted in section 6.1

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

* Biliary obstructive disorders and severe hepatic impairment

* Shock (including cardiogenic shock)

* Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)

* Haemodynamically unstable heart failure after acute myocardial infarction

The concomitant use of telmisartan/amlodipine with aliskiren-containing medicinal products iscontraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (seesections 4.5 and 5.1).

Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin

II receptor blocker therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stoppedimmediately, and, if appropriate, alternative therapy should be started (see section 4.3 and 4.6).

Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepaticinsufficiency can be expected to have reduced clearance.

The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liverfunction; dose recommendations have not been established. Amlodipine should therefore be initiated atthe lower end of the dosing range and caution should be used, both on initial treatment and whenincreasing the dose.

Telmisartan/amlodipine should therefore be used with caution in these patients.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renalartery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal productsthat affect the renin-angiotensin-aldosterone system (RAAS).

When telmisartan/amlodipine is used in patients with impaired renal function, a periodic monitoring ofpotassium and creatinine serum levels is recommended. There is no experience regarding theadministration of telmisartan/amlodipine in patients with a recent kidney transplant. Amlodipine is notdialysable and telmisartan is not removed from blood by haemofiltration and not dialysable.

Volume and/or sodium depleted patients

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/orsodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Suchconditions should be corrected before the administration of telmisartan. If hypotension occurs withtelmisartan/amlodipine, the patient should be placed in the supine position and, if necessary, given anintravenous infusion of normal saline. Treatment can be continued once blood pressure has beenstabilised.

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskirenincreases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renalfailure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptorblockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialistsupervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients withdiabetic nephropathy.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of therenin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlyingrenal disease, including renal artery stenosis), treatment with medicinal products that affect this systemhas been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (seesection 4.8).

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal productsacting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is notrecommended.

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis,or obstructive hypertrophic cardiomyopathy.

Unstable angina pectoris, acute myocardial infarction

There are no data to support the use of telmisartan/amlodipine in unstable angina pectoris and during orwithin one month of a myocardial infarction.

Patients with cardiac failure

In an amlodipine long-term, placebo controlled study in patients with severe heart failure (NYHA class

III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group thanin the placebo group (see section 5.1). Therefore, patients with heart failure should be treated withcaution.

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

Diabetic patients treated with insulin or antidiabetics

In these patients hypoglycaemia may occur under telmisartan treatment. Therefore, in these patients anappropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabeticsmay be required when indicated.

The use of medicinal products that affect the renin-angiotensin-aldosterone system may causehyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in diabeticpatients, in patients concomitantly treated with other medicinal products that may increase potassiumlevels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect therenin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated.

The main risk factors for hyperkalaemia to be considered are:

- Diabetes mellitus, renal impairment, age (>70 years)

- Combination with one or more other medicinal products that affect therenin-angiotensin-aldosterone system and/or potassium supplements. Medicinal products ortherapeutic classes of medicinal products that may provoke hyperkalaemia are salt substitutescontaining potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptorblockers, non steroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.

- Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis,worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases),cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extensive trauma).

Serum potassium should be monitored closely in these patients (see section 4.5).

The increase of the amlodipine dose should take place with care in the elderly patients (see section 4.2and 5.2).

Sorbitol

This medicinal product contains 337.28 mg sorbitol in each tablet.

Sorbitol is a source of fructose. Twynsta is not recommended for use in patients with hereditary fructoseintolerance (HFI).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Ischaemic heart disease

As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients withischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction orstroke.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor blockers (seesection 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptomsresolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed,telmisartan should be discontinued and appropriate monitoring should be initiated until completeresolution of symptoms has occurred.

No interactions between the two components of this fixed dose combinations have been observed inclinical studies.

Interactions linked to the combination

No drug interaction studies have been performed.

To be taken into account with concomitant use

The blood pressure lowering effect of telmisartan/amlodipine can be increased by concomitant use ofother antihypertensive medicinal products.

Medicinal products with blood pressure lowering potential

Based on their pharmacological properties it can be expected that the following medicinal products maypotentiate the hypotensive effects of all antihypertensives including this medicinal product, e.g. baclofen,amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated byalcohol.

Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

Interactions linked to telmisartan

Potassium sparing diuretics or potassium supplements

Angiotensin II receptor blockers such as telmisartan, attenuate diuretic induced potassium loss. Potassiumsparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium supplements, orpotassium-containing salt substitutes may lead to a significant increase in serum potassium. Ifconcomitant use is indicated because of documented hypokalaemia, they should be used with caution andwith frequent monitoring of serum potassium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitantadministration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin II receptorblockers, including telmisartan. If use of the combination proves necessary, careful monitoring of serumlithium levels is recommended.

Other antihypertensive agents acting on the renin-angiotensin-aldosterone system (RAAS)

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 associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections4.3, pct. 4.4 and 5.1).

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dose regimens, COX-2 inhibitors and non-selective

NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor blockers.

In some patients with compromised renal function (e.g. dehydrated patients or elderly patients withcompromised renal function), the co-administration of angiotensin II receptor blockers and medicinalproducts that inhibit cyclo-oxygenase may result in further deterioration of renal function, includingpossible acute renal failure, which is usually reversible. Therefore, the combination should beadministered with caution, especially in the elderly. Patients should be adequately hydrated andconsideration should be given to monitoring of renal function after initiation of concomitant therapy andperiodically thereafter.

Ramipril

In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the

AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Concomitant use to be taken into account

When telmisartan was co-administered with digoxin, median increases in digoxin peak plasmaconcentration (49 %) and in trough concentration (20 %) were observed. When initiating, adjusting, anddiscontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.

Interactions linked to amlodipine

Concomitant use requiring caution

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azoleantifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise tosignificant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinicaltranslation of these PK variations may be more pronounced in the elderly. Clinical monitoring and doseadjustment may thus be required.

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipinemay vary. Therefore, blood pressure should be monitored and dose regulation considered bothduring 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 withhyperkalemia 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 be avoidedin patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Grapefruit and grapefruit juice

Administration of amlodipine with grapefruit or grapefruit juice is not recommended since bioavailabilitymay be increased in certain patients resulting in increased blood pressure lowering effects.

Concomitant use to be taken into account

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but thepharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity oftacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring oftacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Cyclosporine

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteersor other populations with the exception of renal transplant patients, where variable trough concentrationincreases (average 0% - 40%) of cyclosporine were observed. Consideration should be given formonitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dosereductions should be made as necessary.

Mechanistic Target of Rapamycin (mTOR) InhibitorsmTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is aweak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure ofmTOR inhibitors.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with simvastatin 80 mg resulted in anincrease in exposure to simvastatin up to 77 % compared to simvastatin alone. Therefore, the dose ofsimvastatin in patients on amlodipine should be limited to 20 mg daily.

There are limited data from the use of telmisartan/amlodipine in pregnant women. Animal reproductivetoxicity studies with telmisartan/amlodipine have not been performed.

The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy(see section 4.4). The use of angiotensin II receptor blockers is contraindicated during the second andthird trimesters of pregnancy (see sections 4.3 and 4.4).

Studies with telmisartan in animals have shown reproductive toxicity (see section 5.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot beexcluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptorblockers, similar risks may exist for this class of medicinal products. Unless continued angiotensin IIreceptor blocker therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stoppedimmediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor blocker therapy during the second and third trimesters is known toinduce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) andneonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to angiotensin II receptor blockers have occurred from the second trimester ofpregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor blockers should be closely observed forhypotension (see sections 4.3 and 4.4).

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).

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant hasbeen estimated with an interquartile range of 3 - 7%, with a maximum of 15%. The effect of amlodipineon infants is unknown.

Because no information is available regarding the use of telmisartan during breast-feeding,telmisartan/amlodipine is not recommended and alternative treatments with better established safetyprofiles during breast-feeding are preferable, especially while breast-feeding a newborn or preterm infant.

No data from controlled clinical studies with the fixed dose combination or with the individualcomponents are available.

Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not beenconducted.

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 ofspermatozoa have been reported. Clinical data are insufficient regarding the potential effect of amlodipineon fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Twynsta has moderate influence on the ability to drive and use machines. When driving vehicles oroperating machinery it should be taken into account that syncope, somnolence, dizziness, or vertigo mayoccasionally occur when taking antihypertensive therapy (see section 4.8). If patients experience theseadverse reactions, they should avoid potentially hazardous tasks such as driving or using machines.

The most common adverse reactions include dizziness and peripheral oedema. Serious syncope mayoccur rarely (less than 1 case per 1,000 patients).

Adverse reactions previously reported with one of the individual components (telmisartan or amlodipine)may be potential adverse reactions with Twynsta as well, even if not observed in clinical trials or duringthe post-marketing period.

