TWYNSTA Telmisartan / Amlodipine 40mg / 5mg Tablet 1's

Symptoms: There is no experience of overdose with Telmisartan + Amlodipine besilate (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 might also occur. Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome may occur.
Therapy: Supportive treatment should be instituted. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine besilate are not removed by haemodialysis.

 

 

Pregnancy: Telmisartan: The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy and should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy.
Non-clinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity. Angiotensin II receptor antagonists exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.
Amlodipine: Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.
Lactation: It is not known whether telmisartan is excreted in human milk. Non-clinical studies have shown excretion of telmisartan in breast milk. Amlodipine has been identified in breastfed infants of treated women. The effect of amlodipine on infants is unknown. Because of the potential adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of this therapy for the mother (see Contraindications).
Fertility: No data from controlled clinical studies with the Fixed Dose Combination or with the individual components are available.
Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted. In non-clinical studies, no effects of telmisartan on male and female fertility were observed. Similarly, no effects on male and female fertility were reported for amlodipine (see Pharmacology: Toxicology under Actions).

 

 

IMPORTANT: Moisture sensitive tablets - do not remove from blisters until immediately before administration.

 

Store at temperatures not exceeding 30°C.
Store in the original package in order to protect from light and moisture.

 

Pharmacotherapeutic group: angiotensin II antagonists, plain (telmisartan), combinations with dihydropyridine derivatives (amlodipine). ATC Code: C09DB04.
Pharmacology: Mode of action: Telmisartan + Amlodipine besilate (TWYNSTA) combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridinic calcium channel blocker, amlodipine.
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Telmisartan + Amlodipine besilate (TWYNSTA) once daily produces effective and consistent reductions in blood pressure across the 24-hour therapeutic dose range.
Telmisartan: Telmisartan is an orally effective and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity 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 AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan.
Plasma aldosterone levels are 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 also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects.
In man, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
Pharmacodynamics: Telmisartan: 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 weeks after the start of treatment and is sustained during long-term therapy. The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements.
This is confirmed by trough to peak ratios consistently above 80 % seen after doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respect data concerning DBP are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate.
The antihypertensive efficacy of telmisartan is comparable to that of agents representative of other classes of antihypertensive drugs (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan). Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in Left Ventricular Mass and Left Ventricular Mass Index in patients with hypertension and Left Ventricular Hypertrophy.
Telmisartan treatment has been shown in clinical trials (including comparators like losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Amlodipine: In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.
Clinical Trials: Telmisartan Prevention of cardiovascular morbidity and mortality: ONTARGET (ONgoin Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25620 patients aged 55 years or older with a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end-organ damage (e.g. retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high risk patients.
Patients were randomized to one of the three following treatment groups: telmisartan 80 mg (n=8542), ramipril 10 mg (n=8576), or the combination of telmisartan 80 mg plus ramipril 10 mg (n=8502), and followed for a mean observation time of 4.5 years. The population studied was 73 % male, 74 % Caucasian, 14 % Asian and 43 % were 65 years of age or older.
Hypertension was present in nearly 83 % of randomized patients: 69 % of patients had a history of hypertension at randomization and an additional 14 % had actual blood pressure readings above 140/90 mm Hg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76 %), statins (62 %), beta-blockers (57 %), calcium channel blockers (34 %), nitrates (29 %) and diuretics (28 %).
The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure.
Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an ACE-inhibitor. The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.
Telmisartan had similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the telmisartan (16.7 %), ramipril (16.5 %) and telmisartan plus ramipril combination (16.3 %) arms. The hazard ratio for telmisartan vs. ramipril was 1.01 (97.5 % CI 0.93 -1.10, p (non-inferiority) = 0.0019). The treatment effect was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.
Telmisartan was also found to be similarly effective to ramipril in several pre-specified secondary endpoints, including a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, the primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which had investigated the effect of ramipril vs. placebo. The hazard ratio of telmisartan vs. ramipril for this endpoint in ONTARGET was 0.99 (97.5 % CI 0.90 -1.08, p (noninferiority) = 0.0004).
Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.
Amlodipine: Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable 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 failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk 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 III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Fixed dose combination (Telmisartan + Amlodipine besilate (TWYNSTA)): In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study 1461 patients with mild to severe hypertension (mean seated diastolic blood pressure ≥95 and <110 mmHg) underwent a 3-4 week placebo run-in period in order to wash out all antihypertensive medications before they were randomised to a double-blind active treatment. Treatment with each combination dose of Telmisartan + Amlodipine besilate (TWYNSTA) resulted in significantly greater diastolic and systolic blood pressure reductions and higher control rates compared to the respective monotherapy components.
The telmisartan/amlodipine combinations showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic dose range: (See Table 1.)

