Adult patients who take telmisartan and amlodipine tablets separately can replace them with TWYNSTA tablets containing the same doses of the active substances.

twynsta Dosage

Dosage

The recommended dose of TWYNSTA is one tablet per day.
The maximum recommended dose is TWYNSTA 80 mg / 10 mg, one tablet per day. TWYNSTA is indicated as long-term treatment.

Additional treatment

TWYNSTA 80 mg / 10 mg can be administered in patients whose blood pressure is not adequately controlled by TWYNSTA 40 mg / 10 mg or TWYNSTA 80 mg / 5 mg.
Individual titration of the dose of the components (i.e., amlodipine and telmisartan) is recommended before switching to the fixed combination. A direct change from monotherapy to a fixed combination may be considered if it is clinically justified.
Patients treated with 10 mg amlodipine who experience dose-related adverse reactions such as edema may switch to TWYNSTA 40 mg / 5 mg once daily, which allows the dose of amlodipine to be reduced without reducing the response. global antihypertensive agent expected.

Substitution treatment

In patients taking telmisartan and amlodipine tablets separately, treatment may be replaced by TWYNSTA tablets containing the same doses of the active substances in a single tablet to be taken once daily, for example to improve convenience or ‘observance.

Special populations

Elderly patients

No dosage adjustment is necessary in elderly patients. There is little information available in very elderly patients.

Renal impairment (see also section Warnings and precautions for use )

No dosage adjustment is necessary in patients with mild to moderate renal impairment. There is limited experience in patients with severe renal impairment or on hemodialysis. TWYNSTA should be used with caution in these patients because amlodipine and telmisartan are not dialyzable.

Hepatic insufficiency

TWYNSTA should be used with caution in patients with mild to moderate hepatic impairment. As regards telmisartan, the daily dosage should not exceed 40 mg once daily .
TWYNSTA is contraindicated in patients with severe hepatic impairment .

Pediatric population

The safety and efficacy of TWYNSTA in children below 18 years of age have not been established. No data is available.

Methods of administration

TWYNSTA can be taken with or without food. It is recommended that TWYNSTA be taken with some liquid.

twynsta Contraindications

Hypersensitivity to any of the active substances, to dihydropyridine derivatives or to any of the excipients (see Composition section )
2 ^nd and 3 ^rd trimesters of pregnancy (see Warnings and precautions for use and Pregnancy and breast-feeding sections )
Biliary obstruction and severe liver failure
Shock (including cardiogenic shock)
Severe hypotension
Obstruction of the afferent left ventricular pathway (eg high grade aortic stenosis)
Hemodynamically unstable heart failure after acute myocardial infarction

how does twynsta work?

Class Pharmacotherapeutic group: Agents acting on the system renin-angiotensin antagonists, angiotensin II antagonists and calcium channel: ATC Code: C09DB04.
Twynsta combines two antihypertensive drugs with complementary mechanisms for controlling blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a calcium channel blocker from the dihydropyridine family, amlodipine.
The combination of these active ingredients allows an additivity of their antihypertensive effects , and a greater reduction in blood pressure than that observed with each active ingredient taken separately.
Taken daily, Twynsta provides effective and sustained 24 hour blood pressure reduction within the
therapeutic dose range .