The safety and tolerability of Twynsta has been evaluated in five controlled clinical studies with over3,500 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:

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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Twynsta Telmisartan Amlodipine

Class

Uncommon upper respiratory tractinfection includingpharyngitis andsinusitis, urinary tractinfection includingcystitis

Rare cystitis sepsis including fataloutcome1

Uncommon anaemia

Rare thrombocytopenia,eosinophilia

Very rare leukocytopenia,thrombocytopenia

Rare hypersensitivity,anaphylactic reaction

Very rare hypersensitivity

Uncommon hyperkalaemia

Rare hypoglycaemia (indiabetic patients),hyponatraemia

Very rare hyperglycaemia

Uncommon mood change

Rare depression, confusionanxiety,insomnia

Common dizziness

Uncommon somnolence,migraine,headache,paraesthesia

Rare syncope,peripheral neuropathy,hypoaesthesia,dysgeusia,tremor

Very rare extrapyramidalsyndrome,hypertonia

Common visual disturbance(including diplopia)

Uncommon visual impairment

Rare visual disturbance

Ear and labyrinth disorders

Uncommon vertigo tinnitus

Uncommon bradycardia,palpitations

Rare tachycardia

Very rare myocardial infarction,arrhythmia,ventricular tachycardia,atrial fibrillation

Uncommon hypotension,orthostatichypotension, flushing

Very rare vasculitis

Uncommon cough dyspnoea dyspnoea, rhinitis

Very rare interstitial lung disease3

Gastrointestinal disorder

Common altered bowel habits(including diarrhoeaand constipation)

Uncommon abdominal pain, flatulencediarrhoea,nausea

Rare vomiting, stomach discomfortgingival hypertrophy,dyspepsia,dry mouth

Very rare pancreatitis, gastritis

Hepato-biliary disorders

Rare hepatic functionabnormal, liverdisorder2

Very rare hepatitis, jaundice,hepatic enzymeelevations (mostlyconsistent withcholestasis)

Uncommon pruritus hyperhidrosis alopecia, purpura, skindiscolouration,hyperhidrosis

Rare eczema, erythema, angioedema (includingrash fatal outcome),drug eruption,toxic skin eruption,urticaria

Very rare angioedema,erythema multiforme,urticaria,exfoliative dermatitis,

Stevens-Johnsonsyndrome,photosensitivity

Not known toxic epidermalnecrolysis

Common ankle swelling

Uncommon arthralgia,muscle spasms(cramps in legs),myalgia

Rare back pain, tendon pain (tendinitispain in extremity (leg like symptoms)pain)

Uncommon renal impairment micturition disorder,including acute renal pollakiuriafailure

Rare nocturia

Uncommon erectile dysfunction gynaecomastia

General disorders and administration site condition

Common peripheral oedema

Uncommon asthenia, painchest pain, fatigue,oedema

Rare malaise influenza-like illness

Uncommon hepatic enzymes blood creatinine weight increased,increased increased weight decreased

Rare blood uric acid blood creatineincreased phosphokinaseincreased, haemoglobindecreased1: the event may be a chance finding or related to a mechanism currently not known2: most cases of hepatic function abnormal/liver disorder from post-marketing experience withtelmisartan occurred in Japanese patients. Japanese patients are more likely to experience these adversereactions.3: cases of interstitial lung disease (predominantly interstitial pneumonia and eosinophilic pneumonia)have been reported from post-marketing experience with telmisartan

Intestinal angioedema

Cases of intestinal angioedema have been reported after the use of angiotensin II receptor blockers (seesection 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. Themost 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 reflextachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fataloutcome have been reported.

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

The patient should be closely monitored, and the treatment should be symptomatic and supportive.

Management depends on the time since ingestion and the severity of the symptoms. Suggested measuresinclude induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment ofoverdose of both telmisartan and amlodipine.

Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patientshould be placed in a supine position with elevation of extremities, with salt and volume replacementgiven quickly. Supportive treatment should be instituted.

Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hoursafter administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Amlodipine is not dialysable and telmisartan is not removed from blood by haemofiltration and notdialysable.

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II receptorblockers (ARBs) and calcium channel blockers, ATC code: C09DB04.

Twynsta combines two antihypertensive compounds with complementary mechanisms to control bloodpressure in patients with essential hypertension: an angiotensin II receptor blocker, telmisartan, and adihydropyridinic calcium channel blocker, amlodipine.