The proportions of patients reaching a diastolic blood pressure <90 mmHg with a telmisartan/amlodipine combination were: (See Table 2.)

A subset of 1050 patients in the factorial design study had moderate to severe hypertension (DBP ≥100 mmHg). In these patients who are likely to need more than one antihypertensive agent to achieve blood pressure goal, the observed mean changes in systolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg (-22.2/-17.2 mmHg with 40/5 mg; -22.5/-19.1 mmHg with 80/5 mg) were comparable to or greater than those seen with amlodipine 10 mg (-21.0/-17.6 mmHg). Additionally, combination therapy showed notably lower oedema rates (1.4% with 40/5 mg; 0.5% with 80/5 mg; 17.6% with amlodipine 10 mg).
The majority of the antihypertensive effect was attained within 2 weeks after initiation of therapy.
Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patients confirmed the results seen with in-clinic systolic and diastolic blood pressure reductions consistently over the entire 24-hours dosing period.
In a further multicentre, double-blind, active-controlled study, a total of 1097 patients with mild to severe hypertension who were not adequately controlled on amlodipine 5 mg received Telmisartan + Amlodipine besilate (TWYNSTA) (40/5 mg or 80/5 mg) or amlodipine alone (5 mg or 10 mg). After 8 weeks of treatment, each of the combination was statistically significantly superior to both amlodipine monotherapy doses in reducing systolic and diastolic blood pressures: (See Table 3.)

The proportions of patients with normalisation of blood pressure (trough seated diastolic blood pressure <90 mmHg at the end of the trial) were 56.7% with Telmisartan + Amlodipine besilate (TWYNSTA) 40/5 mg and 63.8% with Telmisartan + Amlodipine besilate (TWYNSTA) 80/5 mg compared to 42.0% with amlodipine 5 mg and 56.7% with amlodipine 10 mg.
Oedema related events (peripheral oedema, generalised oedema, and oedema) were significantly lower in patients who received Telmisartan + Amlodipine besilate (TWYNSTA) (40/5 mg or 80/5 mg) as compared to patients who received amlodipine 10 mg (4.4% vs. 24.9%, respectively).
In another multicentre, double-blind, active-controlled study, a total of 947 patients with mild to severe hypertension who were not adequately controlled on amlodipine 10 mg received Telmisartan + Amlodipine besilate (TWYNSTA) (40/10 mg or 80/10 mg) or amlodipine alone (10 mg). After 8 weeks, each of the combination treatments was statistically significantly superior to amlodipine monotherapy in reducing diastolic and systolic blood pressures: (See Table 4.)

