ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
TWYNSTA 40 mg/5 mg tablets
2.
Each tablet contains 40 mg telmisartan and 5 mg amlodipine (as amlodipine besilate).
Excipient(s): Each tablet contains 168.64 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet
Blue and white oval shaped two layer tablet engraved with the product code A1.
4.
Treatment of essential hypertension in adults:
Add on therapy
TWYNSTA is indicated in adults whose blood pressure is not adequately controlled on amlodipine.
Replacement therapy
Adult patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses.
Posology
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 for long term treatment.
Add on therapy
TWYNSTA 40 mg/5 mg tablets may be administered in patients whose blood pressure is not
adequately controlled with amlodipine 5 mg alone.
Individual dose titration with the components (i.e. amlodipine and telmisartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed combination may be considered.
Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such as
oedema, may be switched to TWYNSTA 40 mg/5 mg once daily, reducing the dose of amlodipine
without reducing the overall expected antihypertensive response.
2
Replacement therapy
Patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses in one tablet once daily, e.g. to enhance
convenience or compliance
Special population
Elderly
No dose adjustment is necessary for elderly patients. Little information is available in the very elderly
patients.
Renal impairment (see also section 4.4)
No posology adjustment is required for patients with mild to moderate renal impairment. Limited
experience is available in patients with severe renal impairment or haemodialysis. Caution is advised
when using TWYNSTA in such patients as amlodipine and telmisartan are not dialysable.
Hepatic impairment
In patients with mild to moderate hepatic impairment TWYNSTA should be administered with
caution. For telmisartan the posology should not exceed 40 mg once daily (see section 4.4).
TWYNSTA is contraindicated in patients with severe hepatic impairment (see section 4.3).
Paediatric population
The safety and efficacy of TWYNSTA in children aged below 18 years have not been established. No
data are available.
Methods of administration
TWYNSTA can be taken with or without food. It is recommended to take TWYNSTA with some
liquid.
•
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the
excipients (see 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)
•
Severe hypotension
•
Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)
•
Haemodynamically unstable heart failure after acute myocardial infarction
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see section 4.3 and
4.6).
Hepatic impairment
Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic
insufficiency can be expected to have reduced clearance. Furthermore as with all calcium antagonists,
amlodipine half-life is prolonged in patients with impaired liver function and dose recommendations
have not been established. TWYNSTA should therefore be used with caution in these patients.
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.
Renal impairment and kidney transplantation
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 and amlodipine are not dialysable.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or
sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such
conditions should be corrected before the administration of telmisartan. If hypotension occurs with
TWYNSTA, the patient should be placed in the supine position and, if necessary, given an intravenous
infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
Dual blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, hypotension and changes in
renal function (including acute renal failure) have been reported in susceptible individuals, especially
if combining medicinal products that affect this system. TWYNSTA can be administered with other
antihypertensive medicinal products, however dual blockade of the renin-angiotensin-aldosterone
system (e.g. by adding an angiotensin converting enzyme (ACE)-inhibitor to an angiotensin II receptor
antagonist) is not recommended in patients with already controlled blood pressure and should
therefore be limited to individually defined cases with close monitoring of renal function.
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 medicinal products that affect this system has
been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see
section 4.8).
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 telmisartan is not
recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
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 TWYNSTA in unstable angina pectoris and during or within
one month of a myocardial infarction.
Heart failure
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV
heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of
pulmonary oedema despite no significant difference in the incidence of worsening heart failure as
compared to placebo (see section 5.1).
4
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in
diabetic patients, in patients concomitantly treated with other medicinal products that may increase
potassium levels, and/or in patients with intercurrent events,.
Before considering the concomitant use of medicinal products that affect the renin-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 the renin-angiotensin-
aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes of
medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal
anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.
-
Intercurrent events, in particular dehydratation, 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, extend trauma).
Serum potassium should be monitored closely in these patients (see section 4.5).
Sorbitol
This medicinal product contains sorbitol (E420). Patients with rare hereditary problems of fructose
intolerance should not take TWYNSTA.