The combination of these substances has an additive antihypertensive effect, reducing blood pressure to agreater degree than either component alone.

Twynsta once daily produces effective and consistent reductions in blood pressure across the 24-hourtherapeutic dose range.

Telmisartan is an orally active and specific angiotensin II receptor (type AT1) blocker. Telmisartandisplaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which isresponsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonistactivity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting.

Telmisartan does not show affinity for other receptors, including AT2 and other less characterised ATreceptors. The functional role of these receptors is not known, nor is the effect of their possibleoverstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levelsare decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels.

Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which alsodegrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse reactions.

In humans, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked bloodpressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.

After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours.

The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatmentand is sustained during long-term therapy.

The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hoursbefore the next dose as shown by ambulatory blood pressure measurements. This is confirmed by troughto peak ratios consistently above 80 % seen after doses of 40 and 80 mg of telmisartan in placebocontrolled clinical studies. There is an apparent trend to a dose relationship to a time to recovery ofbaseline systolic blood pressure. In this respect data concerning diastolic blood pressure are inconsistent.

In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure withoutaffecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to itshypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable tothat of substances representative of other classes of antihypertensive medicinal products (demonstrated inclinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, andlisinopril).

Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatmentvalues over a period of several days without evidence of rebound hypertension.

The incidence of dry cough was significantly lower in patients treated with telmisartan than in those givenangiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensivetreatments.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combinationwith Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in

Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptorblocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovasculardisease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-Dwas a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as comparedto monotherapy was observed. Given their similar pharmacodynamic properties, these results are alsorelevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly inpatients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) wasa study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or anangiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease,cardiovascular disease, or both. The study was terminated early because of an increased risk of adverseoutcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren groupthan in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia,hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in theplacebo group.

Amlodipine

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker orcalcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascularsmooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxanteffect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in bloodpressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascularsmooth muscle cells than on cardiac muscle cells.

In patients with hypertension, once daily dosing provides clinically significant reductions of bloodpressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onsetof action, acute hypotension is not a feature of amlodipine administration.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in adecrease in renal vascular resistance and an increase in glomerular filtration rate and effective renalplasma flow, without change in filtration fraction or proteinuria.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and issuitable for use in patients with asthma, diabetes, and gout.

Use in patients with heart failure

Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failurepatients have shown that amlodipine did not lead to clinical deterioration as measured by exercisetolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failurereceiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase inrisk of mortality or combined mortality and morbidity with heart failure.

In a follow-up, long term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA IIIand IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemicdisease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on totalcardiovascular mortality. In this same population amlodipine was associated with increased reports ofpulmonary oedema.

Telmisartan/Amlodipine

In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study in1461 patients with mild to severe hypertension (mean seated diastolic blood pressure ≥95 and≤119 mmHg), treatment with each combination dose of Twynsta resulted in significantly greater diastolicand systolic blood pressure reductions and higher control rates compared to the respective monotherapycomponents.

Twynsta showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic doserange of −21.8/−16.5 mmHg (40 mg/5 mg), −22.1/−18.2 mmHg (80 mg/5 mg), −24.7/−20.2 mmHg(40 mg/10 mg) and −26.4/−20.1 mmHg (80 mg/10 mg). The reduction in diastolic blood pressure<90 mmHg was achieved in 71.6 %, 74.8 %, 82.1 %, 85.3 % of patients respectively. Values are adjustedfor baseline and country.

The majority of the antihypertensive effect was attained within 2 weeks after initiation of therapy.

In a subset of 1050 patients with moderate to severe hypertension (DBP ≥100 mmHg) 32.7-51.8 %responded sufficiently to monotherapy of either telmisartan or amlodipine. The observed mean changes insystolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg(−22.2/−17.2 mmHg with 40 mg/5 mg; −22.5/−19.1 mmHg with 80 mg/5 mg) were comparable to orgreater than those seen with amlodipine 10 mg (−21.0/−17.6 mmHg) and associated with significantlower oedema rates (1.4 % with 40 mg/5 mg; 0.5 % with 80 mg/5 mg; 17.6 % with amlodipine 10 mg).

Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patientsconfirmed the results seen with in-clinic systolic and diastolic blood pressure reductions consistently overthe entire 24-hours dosing period.