Telmisartan

The telmisartan is a specific antagonist of the AT1 receptor subtype of angiotensin II, orally active. Telmisartan has avery strong affinity for the angiotensin II receptor AT1. It displaces angiotensin II from its binding site on this receptor, which is responsible for the known effects of angiotensin II. It has no partial agonist effect on the AT1 receptor. Telmisartan selectively binds to the AT1 receptor. Binding to the receptor is long lasting. Telmisartan has no affinity for other receptors, including the AT2 receptor and other less well characterized AT receptors . The functional role of these receptors is not known, as well as the effect produced by strong stimulation of these receptors by angiotensin II, the levels of which are increased during treatment with telmisartan. Plasma aldosterone levels are reduced during treatment with telmisartan. Telmisartan does not inhibit human plasma renin and does not block ion channels . Telmisartan does not inhibit the angiotensin converting enzyme (kininase II), which is also responsible for the degradation of bradykinin. There is therefore no need to fear a potentiation of the undesirable effects associated with bradykinin.
In humans, an 80 mg dose of telmisartan almost completely inhibits the increase in blood pressure mediated by angiotensin II. The inhibitory effect is maintained over 24 hours, and remains measurable 48
hours after taking.
After the first dose of telmisartan, the antihypertensive effect manifests itself gradually over the first 3 hours. In general, the maximum reduction in blood pressure is obtained 4 to 8 weeks after the start of treatment. It persists during long-term treatment .
The blood pressure measurements as shown by ambulatory effect antihypertensive persists during the 24 hours following the administration, including during the last four hours
before the next dose. The valley / peak ratio regularly greater than 80%, measured for doses of 40 and 80 mg of telmisartan during placebo-controlled clinical trials, confirms this. There appears to be a tendency for a relationship between dose and time to return to baseline with respect to systolic blood pressure. However, the data obtained on diastolic blood pressure does not confirm this possible relationship.
In hypertensive patients, telmisartan lowers systolic and diastolic blood pressure without affecting the heart rate. Thepossible diuretic and natriuretic effects of the drug, which maycontribute to its antihypertensive activity, remain to be confirmed. The antihypertensive effect of telmisartan is comparable to that observed with antihypertensive drugs from other classes (this efficacy has been demonstrated in comparative clinical trials versus amlodipine, atenolol, enalapril, hydrochlorothiazide and lisinopril).
In case of sudden interruption of treatment with telmisartan, blood pressure gradually returns in a few days to its initial value before treatment, no rebound effect.
In clinical trials comparing telmisartan with ACE inhibitors , the incidence of dry cough was
significantly lower in the groups of patients treated with telmisartan than in the groups of patients treated with inhibitors. the converting enzyme.
The use of the combination of an ACE inhibitor with an angiotensin II receptor antagonist (ARA II) has been analyzed in two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes).
The ONTARGET study was performed in patients with a history of cardiovascular disease or cerebrovascular disease, or type 2 diabetes with target organ damage. The VA NEPHRON-D study was performed in patients with type 2 diabetes and diabetic nephropathy.
In comparison with monotherapy, these studies did not demonstrate a significant beneficial effect on the evolution of renal and / or cardiovascular damage and on mortality, while an increased risk of hyperkalaemia was observed. , acute renal failure and / or hypotension. These results are also applicable to other ACE inhibitors and ARBs II, given the similarity of their pharmacodynamic properties .
ACE inhibitors and ARBs II should therefore not be combined in patients with diabetic nephropathy.
The ALTITUDE study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and
Renal Disease Endpoints) was performed to assess the benefit of adding aliskiren to standard ACE inhibitor or ARB II therapy in patients with type 2 diabetes and chronic renal failure, with or without cardiovascular disorders. This study was terminated prematurely due to an increased risk of adverse events. Cardiovascular deaths and strokes were more common in the aliskiren group than in the placebo group; likewise adverse events and certain serious adverse events such as hyperkalaemia, hypotension and renal failure were reported more frequently in the aliskiren group than in the placebo group .

Amlodipine

Amlodipine is a calcium antagonist belonging to the family of dihydropyridines; it inhibits the transmembrane entry of calcium ions into heart muscle and vascular smooth muscle. The
mechanism of the antihypertensive action of amlodipine is linked to a direct relaxing effect in vascular smooth muscle, leading to a decrease in peripheral vascular resistance and arterial pressure. Experimental data suggests that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites . Amlodipine has a relatively selective vascular effect , with a greater effect on vascular smooth muscle cells than heart muscle cells.
In hypertensive patients, a single daily dose results in a clinically significant reduction in blood pressure when lying or standing over the entire nycthemere.
The progressive action of amlodipine makes it possible to avoid attacks of hypotension.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in decreased renal vascular resistance and increased glomerular filtration rate and effective renal plasma flow, with no change in filtration fraction or proteinuria. .
Amlodipine is metabolically neutral and does not alter plasma lipid levels. It can be used in patients with asthma, diabetes or gout.

Use in patients with heart failure

The hemodynamic studies and clinical trials using tests of effort among patients with heart failure of NYHA class II-IV have demonstrated that amlodipine does not lead to clinical deterioration from measurements of tolerance in effort, left ventricular ejection fraction and clinical symptomatology .
A placebo-controlled study (PRAISE) to evaluate patients with NYHA class III-IV heart failure treated with digoxin, diuretics and ACE inhibitors showed that amlodipine does not increase the risk of death or morbidity and mortality. .
In a long-term follow-up study of amlodipine, placebo- controlled (PRAISE-2), performed in patients with
NYHA class III or IV heart failure, without clinical symptoms or objective findings suggestive of ischemic involvement under -jacent, treated with stable doses of ACE inhibitors, digitalis and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population, amlodipine has been associated with an increase in reported cases of pulmonary edema.