Other
As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with
ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction
or stroke.
No interactions between the two components of this fixed dose combinations have been observed in
clinical studies.
Interactions common to the combination
No drugs interaction studies have been performed.
To be taken into account with concomitant use
Other antihypertensive medicinal products
The blood pressure lowering effect of TWYNSTA can be increased by concomitant use of other
antihypertensive medicinal products.
Medicinal products 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 all antihypertensives including TWYNSTA, e.g. baclofen,
amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated
by alcohol.
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
5
Interactions linked to telmisartan
Concomitant use not recommended
Potassium sparing diuretics or potassium supplements
Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss.
Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium
supplements, or potassium-containing salt substitutes may lead to a significant increase in serum
potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used
with caution and with frequent monitoring of serum potassium.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with
angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary,
careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Non-steroidal anti-inflammatory medicinal products
NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-
selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with
compromised renal function), the co-administration of angiotensin II receptor antagonists and
medicinal products that inhibit cyclo-oxygenase may result in further deterioration of renal function,
including possible acute renal failure, which is usually reversible. Therefore, the combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring of renal function after initiation of concomitant therapy
and periodically thereafter.
Ramipril
In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the
AUC
0-24
and C
max
of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Interactions linked to amlodipine
Concomitant use requiring caution
CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients
and diltiazem in elderly patients respectively, the plasma concentration of amlodipine increased by
22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be
ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the
plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used
with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such
interaction have been reported.
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine.
The concomitant use of CYP3A4 inducers (i.e. rifampicin,
Hypericum perforatum
) may lead to a
lower plasma concentration of amlodipine.
Concomitant use to be taken into account
Others
Amlodipine has been safely administered with digoxin, warfarin, atorvastatin, sildenafil, anti-acid
medicinal products (aluminium hydroxide, magnesium hydroxide, simeticone), cimetidine,
6
ciclosporin, antibiotics and oral hypoglycaemic medicinal products. When amlodipine and sildenafil
were used in combination, each agent independently exerted its own blood pressure lowering effect.
Additional information
Concomitant administration of 240 ml of grapefruit juice with a single oral dose of 10 mg amlodipine
in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of
amlodipine.
Pregnancy
There are no adequate data from the use of TWYNSTA in pregnant women. Animal reproductive
toxicity studies with TWYNSTA have not been performed.
Telmisartan
The use of angiotensin II receptor antagonists is not recommended during the first trimester of
pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during
the second and third 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 inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II
receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy 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) (see section 5.3).
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 (see sections 4.3 and 4.4).
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.
Breastfeeding
Because no information is available regarding the use of telmisartan and/or amlodipine during
breastfeeding, TWYNSTA is not recommended and alternative treatments with better established
safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or
preterm infant.
7
Fertility
Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been
observed for calcium channel blockers in preclinical and
in vitro
studies. No clinical relevance has
been established.
No studies on the effects on the ability to drive and use machines have been performed. However,
patients should be advised that they may experience adverse reactions such as syncope, somnolence,
dizziness, or vertigo during treatment (see section 4.8). Therefore, caution should be recommended
when driving a car or using machines. If patients experience these adverse reactions, they should avoid
potentially hazardous tasks such as driving or using machines.
Fixed dose combination
The most common adverse reactions include dizziness and peripheral oedema. Serious syncope may
occur rarely (less than 1 case per 1,000 patients).
The safety and tolerability of TWYNSTA has been evaluated in five controlled clinical studies with
over 3500 patients, over 2500 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.