In a further multicentre, randomised, double-blind, active-controlled, parallel group study, a total of 1097patients with mild to severe hypertension who were not adequately controlled on amlodipine 5 mgreceived Twynsta (40 mg/5 mg or 80 mg/5 mg) or amlodipine alone (5 mg or 10 mg). After 8 weeks oftreatment, each of the combinations was statistically significantly superior to both amlodipinemonotherapy doses in reducing systolic and diastolic blood pressures (−13.6/−9.4 mmHg,−15.0/−10.6 mmHg with 40 mg/5 mg, 80 mg/5 mg versus −6.2/−5.7 mmHg, −11.1/−8.0 mmHg withamlodipine 5 mg and 10 mg and higher diastolic blood pressure control rates compared to the respectivemonotherapies were achieved (56.7 %, 63.8 % with 40 mg/5 mg and 80 mg/5 mg versus 42 %, 56.7 %with amlodipine 5 mg and 10 mg). Oedema rates were significantly lower with 40 mg/5 mg and80 mg/5 mg compared to amlodipine 10 mg (4.4 % versus 24.9 %, respectively).

In another multicentre, randomised, double-blind, active-controlled, parallel group study, a total of947 patients with mild to severe hypertension who were not adequately controlled on amlodipine 10 mgreceived Twynsta (40 mg/10 mg or 80 mg/10 mg) or amlodipine alone (10 mg). After 8 weeks oftreatment, each of the combination treatments was statistically significantly superior to amlodipinemonotherapy in reducing diastolic and systolic blood pressure (−11.1/−9.2 mmHg, −11.3/ −9.3 mmHgwith 40 mg/10 mg, 80 mg/10 mg versus −7.4/−6.5 mmHg with amlodipine 10 mg) and higher diastolicblood pressure normalisation rates compared to monotherapy were achieved (63.7 %, 66.5 % with40 mg/10 mg, 80 mg/10 mg versus 51.1 % with amlodipine 10 mg).

In two corresponding open-label long-term follow up studies performed over a further 6 months the effectof Twynsta was maintained over the trial period. Furthermore it was shown that some patients notadequately controlled with Twynsta 40 mg/10 mg had additional blood pressure reduction by up-titrationto Twynsta 80 mg/10 mg.

The overall incidence of adverse reactions with Twynsta in the clinical trial programme was low withonly 12.7 % of patients on treatment experiencing adverse reactions. The most common adverse reactionswere peripheral oedema and dizziness, see also section 4.8. The adverse reactions reported were inagreement with those anticipated from the safety profiles of the components telmisartan and amlodipine.

No new or more severe adverse reactions were observed. The oedema related events (peripheral oedema,generalised oedema, and oedema) were consistently lower in patients who received Twynsta as comparedto patients who received amlodipine 10 mg. In the factorial design trial the oedema rates were 1.3 % with

Twynsta 40 mg/5 mg and 80 mg/5 mg, 8.8 % with Twynsta 40 mg/10 mg and 80 mg/10 mg and 18.4 %with Amlodipine 10 mg. In patients not controlled on amlodipine 5 mg the oedema rates were 4.4 % for40 mg/5 mg and 80 mg/5 mg and 24.9 % for amlodipine 10 mg.

The antihypertensive effect of Twynsta was similar irrespective of age and gender, and was similar inpatients with and without diabetes.

Twynsta has not been studied in any patient population other than hypertension. Telmisartan has beenstudied in a large outcome study in 25,620 patients with high cardiovascular risk (ONTARGET).

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

The European Medicines Agency has waived the obligation to submit the results of studies with Twynstain all subsets of the paediatric population in hypertension (see section 4.2 for information on paediatricuse).

Pharmacokinetic of the fixed dose combination

The rate and extent of absorption of Twynsta are equivalent to the bioavailability of telmisartan andamlodipine when administered as individual tablets.

Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolutebioavailability for telmisartan is about 50 %. When telmisartan is taken with food, the reduction in thearea under the plasma concentration-time curve (AUC0-∞) of telmisartan varies from approximately 6 %(40 mg dose) to approximately 19 % (160 mg dose). By 3 hours after administration, plasmaconcentrations are similar whether telmisartan is taken fasting or with food.

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levelsbetween 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80 %.

Amlodipine bioavailability is not affected by food ingestion.

Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid glycoprotein.

The mean steady state apparent volume of distribution (Vdss) is approximately 500 l.

The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown thatapproximately 97.5 % of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. Nopharmacological activity has been shown for the conjugate.