Telmisartan / Amlodipine

In an 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group factorial study conducted in 1461 patients with mild to severe hypertension (mean diastolic blood pressure when sitting ≥ 95 and ≤ 119 mmHg) , treatment with each of the doses of Twynsta combined resulted in significantly greater reductions in diastolic and systolic blood pressure and higher blood pressure control rates than each of the respective components taken as monotherapy.
Twynsta produced dose-dependent reductions in
systolic / diastolic blood pressure over the entire therapeutic dose range 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). A reduction in diastolic blood pressure <90 mmHg was obtained in 71.6%, 74.8%, 82.1%, 85.3% of patients, respectively. The values are adjusted according to the initial values and the country.
The majority of the antihypertensive effect was achieved during the 2 weeks following initiation of treatment. In a subgroup of 1050 patients with moderate to severe hypertension (DBP ≥ 100 mmHg), 32.7-51.8% of patients had a sufficient response to monotherapy treatment with telmisartan or amlodipine. The mean changes in systolic / diastolic blood pressure observed with a combination therapy containing 5 mg amlodipine (-22.2 / -17.2 mmHg with 40 mg / 5 mg; -22.5 / -19.1 mmHg with 80 mg / 5 mg) were greater than or equal to those seen with amlodipine 10 mg (-21.0 / -17.6 mmHg) and were associated with significantly lower rate of edema (1.4% with 40 mg / 5 mg; 0.5% with 80 mg / 5 mg; 17.6% with amlodipine 10 mg).
The ambulatory blood pressure measurement (ABPM) performed in a subset of 562 patients confirmed the results observed in measurements of systolic blood pressure and diastolic
made clinically, with reductions maintained over the entire nycthemeron.
In another multicenter, randomized, double-blind,controlled versus active treatment, parallel group study, a total of 1097 patients with mild to severe arterial hypertension and whose arterial pressure was not sufficiently controlled by amlodipine 5 mg had received Twynsta (40 mg / 5 mg or 80 mg / 5 mg) or amlodipine as monotherapy (5 mg or 10 mg). After 8 weeks of treatment, each of the doses of the combinations was found to be statistically significantly superior to the two doses of amlodipine as monotherapy in terms of reduction in systolic and diastolic blood pressure (-13.6 / – 9.4 mmHg with 40 mg / 5 mg,-15.0 / -10.6 mmHg with 80 mg / 5 mg versus -6.2 / -5.7 mmHg, -11.1 / -8.0 mmHg with amlodipine 5 mg and 10 mg) and higher
diastolic blood pressure control rates than with each of the respective monotherapies were obtained (56.7% with 40 mg / 5 mg, 63.8% with 80 mg / 5 mg versus 42%, 56.7% with amlodipine 5 mg and 10 mg). The
edema rates were significantly lower with 40 mg / 5 mg and 80 mg / 5 mg than with amlodipine 10 mg (respectively 4.4% versus 24.9%).
In another multicenter, randomized, double-blind, controlled versus active treatment, parallel group study, a total of 947 patients with mild to severe arterial hypertension and whose arterial pressure was not sufficiently controlled by amlodipine 10 mg received Twynsta (40 mg / 10 mg or 80 mg / 10 mg) or amlodipine as monotherapy (10 mg). After 8 weeks of treatment, each dose of the combination was found to be statistically
significantly superior to amlodipine monotherapy in terms of reduction in systolic and diastolic blood pressure (-11.1 / -9.2 mmHg with 40 mg / 10 mg, -11.3 / -9.3 mmHg with 80 mg / 10 mg versus -7.4 / -6.5 mmHg with amlodipine 10 mg) and higher rates of stabilization of diastolic blood pressure than with monotherapy were obtained (63.7% with 40 mg / 10 mg, 66.5% with 80 mg / 10 mg versus 51.1% with amlodipine 10 mg).
In two corresponding open- label long-term follow-up studies carried out over an additional 6 months, the effect of Twynsta was maintained throughout the study period. In addition, some patients whose blood pressure was not sufficiently controlled by Twynsta 40 mg / 10 mg have been shown to achieve further reduction in blood pressure when switching to Twynsta 80 mg / 10 mg.
The overall incidence of adverse reactions seen in clinical developmen with Twynsta was low, with only 12.7% of patients on treatment experiencing adverse reactions. The
most common side effects were peripheral edema and dizziness, . The adverse reactions reported were consistent with the effectsexpected from the safety profiles of the two components
telmisartan and amlodipine. No new or more severe side effects were observed. Edema (peripheral edema, generalized edema and edema) was consistently lower in patients with patients who received Twynsta than in patients who received amlodipine 10 mg. In the factorial study, the edema 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 with amlodipine 5 mg, the edema rates were 4.4% with 40 mg / 5 mg and 80 mg / 5 mg and 24.9% with amlodipine10 mg.
The antihypertensive effect of Twynsta was comparable across age and sex, and in patients with and without diabetes.
Twynsta has not been studied in any population other than hypertensive patients . Telmisartan has been studied in a large study in 25,620 patients at high cardiovascular risk (ONTARGET).
Amlodipine has been studied in patients with stable chronic angina, vasospastic angina, and ischemic heart disease documented by angiography.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Twynsta in all subgroups of the pediatric population in hypertension for information. concerning pediatric use).