8
System Organ
Class
Common
Uncommon
Rare
Infections and
infestations
cystitis
Psychiatric disorders
depression,
anxiety,
insomnia
Nervous system
disorders
dizziness
somnolence,
migraine,
headache paraesthesia
syncope,
peripheral neuropathy,
hypoaesthesia,
dysgeusia,
tremor
Ear and labyrinth
disorders
vertigo
Cardiac disorders
bradycardia,
palpitations
Vascular disorders
hypotension,
orthostatic
hypotension, flushing
Respiratory, thoracic
and mediastinal
disorders
cough
Gastro-intestinal
disorders
abdominal pain,
diarrhoea,
nausea
vomiting,
gingival hypertrophy,
dyspepsia,
dry mouth
Skin and subcutaneous
tissue disorders
pruritus
eczema, erythema,
rash
Musculoskeletal and
connective tissue
disorders
arthralgia,
muscle spasms
(cramps in legs),
myalgia
back pain,
pain in extremity (leg
pain)
Renal and urinary
disorders
nocturia
Reproductive system,
and breast disorders
erectile dysfunction
General disorders and
administration site
conditions
peripheral oedema
asthenia,
chest pain, fatigue,
oedema
malaise
Investigations
hepatic enzymes
increased
blood uric acid
increased
Additional information on individual components
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 during the post-marketing period.
Telmisartan
Infections and infestations
Uncommon:
Upper respiratory tract infection including pharyngitis and
sinusitis, urinary tract infection including cystitis
9
Rare: Sepsis including fatal outcome
1
Blood and lymphatic system disorders
Uncommon:
Anaemia
Rare:
Thrombocytopenia, eosinophilia
Immune system disorders
Rare: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon:
Hyperkalaemia
Eye disorders
Rare: Visual disturbance
Cardiac disorders
Rare: Tachycardia
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea
Gastrointestinal disorders
Uncommon:
Flatulence
Stomach discomfort
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal, liver disorder
Skin and subcutaneous tissue disorders
Uncommon:
Hyperhidrosis
Angioedema, drug eruption, toxic skin eruption, urticaria
Rare:
Muscoloskeletal and connective tissue disorders
Rare:
Tendon pain (tendinitis like symptoms)
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Rare:
Influenza-like illness
Investigations
Uncommon:
Blood creatinine increased
Blood creatine phosphokinase increased, haemoglobin decreased
1
: the event may be a chance finding or related to a mechanism currently not known
Amlodipine
Blood and lymphatic system disorders
Very rare:
Leukocytopenia, thrombocytopenia
Immune system disorders
Very rare:
Hypersensitivity
Metabolism and nutrition disorders
10
Rare:
Very rare:
Hyperglycaemia
Psychiatric disorders
Uncommon:
Mood change
Rare:
Confusion
Nervous system disorders
Uncommon:
Paraesthesia
Very rare:
Peripheral neuropathy, extrapyramidal syndrome
Eye disorders
Uncommon:
Visual impairment
Ear and labyrinth disorders
Uncommon:
Tinnitus
Cardiac disorders
Very rare:
Myocardial infarction, arrhythmia, ventricular tachycardia, atrial
fibrillation
Vascular disorders
Very rare:
Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea, rhinitis
Gastrointestinal disorders
Uncommon:
Change of bowel habit
Very rare:
Pancreatitis, gastritis
Hepatobiliary disorders
Very rare:
Hepatitis, jaundice, hepatic enzyme elevations (mostly consistent
with cholestasis
Skin and subcutaneous tissue disorders
Uncommon:
Alopecia, purpura, skin discolouration, hyperhidrosis
Very rare:
Angioedema, erythema multiforme, urticaria, exfoliative dermatitis,
Stevens-Johnson syndrome, photosensitivity
Renal and urinary disorders
Uncommon:
Micturition disorder, pollakiuria
Reproductive system and breast disorders
Uncommon:
Gynaecomastia
General disorders and administration site conditions
Uncommon:
Pain
Investigations
Uncommon:
Weight increased, weight decreased
11
Symptoms
: Signs and symptoms of overdose are expected to be in line with exaggerated
pharmacological effects. The most 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.
tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with
fatal outcome have been reported.
Treatment:
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 measures include induction of emesis and / or gastric lavage. Activated charcoal may be
useful in the treatment of overdose of both telmisartan and amlodipine.
Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient
should be placed in a supine position with elevation of extremities, with salt and volume replacement
given quickly. Supportive treatment should be instituted. Intravenous calcium gluconate may be
beneficial in reversing the effects of calcium channel blockade. Telmisartan and Amlodipine are not
removed by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists
and calcium channel blockers; ATC Code: C09DB04.
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.
TWYNSTA once daily produces effective and consistent reductions in blood pressure across the 24-
hour therapeutic dose range.
Telmisartan
Telmisartan is an orally active and specific angiotensin II receptor (type AT
1
) antagonist. Telmisartan
displaces angiotensin II with very high affinity from its binding site at the AT
1
receptor subtype,
which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial
agonist activity at the AT
1
receptor. Telmisartan selectively binds the AT
1
receptor. The binding is
long-lasting. Telmisartan does not show affinity for other receptors, including AT
2
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 reactions.
In human, 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.
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
treatment and is sustained during long-term therapy.
12
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 systolic blood pressure (SBP). In this respect data concerning diastolic blood
pressure (DBP) are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its
hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable
to that of substances representative of other classes of antihypertensive medicinal products
(demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril,
hydrochlorothiazide, and lisinopril).
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.
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
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.
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.
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.
13
Telmisartan/Amlodipine
In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study
in 1461 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
diastolic and systolic blood pressure reductions and higher control rates compared to the respective
monotherapy components.
TWYNSTA showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic
dose range of
−
21.8/
−
16.5 mmHg (40 mg/5 mg),
−
22.1/
−
18.2 mmHg (80 mg/5 mg),
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 adjusted for baseline and country.
24.7/
−
20.2 mmHg (40 mg/10 mg) and
−
26.4/
−
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 in systolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg
(
−
22.2/
−
17.2 mmHg with 40 mg/5 mg;
−
22.5/
−
17.6 mmHg) and associated with significant
lower oedema rates (1.4% with 40 mg/5 mg; 0.5% with 80 mg/5 mg; 17.6% with amlodipine 10 mg).
−
21.0/
−
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, randomised, double-blind, active-controlled, parallel group study, a total of
1097 patients with mild to severe hypertension who were not adequately controlled on amlodipine 5
mg received TWYNSTA (40 mg/5 mg or 80 mg/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 (
−
13.6/
−
9.4 mmHg,
8.0 mmHg with
amlodipine 5 mg and 10 mg and higher diastolic blood pressure control rates compared to the
respective monotherapies 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 and 80 mg/5 mg compared to amlodipine 10 mg (4.4% versus 24.9%, respectively).
15.0/
−
10.6 mmHg with 40 mg/5 mg, 80 mg/5 mg versus
−
6.2/
−
5.7 mmHg,
−
11.1/
−
In another multicentre, randomised, double-blind, active-controlled, parallel group study, a total of
947 patients with mild to severe hypertension who were not adequately controlled on amlodipine
10 mg received TWYNSTA (40 mg/10 mg or 80 mg/10 mg) or amlodipine alone (10 mg). After 8
weeks of treatment, each of the combination treatments was statistically significantly superior to
amlodipine monotherapy in reducing diastolic and systolic blood pressures (
−
11.1/
−
9.2 mmHg,
−
11.3/
6.5 mmHg with amlodipine 10 mg) and
higher diastolic blood pressure normalisation rates compared to monotherapy were achieved (63.7%,
66.5% with 40 mg/10 mg, 80 mg/10 mg versus 51.1% with amlodipine 10 mg).
9.3 mmHg with 40 mg/10 mg, 80 mg/10 mg versus
−
7.4/
−
In two corresponding open-label long-term follow up studies performed over a further 6 months the
effect of TWYNSTA was maintained over the trial period. Furthermore it was shown that some
patients not adequately controlled with TWYNSTA 40 mg/10 mg had additional blood pressure
reduction by up-titration to TWYNSTA 80 mg/10 mg.