The proportions of patients with normalisation of blood pressure (trough seated diastolic blood pressure <90 mmHg at the end of the trial) were 63.7% with Telmisartan + Amlodipine besilate (TWYNSTA) 40/10 mg and 66.5% with Telmisartan + Amlodipine besilate (TWYNSTA) 80/10 mg compared to 51.1% with amlodipine 10 mg.
In two corresponding open-label long-term follow up studies performed over a further 6 months the effect of Telmisartan + Amlodipine besilate (TWYNSTA) was maintained over the trial period.
In patients not adequately controlled on amlodipine 5 mg, Telmisartan + Amlodipine besilate (TWYNSTA) achieved similar (40/5 mg) or better (80/5mg) blood pressure control compared to amlodipine 10 mg with significantly less oedema.
In patients adequately controlled on amlodipine 10 mg but who experience unacceptable oedema, Telmisartan + Amlodipine besilate (TWYNSTA) 40/5 mg or 80/5 mg may achieve similar blood pressure control with less oedema.
The antihypertensive effect of Telmisartan + Amlodipine besilate (TWYNSTA) was similar irrespective of age and gender, and was similar in patients with and without diabetes.
Telmisartan + Amlodipine besilate (TWYNSTA) has not been studied in any patient population other than hypertension. Telmisartan has been studied 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 and angiographically documented coronary artery disease.
Pharmacokinetics: Pharmacokinetics of the Fixed Dose Combination: The rate and extent of absorption of Telmisartan + Amlodipine besilate (TWYNSTA) are equivalent to the bioavailability of telmisartan and amlodipine when administered as individual tablets.
Pharmacokinetic of the single components: Absorption: Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%.
When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration plasma concentrations are similar whether telmisartan is taken fasting or with food.
The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy.
After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid glycoprotein. The mean steady state apparent volume of distribution (Vss) is approximately 500 L.
The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins in hypertensive patients.
Metabolism: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Amlodipine is extensively (approximatively 90%) metabolised by the liver to inactive metabolites.
Elimination: Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (C_max) and, to a smaller extent, area under the plasma concentration-time curve (AUC) increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan. After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose. Total plasma clearance (CL_tot) is high (approximately 900 mL/min compared with hepatic blood flow (about 1500 mL/min).
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. 10% of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Paediatric population (age below 18 years): No pharmacokinetic data are available in the paediatric population.
Gender effects: Gender differences in plasma concentrations of telmisartan were observed, C_max and AUC being approximately 3-and 2-fold higher, respectively, in females compared to males without relevant influence on efficacy.
Elderly: The pharmacokinetics of telmisartan do not differ between younger and elderly patients. Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life.
Renal impairment: Lower plasma concentrations of telmisartan were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC.
Toxicology: Since the non-clinical toxicity profiles of telmisartan and amlodipine besilate are not overlapping, no exacerbation of toxicity was expected for the combination.
This has been shown 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 and amlodipine besilate were tested. In this study no additive or greater than additive adverse effects of amlodipine and telmisartan in combination as well as no change of the toxicity profile with regard to target organs were observed.
With respect to Telmisartan + Amlodipine besilate (TWYNSTA), separate reproductive toxicity studies assessing the potential effects of telmisartan and amlodipine on male and female fertility when both compounds are given in combination, have not been conducted.
Non-clinical data available for the components of this fixed dose combination are reported as follows.
Telmisartan: In non-clinical safety studies doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit) and changes in renal haemodynamics (increased blood urea nitrogen and creatinine), as well as increased serum potassium in normotensive 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 mediated side effects, known from non-clinical studies with both angiotensin converting enzyme inhibitors and angiotensin II antagonists, were prevented by oral saline supplementation.
In both species increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of ACE-inhibitors and other angiotensin II antagonists, do not appear to have clinical significance.
No clear evidence of a teratogenic effect was observed; at toxic doses levels, however, non-clinical studies indicated some hazardous potential of telmisartan to fetal development (increased number of late resorptions in rabbits) and to the postnatal development of the offspring: lower body weight, delayed eye opening, and higher mortality.
No effects of telmisartan on male and female fertility were observed.
There was no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Amlodipine: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproductive toxicity studies in rats, delayed parturition, difficult labour and impaired fetal and pup survival were seen at high doses. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).
No effects of amlodipine on male and female fertility were observed.