twynsta Side Effects

.Fixed dose combination

The most common side effects included dizziness and peripheral edema. Severe syncope can rarely occur (less than 1 case per 1000 patients).
The safety and tolerability of TWYNSTA have been evaluated in five controlled clinical trials conducted in more than 3,500 patients, of which more than 2,500 received telmisartan in combination with amlodipine.
Adverse reactions were classified according to their frequency using the following classification: Very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1 / 10,000 to <1 / 1,000); very rare (<1 / 10,000); not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class	Frequent	Rare	Rare
Infections and infestations			cystitis
Psychiatric disorders			depression, anxiety, insomnia
Nervous system disorders	dizziness	drowsiness, migraine, headache, paraesthesia	syncope, peripheral neuropathy, hypoaesthesia, dysgeusia, tremor
Ear and labyrinth disorders		dizziness
Cardiac disorders		bradycardia, palpitations
Vascular disorders		hypotension, orthostatic hypotension, flushing
Respiratory, thoracic and mediastinal disorders		cough
Gastrointestinal disorders		abdominal pain, diarrhea, nausea	vomiting, gingival enlargement, dyspepsia, dry mouth
Skin and subcutaneous tissue disorders		itching	eczema, erythema, rash
Musculoskeletal and connective tissue disorders		arthralgia, muscle spasms (leg cramps), myalgia	back pain, limb pain (leg pain)
Kidney and urinary tract disorders			nocturia
Reproductive system and breast disorders		erectile dysfunction
General disorders and administration site conditions	peripheral edema	asthenia, chest pain, fatigue, edema	discomfort
Investigations		increased liver enzymes	increased uricemia

Additional information on the active ingredients taken individually

The undesirable effects previously reported for each of the active substances taken individually (telmisartan or amlodipine) can potentially occur during treatment with TWYNSTA, even if they have not been demonstrated during clinical trials or after being put on the drug. market.

Telmisartan

Infections and infestations
Rare :	Infections of the upper respiratory tract such as pharyngitis and sinusitis, urinary tract infection including cystitis
Rare:	Sepsis including fatal evolution ¹
Blood and lymphatic system disorders
Rare :	Anemia
Rare:	Thrombocytopenia, eosinophilia
Immune system disorders
Rare:	Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Rare :	Hyperkalaemia
Eye disorders
Rare:	Vision disturbances
Cardiac disorders
Rare:	Tachycardia
Respiratory, thoracic and mediastinal disorders
Rare :	Dyspnea
Gastrointestinal disorders
Rare :	Flatulence
Rare:	Gastric discomfort
Hepatobiliary disorders
Rare:	Abnormal liver function, liver damage
Skin and subcutaneous tissue disorders
Rare :	Hyperhidrosis
Rare:	Angioedema, drug rash, toxic rash, urticaria
Musculoskeletal and connective tissue disorders
Rare:	Tendon pain (tendonitis-like symptoms)
Kidney and urinary tract disorders
Rare :	Renal failure including acute renal failure
General disorders and administration site abnormality
Rare:	Flu-like syndrome
Investigations
Rare :	Increased blood creatinine level
Rare:	Blood creatine phosphokinase increased, hemoglobin level decreased

¹ : this event can be due to chance or linked to a mechanism currently unknown

Amlodipine:

Blood and lymphatic system disorders
Very rare :	Leukopenia, thrombocytopenia
Immune system disorders
Very rare :	Hypersensitivity
Metabolism and nutrition disorders
Very rare :	Hyperglycemia
Psychiatric disorders
Rare :	Change in mood
Rare:	Confusion
Nervous system disorders
Rare :	Paresthesias
Very rare :	Peripheral neuropathy, extrapyramidal syndrome
Eye disorders
Rare :	Visual disturbances
Ear and labyrinth disorders
Rare :	Tinnitus
Cardiac disorders
Very rare :	Myocardial infarction, arrhythmia, ventricular tachycardia, atrial fibrillation
Vascular disorders
Very rare :	Vasculitis
Respiratory, thoracic and mediastinal disorders
Rare :	Dyspnoea, rhinitis
Gastrointestinal disorders
Rare :	Changes in intestinal transit
Very rare :	Pancreatitis, gastritis
Hepatobiliary disorders
Very rare :	Hepatitis, jaundice, elevated liver enzymes (most often consistent with cholestasis)
Skin and subcutaneous tissue disorders
Rare :	Alopecia, purpura, skin discoloration, hyperhidrosis
Very rare :	Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity
Kidney and urinary tract disorders
Rare :	Urination disorders, pollakiuria
Reproductive system and breast disorders
Rare :	Gynecomastia
General disorders and administration site abnormality
Rare :	Pain
Investigations
Rare :	Weight gain, weight loss

twynsta Interactions

No interaction between the two active substances of this fixed dose combination has been observed in clinical studies.

Interactions linked to the association

No drug interaction studies have been performed.

Associations to take into account

Other antihypertensive drugs

The drop in blood pressure induced by the telmisartan / amlodipine combination may be accentuated by the concomitant use of other antihypertensive drugs.

Medicines with hypotensive potential

Due to their pharmacological properties, some drugs, for example baclofen, amifostine, neuroleptics and antidepressants, may potentiate the hypotensive effects of all antihypertensive drugs, including those of this drug. Additionally, alcohol may potentiate the risk of postural hypotension.

Corticosteroids (systemic route)

Reduction of the antihypertensive effect.

Interactions related to telmisartan

Not recommended associations

Potassium-sparing diuretics and potassium supplementation treatments

The receptor antagonists of angiotensin II such as telmisartan attenuate potassium loss induced by diuretics. The potassium-sparing diuretics eg spironolactone,
eplerenone, triamterene, or amiloride, treatments of potassium supplements or potassium-containing salt substitutes may significantly increase serum potassium. If the combination is warranted because of documented hypokalaemia, their use should be cautious and serum potassium should be
monitored frequently.

Lithium

Of reversible increases in serum concentrations and toxicity of lithium have been observed during concomitant administration of lithium with angiotensin converting enzyme angiotensin well as receptor antagonists of angiotensin II, including telmisartan. If the combination proves necessary, close monitoring of lithemia is recommended.

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

The data from clinical trials have shown that dual blockade of the system renin-angiotensin-aldosterone system (RAAS) through the use concomitant angiotensin converting enzyme inhibitors, antagonists
of angiotensin II receptors or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and impaired renal function (including acute renal failure) compared to the use of a single drug acting on the SARS (see sections Contraindications, Warnings and precautions for use and Pharmacodynamic properties).

Combinations requiring precautions for use

Nonsteroidal anti-inflammatory drugs

The NSAID (e.g. acetylsalicylic acid at doses of anti-inflammatory drugs, COX-2 NSAIDs and
non-selective) may reduce the antihypertensive effect of antagonists of angiotensin II. In some
patients with impaired renal function (eg dehydrated patients or elderly patients with impaired renal function) the combination of angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase may cause further deterioration of kidney function, including acute kidney failure, which is usually reversible. Therefore, mainly in elderly patients, the combination should be used with caution. Patients should be adequately hydrated and renal function monitoring should be initiated when initiating concomitant therapy and periodically thereafter.

Ramipril

In one study, co-administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Associations to take into account

Digoxin

When telmisartan was administered concomitantly with digoxin, a median increase in the maximum (49%) and minimum (20%) plasma concentration of digoxin was observed. Monitor digoxin levels when initiating, adjusting or stopping telmisartan to maintain them within the therapeutic range.

Amlodipine Interactions

Combinations requiring precautions for use

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or
diltiazem) may result in a significant increase in exposure to amlodipine and therefore increase the risk of hypotension. The clinical translation of these pharmacokinetic variations may be more pronounced in elderly patients. A clinical monitoring and dosage adjustment may therefore be necessary.

CYP3A4 inducers

When co-administered with known inducers of CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dosage adjustment should be considered during and after concomitant use of a drug, especially with strong inducers of CYP3A4 (eg, rifampicin, St. John’s wort [hypericum perforatum]).

Dantrolène (perfusion)

In animals, cases of ventricular fibrillation and fatal cardiovascular collapse have been observed in the context of hyperkalaemia after intravenous administration of verapamil and dantrolene . In view of the risk of hyperkalaemia, concomitant administration of calcium channel blockers suchas amlodipine should be avoided in patients susceptible to malignant hyperthermia and during its management.

Grapefruit and grapefruit juice

Administration of Twynsta with grapefruit or grapefruit juice is no recommended as bioavailability may increase in some patients and lead to increased hypotensive effects.