The overall incidence of adverse reactions with TWYNSTA in the clinical trial programme was low
with only 12.7% of patients on treatment experiencing adverse reactions. The most common adverse
reactions were peripheral oedema and dizziness, see also section 4.8. The adverse reactions reported
were in agreement 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
14
−
19.1 mmHg with 80 mg/5 mg) were comparable to or
greater than those seen with amlodipine 10 mg (
−
−
received TWYNSTA as compared to 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% for 40 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
in patients with and without diabetes.
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.
The European Medicines Agency has waived the obligation to submit the results of studies with
TWYNSTA in all subsets of the paediatric population in hypertension (see section 4.2 for information
on paediatric use).
5.2 Pharmacokinetic properties
Pharmacokinetic of the fixed dose combination (FDC)
The rate and extent of absorption of TWYNSTA are equivalent to the bioavailability of telmisartan
and amlodipine when administered as individual tablets.
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
0-∞
) 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.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels
between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
Amlodipine bioavailability is not affected by food ingestion.
Linearity/non-linearity
The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeutic
efficacy. There is no linear relationship between doses and plasma levels. C
max
and to a lesser extent
AUC increase disproportionately at doses above 40 mg.
Amlodipine exhibits linear pharmacokinetics.
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 (V
dss
) is approximately 500 l.
The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown that
approximately 97.5% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Biotransformation
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
15
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, the area
under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no
evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma
concentrations were 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 (Cl
tot
) 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
approximately 30 to 50 hours consistent with once daily dosing. Steady-state plasma levels are
reached after continuous administration for 7–8 days. Ten per cent of original amlodipine and 60% of
amlodipine metabolites are excreted in urine.
Special populations
Paediatric population (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
Gender effects
Differences in plasma concentrations of telmisartan were observed, with C
max
and AUC being
approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly patients
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.
In elderly patients, amlodipine clearance tends to decline with resulting increases in AUC and
elimination half-life.
Patients with renal impairment
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of
telmisartan was observed. However, lower plasma concentrations 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.
Patients with 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 of telmisartan 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.
5.3 Preclinical safety data
Since the non-clinical toxicity profiles of telmisartan and amlodipine are not overlapping, no
exacerbation of 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 and amlodipine were tested.
Preclinical data available for the components of this fixed dose combination are reported below.
16
Telmisartan
: In preclinical safety studies, doses producing exposure comparable to that in the clinical
therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit),
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 undesirable effects, known from preclinical studies with both angiotensin
converting enzyme inhibitors and angiotensin II receptor 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 angiotensin converting
enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical
significance.
There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential of
telmisartan to the postnatal development of the offspring such as lower body weight, delayed eye
opening, and higher mortality.
There was no evidence of mutagenicity and relevant clastogenic activity in
in vitro
studies and no
evidence of carcinogenicity in rats and mice.
Amlodipine:
Preclinical 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 Maximum Recommended Human Dose of 10 mg/day on
an mg/m
2
basis).
6.
6.1 List of excipients
Colloidal anhydrous silica
Brilliant blue FCF (E 133)
Ferric oxide black (E172)
Ferric oxide yellow (E172)
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone K25
Pregelatinised starch
Sodium hydroxide
Sorbitol (E420)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light and moisture.
17
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al) in a carton containing 14, 28, 56, 98 tablets or
aluminium/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.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
18
1.
TWYNSTA 40 mg/10 mg tablets
2.
Each tablet contains 40 mg telmisartan and 10 mg amlodipine (as amlodipine besilate).
Excipient(s): Each tablet contains 168.64 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet
Blue and white oval shaped two layer tablet engraved with the product code A2.
4.
Treatment of essential hypertension in adults:
Add on therapy
TWYNSTA is indicated in adults whose blood pressure is not adequately controlled on amlodipine.
Replacement therapy
Adult patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses.
Posology
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 for long term treatment.
Add on therapy
TWYNSTA 40 mg/10 mg may be administered in patients whose blood pressure is not adequately
controlled with amlodipine 10 mg.
Individual dose titration with the components (i.e. amlodipine and telmisartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed combination may be considered.
Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such as
oedema, may be switched to TWYNSTA 40 mg/5 mg once daily, reducing the dose of amlodipine
without reducing the overall expected antihypertensive response.
19
Replacement therapy
Patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses in one tablet once daily, e.g. to enhance
convenience or compliance
Special population
Elderly
No dose adjustment is necessary for elderly patients. Little information is available in the very elderly
patients.
Renal impairment (see also section 4.4)
No posology adjustment is required for patients with mild to moderate renal impairment. Limited
experience is available in patients with severe renal impairment or haemodialysis. Caution is advised
when using TWYNSTA in such patients as amlodipine and telmisartan are not dialysable.
Hepatic impairment
In patients with mild to moderate hepatic impairment TWYNSTA should be administered with
caution. For telmisartan the posology should not exceed 40 mg once daily (see section 4.4).
TWYNSTA is contraindicated in patients with severe hepatic impairment (see section 4.3).
Paediatric population
The safety and efficacy of TWYNSTA in children aged below 18 years have not been established. No
data are available.
Methods of administration
TWYNSTA can be taken with or without food. It is recommended to take TWYNSTA with some
liquid.
•
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the
excipients (see 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)
•
Severe hypotension
•
Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)
•
Haemodynamically unstable heart failure after acute myocardial infarction
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see section 4.3 and
4.6).
Hepatic impairment
Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic
insufficiency can be expected to have reduced clearance. Furthermore as with all calcium antagonists,
amlodipine half-life is prolonged in patients with impaired liver function and dose recommendations
have not been established. TWYNSTA should therefore be used with caution in these patients.
20
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.
Renal impairment and kidney transplantation
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 and amlodipine are not dialysable.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or
sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such
conditions should be corrected before the administration of telmisartan. If hypotension occurs with
TWYNSTA, the patient should be placed in the supine position and, if necessary, given an intravenous
infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
Dual blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, hypotension and changes in
renal function (including acute renal failure) have been reported in susceptible individuals, especially
if combining medicinal products that affect this system. TWYNSTA can be administered with other
antihypertensive medicinal products, however dual blockade of the renin-angiotensin-aldosterone
system (e.g. by adding an angiotensin converting enzyme (ACE)-inhibitor to an angiotensin II receptor
antagonist) is not recommended in patients with already controlled blood pressure and should
therefore be limited to individually defined cases with close monitoring of renal function.
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 medicinal products that affect this system has
been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see
section 4.8).
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 telmisartan is not
recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
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 TWYNSTA in unstable angina pectoris and during or within
one month of a myocardial infarction.
Heart failure
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV
heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of
pulmonary oedema despite no significant difference in the incidence of worsening heart failure as
compared to placebo (see section 5.1).
21
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in
diabetic patients, in patients concomitantly treated with other medicinal products that may increase
potassium levels, and/or in patients with intercurrent events,.
Before considering the concomitant use of medicinal products that affect the renin-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 the renin-angiotensin-
aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes of
medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal
anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.
-
Intercurrent events, in particular dehydratation, 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, extend trauma).
Serum potassium should be monitored closely in these patients (see section 4.5).
Sorbitol
This medicinal product contains sorbitol (E420). Patients with rare hereditary problems of fructose
intolerance should not take TWYNSTA.
Other
As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with
ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction
or stroke.
No interactions between the two components of this fixed dose combinations have been observed in
clinical studies.
Interactions common to the combination
No drugs interaction studies have been performed.
To be taken into account with concomitant use
Other antihypertensive medicinal products
The blood pressure lowering effect of TWYNSTA can be increased by concomitant use of other
antihypertensive medicinal products.
Medicinal products 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 all antihypertensives including TWYNSTA, e.g. baclofen,
amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated
by alcohol.
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
22
Interactions linked to telmisartan
Concomitant use not recommended
Potassium sparing diuretics or potassium supplements
Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss.
Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium
supplements, or potassium-containing salt substitutes may lead to a significant increase in serum
potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used
with caution and with frequent monitoring of serum potassium.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with
angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary,
careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Non-steroidal anti-inflammatory medicinal products
NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-
selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with
compromised renal function), the co-administration of angiotensin II receptor antagonists and
medicinal products that inhibit cyclo-oxygenase may result in further deterioration of renal function,
including possible acute renal failure, which is usually reversible. Therefore, the combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring of renal function after initiation of concomitant therapy
and periodically thereafter.
Ramipril
In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the
AUC
0-24
and C
max
of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Interactions linked to amlodipine
Concomitant use requiring caution
CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients
and diltiazem in elderly patients respectively, the plasma concentration of amlodipine increased by
22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be
ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the
plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used
with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such
interaction have been reported.
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine.
The concomitant use of CYP3A4 inducers (i.e. rifampicin,
Hypericum perforatum
) may lead to a
lower plasma concentration of amlodipine.
Concomitant use to be taken into account
Others
Amlodipine has been safely administered with digoxin, warfarin, atorvastatin, sildenafil, anti-acid
medicinal products (aluminium hydroxide, magnesium hydroxide, simeticone), cimetidine,
23
ciclosporin, antibiotics and oral hypoglycaemic medicinal products. When amlodipine and sildenafil
were used in combination, each agent independently exerted its own blood pressure lowering effect.
Additional information
Concomitant administration of 240 ml of grapefruit juice with a single oral dose of 10 mg amlodipine
in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of
amlodipine.
Pregnancy
There are no adequate data from the use of TWYNSTA in pregnant women. Animal reproductive
toxicity studies with TWYNSTA have not been performed.
Telmisartan
The use of angiotensin II receptor antagonists is not recommended during the first trimester of
pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during
the second and third 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 inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II
receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy 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) (see section 5.3).
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 (see sections 4.3 and 4.4).
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.
Breastfeeding
Because no information is available regarding the use of telmisartan and/or amlodipine during
breastfeeding, TWYNSTA is not recommended and alternative treatments with better established
safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or
preterm infant.
24
Fertility
Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been
observed for calcium channel blockers in preclinical and
in vitro
studies. No clinical relevance has
been established.
No studies on the effects on the ability to drive and use machines have been performed. However,
patients should be advised that they may experience adverse reactions such as syncope, somnolence,
dizziness, or vertigo during treatment (see section 4.8). Therefore, caution should be recommended
when driving a car or using machines. If patients experience these adverse reactions, they should avoid
potentially hazardous tasks such as driving or using machines.
Fixed dose combination
The most common adverse reactions include dizziness and peripheral oedema. Serious syncope may
occur rarely (less than 1 case per 1,000 patients).
The safety and tolerability of TWYNSTA has been evaluated in five controlled clinical studies with
over 3500 patients, over 2500 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.
25
System Organ
Class
Common
Uncommon
Rare
Infections and
infestations
cystitis
Psychiatric disorders
depression,
anxiety,
insomnia
Nervous system
disorders
dizziness
somnolence,
migraine,
headache paraesthesia
syncope,
peripheral neuropathy,
hypoaesthesia,
dysgeusia,
tremor
Ear and labyrinth
disorders
vertigo
Cardiac disorders
bradycardia,
palpitations
Vascular disorders
hypotension,
orthostatic
hypotension, flushing
Respiratory, thoracic
and mediastinal
disorders
cough
Gastro-intestinal
disorders
abdominal pain,
diarrhoea,
nausea
vomiting,
gingival hypertrophy,
dyspepsia,
dry mouth
Skin and subcutaneous
tissue disorders
pruritus
eczema, erythema,
rash
Musculoskeletal and
connective tissue
disorders
arthralgia,
muscle spasms
(cramps in legs),
myalgia
back pain,
pain in extremity (leg
pain)
Renal and urinary
disorders
nocturia
Reproductive system,
and breast disorders
erectile dysfunction
General disorders and
administration site
conditions
peripheral oedema
asthenia,
chest pain, fatigue,
oedema
malaise
Investigations
hepatic enzymes
increased
blood uric acid
increased
Additional information on individual components
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 during the post-marketing period.