Amlodipine is extensively (approximatively 90 %) metabolised by the liver to inactive metabolites.

Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (Cmax) and, to a smaller extent, the area under theplasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence ofclinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrationswere higher in females than in males, without relevant influence on efficacy.

After oral (and intravenous) administration, telmisartan is nearly exclusively excreted with the faeces,mainly as unchanged compound. Cumulative urinary excretion is <1 % of dose. Total plasma clearance(Cltot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately30 to 50 hours consistent with once daily dosing. Steady-state plasma levels are reached after continuousadministration for 7-8 days. Ten per cent of original amlodipine and 60 % of amlodipine metabolites areexcreted in urine.

The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeuticefficacy. There is no linear relationship between doses and plasma levels. Cmax and to a lesser extent AUCincrease disproportionately at doses above 40 mg.

Amlodipine exhibits linear pharmacokinetics.

Paediatric population (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Differences in plasma concentrations of telmisartan were observed, with Cmax and AUC beingapproximately 3- and 2-fold higher, respectively, in females compared to males.

The pharmacokinetics of telmisartan do not differ in young and elderly patients.

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Inelderly patients, amlodipine clearance tends to decline with resulting increases in AUC and eliminationhalf-life.

In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations oftelmisartan was observed. However, lower plasma concentrations were observed in patients with renalinsufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficientsubjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renalimpairment. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolutebioavailability of telmisartan up to nearly 100 %. The elimination half-life of telmisartan is not changedin patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance ofamlodipine with resulting increase of approximately 40-60 % in AUC.

Since the non-clinical toxicity profiles of telmisartan and amlodipine are not overlapping, no exacerbationof toxicity was expected for the combination. This has been confirmed in a subchronic (13-week)toxicology study in rats, in which dose levels of 3.2/0.8, 10/2.5 and 40/10 mg/kg of telmisartan andamlodipine were tested.

Preclinical data available for the components of this fixed dose combination are reported below.

In preclinical safety studies, doses producing exposure comparable to that in the clinical therapeutic rangecaused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit), changes in renalhaemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium innormotensive animals. In dogs, renal tubular dilation and atrophy were observed. Gastric mucosal injury(erosion, ulcers or inflammation) also was noted in rats and dogs. These pharmacologically-mediatedundesirable effects, known from preclinical studies with both angiotensin converting enzyme inhibitorsand angiotensin II receptor blockers, were prevented by oral saline supplementation. In both species,increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells wereobserved. These changes, also a class effect of angiotensin converting enzyme inhibitors and otherangiotensin II receptor blockers, do not appear to have clinical significance.

No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan aneffect on the postnatal development of the offspring such as lower body weight and delayed eye openingwas observed.

There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and noevidence of carcinogenicity in rats and mice.

Amlodipine

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

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days andfemales for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 8 times* themaximum recommended human dose of 10 mg/day on an mg/m2 basis).

In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dosecomparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone andtestosterone 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 providedaily dose levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highestdose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on amg/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

Colloidal anhydrous silica

Brilliant blue FCF (E133)

Ferric oxide black (E172)

Ferric oxide yellow (E172)

Magnesium stearate

Maize starch

Meglumine

Microcrystalline cellulose

Povidone K25

Pregelatinised starch (prepared from maize starch)

Sodium hydroxide

Sorbitol (E420)

Not applicable.

3 years

This medicinal product does not require any special temperature storage conditions.

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

Aluminium/aluminium blisters (PA/Al/PVC/Al) in a carton containing 14, 28, 56, 98 tablets oraluminium/aluminium perforated unit dose blisters (PA/Al/PVC/Al) in a carton containing 30 x 1,90 x 1 tablets and multipacks containing 360 (4 packs of 90 x 1) tablets.

Not all pack sizes may be marketed.

Telmisartan should be kept in the sealed blister due to the hygroscopic property of the tablets. Tabletsshould be taken out of the blister shortly before administration.

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

EU/1/10/648/015 (14 tablets)

EU/1/10/648/016 (28 tablets)

EU/1/10/648/017 (30 x 1 tablets)

EU/1/10/648/018 (56 tablets)

EU/1/10/648/019 (90 x 1 tablets)

EU/1/10/648/020 (98 tablets)

EU/1/10/648/021 (360 (4 x 90 x 1) tablets)

Date of first authorisation: 07 October 2010

Date of latest renewal: 20 August 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.