Associations to take into account

Tacrolimus
There is a risk of increased blood level of tacrolimus when co-administered with amlodipine, but the mechanism of this interaction is not fully understood. In order to avoid tacrolimus toxicity, administration of amlodipine in patients treated with tacrolimus requires monitoring of tacrolimus blood levels and adjustment of the tacrolimus dose if necessary.

Ciclosporin

No interaction studies with ciclosporin and amlodipine have been performed in healthy volunteers or any other population, with the exception of kidney transplant patients. In the latter, varying increases in trough concentrations of ciclosporin were observed (mean 0% -40%). Monitoring of ciclosporin concentrations should be considered in renal transplant patients treated with amlodipine, and dose of ciclosporin. should be reduced if necessary.

Rapamycin Functional Target Inhibitors (mTOR)

The mTOR inhibitors such as sirolimus, temsirolimus and everolimus, are CYP3A substrates. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may increase
exposure to mTOR inhibitors.

Simvastatin

Co-
administration of multiple doses of 10 mg amlodipine
with 80 mg simvastatin increased exposure to
simvastatin by up to 77% compared to simvastatin administered alone. As
a result, the dose of simvastatin should be limited to 20 mg per
day in patients on amlodipine.
Not applicable.

Drive and use machines

This medicine has moderate influence on the ability to drive and use machines. Patients should take into account that side effects such as syncope, drowsiness, dizziness or dizziness may occur during treatment ( see Undesirable effects ).
Caution is therefore recommended when driving vehicles or using machines. If patients experience these side effects, they should avoid performing potentially hazardous tasks such as driving or using machines.

Warnings and Precautions

Pregnancy

The antagonists of the angiotensin II (angiotensin II receptor antagonists) should not be initiated during pregnancy. Unless treatment with ARAII is considered essential, it is recommended in patients planning to become pregnant to change antihypertensive therapy to a medicine with an established safety profile
during pregnancy. If pregnancy is diagnosed, treatment with ARAII should be stopped immediately and if necessary an alternative treatment should be started (see sections Contraindications and Pregnancy and breast-feeding).

Hepatic insufficiency

The Telmisartan is mostly eliminated with the bile. Hepatic clearance is likely to be reduced in patients with
biliary obstruction or hepatic impairment.
In patients with impaired hepatic function the half-life of amlodipine is prolonged and the area under the curve (AUC) values are higher; dosage recommendations have not been established to follow. Therefore, treatmentwith amlodipine should be started at the lowest dose and
caution is advised both when initiating treatment and when increasing the dose.
The combination telmisartan / amlodipine should therefore be used with caution in these patients.

Renovascular hypertension

When drugs active on the renin-angiotensin-aldosterone system (RAAS) are administered to patients with bilateral renal artery stenosis or renal artery stenosis in a functionally single kidney, the risk of severe hypotension and renal failure is increased.

Kidney failure and kidney transplantation

When telmisartan / amlodipine is administered to patients with impaired renal function,
regular monitoring of serum potassium and serum creatinine levels is recommended. No data are available on the use oftelmisartan / amlodipine in patients with recent kidney transplantation. Telmisartan and amlodipine are
not dialyzable.

Intravascular hypovolemia

A symptomatic hypotension may occur, particularly after the first administration in patients who are volume
and / or sodium depletion, for example after a treatment diuretic high dose of a low-salt diet, diarrhea or vomiting. These problems must be corrected before any administration of telmisartan. If hypotension occurs duringtreatment with telmisartan / amlodipine, the patient should be lying on their back and, if necessary, given an intravenous infusion of physiological saline. Treatment can be continued after stabilization of blood pressure.

Double blockage of the renin-angiotensin-aldosterone system (RAAS)

It is established that the combination of angiotensin converting enzyme (ACE) inhibitors, receptor antagonists of angiotensin II (ARB) or aliskiren increases the risk of hypotension, hyperkalaemia and impaired renal function (including the risk of acute renal failure). Therefore, the double blockade of RAAS by the combination of ACEI, ARA II or aliskiren is not recommended.
However, if such a combination is considered absolutely necessary, it can only be done under the supervision of a specialist and with close and frequent monitoring of renal function, blood ionogram and blood pressure.
ACE inhibitors and ARBs II should not be combined in patients with diabetic nephropathy.

Other conditions related to the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function are predominantly dependent on the activity of the
renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure, or underlying renal impairment , including stricture arterial artery disease), treatment with drugs that affect this system has been associated with acute hypotension, hyperazotemia, oliguria, or rarely,
acute renal failure.

