Twynsta_ 5 Mg/10 Mg 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

TWYNSTA is indicated in patients whose blood pressure is not adequately controlled on amlodipine monotherapy.

Posology

Adults

TWYNSTA should be taken once daily.

Replacement therapy

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

Add on therapy

TWYNSTA may be administered in patients whose blood pressure is not adequately controlled with amlodipine alone. The usual starting dose of TWYNSTA 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). Telmisartan is not removed from blood by haemofiltration and is not dialysable. Amlodipine is not dialysable.

Hepatic impairment

In patients with mild to moderate hepatic impairment TWYNSTA should be administered with caution. For telmisartan the dose should not exceed 40 mg once daily (i.e. TWYNSTA 40/5 or 40/10 mg) (see section 4.3).

Elderly patients

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 section 4.4 and section 5.2).

Paediatric population

TWYNSTA is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Method of administration

TWYNSTA tablets are for once-daily oral administration and should be swallowed whole with water. TWYNSTA can be taken with or without food. Due to the hygroscopic property of the tablets they should be taken out of the sealed blister immediately before intake.

• Hypersensitivity to any of the ingredients of TWYNSTA
• 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
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.4)
• Porphyria
• Lithium therapy: Concomitant administration with TWYNSTA may lead to toxic blood concentrations of lithium (see section 4.5)
• Pregnancy and lactation (see section 4.4 and section 4.6)
• The concomitant use of TWYNSTA with aliskiren-containing products is contraindicated (see section 4.4 and section 4.5)
• Biliary obstructive disorders
• Severe hepatic impairment
• Severe hypotension
• 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
• Concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30 mL/min) and in elderly patients. In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of TWYNSTA is contraindicated. TWYNSTA contains sorbitol (see section 4.4).

Should a woman become pregnant while receiving TWYNSTA, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see section 4.3 and section 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 TWYNSTA and aliskiren is therefore contraindicated (see section 4.3). TWYNSTA should not be used concomitantly with aliskiren (see section 4.3).

Pregnancy

TWYNSTA 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 TWYNSTA should be stopped immediately, and if appropriate, alternative therapy should be started (see section 4.6).

Hepatic impairment

Telmisartan (ingredient of TWYNSTA) 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 is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range (i.e. TWYNSTA 40/5 mg or TWYNSTA 80/5 mg) and caution should be used, both on initial treatment and when increasing the dose.

TWYNSTA 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 medicinal products that affect the renin- angiotensin-aldosterone system (see section 4.3).

Renal impairment and kidney transplant

When TWYNSTA 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 TWYNSTA in patients with a recent kidney transplant. Telmisartan is not removed from blood by haemofiltration and is not dialysable. Amlodipine is not dialysable.

Volume and/or sodium depleted patients

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 TWYNSTA.

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 TWYNSTA, 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 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 whether used separately and/or concomitantly.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin- angiotensin-system. Therefore, the use of TWYNSTA is not recommended.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

TWYNSTA 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 TWYNSTA in unstable angina pectoris and during or within 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 than in the placebo group. Therefore, patients with heart failure should be treated with caution. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Hyperkalaemia

During treatment with TWYNSTA 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 medicinal products that affect the renin-angiotensin-system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with TWYNSTA.

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 TWYNSTA.

Elderly patients

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

Ischaemic heart disease

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

Sorbitol

TWYNSTA tablets contain sorbitol. Patients with the rare hereditary condition of fructose intolerance should not take this medicine.

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 TWYNSTA and other medicinal products.

Other antihypertensive agents

The blood pressure lowering effect of TWYNSTA can be increased by concomitant use of other antihypertensive medicinal products.

Medicines with blood pressure lowering potential

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of TWYNSTA: 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 TWYNSTA

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.

Ramipril and Ramiprilat

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 (see section 4.4).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including telmisartan. Increased serum levels have also been reported with telmisartan. Concomitant administration of TWYNSTA with lithium is contraindicated (see section 4.3).

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. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and TWYNSTA should be adequately hydrated and their renal function should be monitored at the beginning of combined treatment. A reduced effect of antihypertensive medicines like TWYNSTA 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 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 section 4.3 and section 4.4).

Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers 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).

Interactions linked to the amlodipine component of TWYNSTA

Grapefruit and grapefruit juice

Administration of amlodipine (as in TWYNSTA) with grapefruit or grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.

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 TWYNSTA be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

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 TWYNSTA 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 TWYNSTA, 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, TWYNSTA 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.

TWYNSTA 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, TWYNSTA should be discontinued (see section 4.3 and section 4.4). Medicines affecting the renin-angiotensin system, such as TWYNSTA, 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 TWYNSTA should be stopped immediately, and, if appropriate, alternative therapy should be started. Should exposure to TWYNSTA have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken TWYNSTA 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

TWYNSTA 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 - 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in breastfed infants, TWYNSTA should not be used by breastfeeding mothers (see section 4.3).

Twynsta has moderate influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it should be taken into account that syncope, somnolence, dizziness, or vertigo may occasionally occur during antihypertensive therapy. If patients experience these adverse events, they should avoid potentially hazardous tasks such as driving or operating machinery.

Summary of the safety profile

The safety and tolerability of TWYNSTA has been evaluated in five controlled clinical studies with over 3 500 patients, over 2 500 of whom received telmisartan in combination with amlodipine.

Tabulated summary of adverse reactions

The following side effects derived from the use of the TWYNSTA (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. The following frequency classification is used: very common u2265 1/10; common u2265 1/100 and < 1/10; uncommon u2265 1/1 000 and < 1/100; rare u2265 1/10 000 and < 1/1 000; very rare < 1/10 000; not known: cannot be estimated from the available data.

Symptoms

There is no experience of overdose with TWYNSTA. 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 also occurred. Available data for amlodipine suggest that gross overdosage could 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.

Therapy

If symptomatic hypotension should occur, supportive treatment should be instituted. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. 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. Telmisartan is not removed from blood by haemofiltration and is not dialysable. Amlodipine is not dialysable.