Primary hyperaldosteronism

The patients with primary aldosteronism not meet generally to antihypertensive drugs acting through inhibition of the renin-angiotensin system. The use of telmisartan is therefore not recommended in these patients.

Mitral and aortic valve stenosis, hypertrophic obstructive cardiomyopathy

As with other vasodilator treatments, caution should be exercised in patients with mitral or aortic stenosis or hypertrophic obstructive cardiomyopathy.

Unstable angina, acute myocardial infarction

There are no data on the use of telmisartan / amlodipine in unstable angina and during a myocardial
infarction, or in the month following a myocardial infarction.

Patients with heart failure

In a long-term, placebo- controlled study with amlodipine in patients with severe heart failure (NYHA class III or IV), the reported incidence of pulmonary edema was higher in the amlodipine group compared to the group. placebo (see section 5.1). Treatment should therefore be administered with caution in patients with heart failure.
The calcium channel antagonists, including amlodipine, should be used with caution in patients with impaired congestive heart because they may increase the risk of subsequent cardiovascular events and mortality.

Diabetic patients treated with insulin or antidiabetic drugs

In these patients hypoglycaemia may occur during treatment with telmisartan. Therefore, appropriate monitoring of blood glucose should be considered in these patients; It may be necessary to adjust the dose of insulin or anti-diabetics depending on the results.

Hyperkaliémie

The use of drugs that affect the renin-angiotensin-aldosterone system can lead to hyperkalaemia. Hyperkalaemia can be fatal in elderly patients, patients with renal insufficiency, diabetic patients, patients concomitantly treated with drugs which may increase serum potassium and / or in patients with intercurrent events.
Before considering the concomitant use of medicinal products affecting the renin-angiotensin-aldosterone system, the benefit-risk balance should be assessed.

The main risk factors to consider for hyperkalaemia are:

Diabetes mellitus, renal failure, age (> 70 years)
Combination with one or more drugs affecting the renin-angiotensin-aldosterone system and / or potassium supplementation treatment. Drugs or therapeutic classes of drugs which may cause hyperkalaemia are diet salts containing potassium, potassium- sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non- steroidal anti-inflammatory drugs (NSAIDs) , including selective COX-2 inhibitors), heparin, immunosuppressants (ciclosporin or tacrolimus) and trimethoprim.
The intercurrent events, in particular dehydration, decompensated acute cardiac, metabolic acidosis,
worsening of renal function, sudden worsening of renal function (eg infectious diseases), cellular lysis
(eg, ischemia aiguëd’un limb, rhabdomyolysis, extensive trauma).
Serum potassium should be closely monitored in these patients.

Elderly patients

Caution is required when increasing the dose of amlodipine in elderly patients (see sections 4.2 and Pharmacokinetics).

Sorbitol

This medicine contains 337.28 mg of sorbitol per tablet.
Sorbitol is a source of fructose. The use of Twynsta is not recommended in patients with hereditary fructose intolerance (IHF).

Other precautions

As with all antihypertensive therapy, too much reduction in blood pressure in patients with
ischemic cardiomyopathy or ischemic cardiovascular disease could lead to myocardial infarction or stroke.

PREGNANCY & BREAST-FEEDING & FERTILITY

Pregnancy

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

Telmisartan :

The use of angiotensin II receptor antagonists (ARB II) is not recommended during the 1 ^st trimester of pregnancy ( see Warnings and Precautions for use ). The use of ARA II is contraindicated in the 2 ^nd and 3 ^rd trimesters of pregnancy ( see Contraindications , Warnings and Precautions for use ).
Studies of telmisartan in animals have shown reproductive toxicity ( see Preclinical Safety ).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the 1 ^st trimester of pregnancy does not suggest. However, a small increase in the risk of birth defects cannot be excluded. There are no epidemiological studies available concerning the use of ARA II in the ^1st trimester of pregnancy; however, a risk similar to that of ACE inhibitors could exist for this class. Unless ARA II therapy is considered essential, it is recommended in patients planning to become pregnant to change antihypertensive therapy to a drug with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with ARA II should be stopped immediately and, if necessary, alternative treatment should be started.
Exposure to ARBs during the 2 ^e and 3 ^e trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, delayed ossification of the skull) and toxicity in newborns (renal failure, hypotension, hyperkalaemia): see Preclinical safety . If exposed from 2 ^th trimester of pregnancy, it is recommended to do a fetal ultrasound check of renal function and the bones of the skull. Newborns of mothers treated with ARA II should be monitored for blood pressure ( see Contraindications , Warnings and Precautions for use ).

Amlodipine :

The safety of amlopidine in pregnant women has not been established.
Studies in animals have shown reproductive toxicity at high doses ( see Preclinical safety ).

Feeding with milk

Amlodipine is excreted in breast milk. The proportion of the maternal dose received by the infant has been estimated at an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
Due to the lack of information available on the use of telmisartan during breast-feeding, the combination telmisartan / amlodipine is not recommended. It is preferable to use other treatments with a well-established safety profile during breastfeeding, especially in newborns or premature babies.

Fertility

No data from controlled clinical studies with the fixed combination or with each of the components taken separately are available.
Reproduction toxicity studies have not been performed specifically with the combination of telmisartan and amlodipine.
In preclinical studies, no effect of telmisartan was observed on fertility in males and females.
In some patients treated with calcium channel blockers, reversible biochemical changes have been reported in the sperm head. There are insufficient clinical data to conclude on the potential effect of amlodipine on fertility. In a study conducted in rats, deleterious effects on male fertility were observed ( see Preclinical safety ).

What happens if I overdose from twynsta ?

Symptoms :

The expected signs and symptoms of overdose should be those of an exaggerated pharmacological response. The most prominent manifestations of telmisartan overdose are hypotension and tachycardia; Bradycardia, dizziness, increased serum creatinine and acute renal failure have also been reported.
Overdose of amlodipine could cause severe peripheral vasodilation and possibly reflex tachycardia. Pronounced and possibly prolonged systemic hypotension, up to fatal shock, has been reported.

Treatment :

Close monitoring of the patient should be initiated, as well as symptomatic and supportive treatment. Management should take into account the time since ingestion and the severity of symptoms. Administration of emetic drugs and / or gastric lavage may be considered. Activated charcoal may be useful for the treatment of a possible overdose of both telmisartan and amlodipine.
Electrolyte workup and serum creatinine monitoring should be performed frequently. In the event of hypotension, the patient should be laid on the back with the limbs elevated, and treatment with saline vascular solution should be initiated promptly. Supportive treatment should be initiated.
Intravenous administration of calcium gluconate may be helpful in reversing the effects of calcium channel inhibition.
Gastric lavage may be warranted in some cases. In healthy volunteers, the use of charcoal for up to 2 hours after administration of amlopidine 10 mg has shown a reduction in the rate of absorption of amlopidine.
Telmisartan and amlodipine are not removed by hemodialysis.

What is Forms and Composition ?

SHAPES and PRESENTATIONS

40 mg / 5 mg tablet (oval, bilayer, engraved with the product code “A1” and the laboratory logo on the white layer; blue and white), 40 mg / 10 mg (oval, bilayer, engraved with the code of the product “A2” and the laboratory logo on the white layer; blue and white), at 80 mg / 5 mg (oval, bilayer, engraved with the product code “A3” and the laboratory logo on the white layer; blue and white) and 80 mg / 10 mg (oval, bilayer, engraved with the product code “A4” and the laboratory logo on the white layer; blue and white): Boxes of 30 and 90, in blister packs, pre-cut in doses unitary.

COMPOSITION

	p tablet
Telmisartan (DCI)	40 mg	40 mg	80 mg	80 mg
Amlodipine (INN) besilate expressed as amlodipine	5 mg	10 mg	5 mg	10 mg

Excipients (common): colloidal anhydrous silica, brilliant blue FCF (E133), black iron oxide (E172), yellow iron oxide (E172), magnesium stearate, corn starch, meglumine, microcrystalline cellulose, povidone K25, pregelatinized starch (prepared from corn starch), sodium hydroxide, sorbitol (E420).
Excipients with known effect: sorbitol E420 (168.64 mg / tab 40 mg / 5 mg and 40 mg / 10 mg; 337.28 mg / tab 80 mg / 5 mg and 80 mg / 10 mg).
Each tablet contains less than 1 mmol (23 mg) sodium per tablet, that is, it is essentially “sodium-free”.

NOT’s

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general information:

Includes a general description of the drug, its use, brand names, FAQs, and relevant news and articles

Additional information:

General explanation about dealing with the medicine: how to take the medicine, the doses and times of it, the start and duration of its effectiveness, the recommended diet during the period of taking the medicine, the method of storage and storage, recommendations in cases for forgetting the dose and instructions to stop taking the drug and take additional doses.

Special warnings:

For pregnant and breastfeeding women, the elderly, boys and drivers, and use before surgery.

Side effects:

It treats possible side effects and drug interactions that require attention and its effect on continuous use.
The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.

Amlodipine Telmisartan