Telmisartan
Infections and infestations
Uncommon:
Upper respiratory tract infection including pharyngitis and
sinusitis, urinary tract infection including cystitis
26
Rare: Sepsis including fatal outcome
1
Blood and lymphatic system disorders
Uncommon:
Anaemia
Rare:
Thrombocytopenia, eosinophilia
Immune system disorders
Rare: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon:
Hyperkalaemia
Eye disorders
Rare: Visual disturbance
Cardiac disorders
Rare: Tachycardia
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea
Gastrointestinal disorders
Uncommon:
Flatulence
Stomach discomfort
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal, liver disorder
Skin and subcutaneous tissue disorders
Uncommon:
Hyperhidrosis
Angioedema, drug eruption, toxic skin eruption, urticaria
Rare:
Muscoloskeletal and connective tissue disorders
Rare:
Tendon pain (tendinitis like symptoms)
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Rare:
Influenza-like illness
Investigations
Uncommon:
Blood creatinine increased
Blood creatine phosphokinase increased, haemoglobin decreased
1
: the event may be a chance finding or related to a mechanism currently not known
Amlodipine
Blood and lymphatic system disorders
Very rare:
Leukocytopenia, thrombocytopenia
Immune system disorders
Very rare:
Hypersensitivity
Metabolism and nutrition disorders
27
Rare:
Very rare:
Hyperglycaemia
Psychiatric disorders
Uncommon:
Mood change
Rare:
Confusion
Nervous system disorders
Uncommon:
Paraesthesia
Very rare:
Peripheral neuropathy, extrapyramidal syndrome
Eye disorders
Uncommon:
Visual impairment
Ear and labyrinth disorders
Uncommon:
Tinnitus
Cardiac disorders
Very rare:
Myocardial infarction, arrhythmia, ventricular tachycardia, atrial
fibrillation
Vascular disorders
Very rare:
Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea, rhinitis
Gastrointestinal disorders
Uncommon:
Change of bowel habit
Very rare:
Pancreatitis, gastritis
Hepatobiliary disorders
Very rare:
Hepatitis, jaundice, hepatic enzyme elevations (mostly consistent
with cholestasis
Skin and subcutaneous tissue disorders
Uncommon:
Alopecia, purpura, skin discolouration, hyperhidrosis
Very rare:
Angioedema, erythema multiforme, urticaria, exfoliative dermatitis,
Stevens-Johnson syndrome, photosensitivity
Renal and urinary disorders
Uncommon:
Micturition disorder, pollakiuria
Reproductive system and breast disorders
Uncommon:
Gynaecomastia
General disorders and administration site conditions
Uncommon:
Pain
Investigations
Uncommon:
Weight increased, weight decreased
28
Symptoms
: Signs and symptoms of overdose are expected to be in line with exaggerated
pharmacological effects. The most 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.
tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with
fatal outcome have been reported.
Treatment:
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 measures include induction of emesis and / or gastric lavage. Activated charcoal may be
useful in the treatment of overdose of both telmisartan and amlodipine.
Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient
should be placed in a supine position with elevation of extremities, with salt and volume replacement
given quickly. Supportive treatment should be instituted. Intravenous calcium gluconate may be
beneficial in reversing the effects of calcium channel blockade. Telmisartan and Amlodipine are not
removed by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists
and calcium channel blockers; ATC Code: C09DB04.
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.
TWYNSTA once daily produces effective and consistent reductions in blood pressure across the 24-
hour therapeutic dose range.
Telmisartan
Telmisartan is an orally active and specific angiotensin II receptor (type AT
1
) antagonist. Telmisartan
displaces angiotensin II with very high affinity from its binding site at the AT
1
receptor subtype,
which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial
agonist activity at the AT
1
receptor. Telmisartan selectively binds the AT
1
receptor. The binding is
long-lasting. Telmisartan does not show affinity for other receptors, including AT
2
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 reactions.
In human, 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.
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
treatment and is sustained during long-term therapy.
29
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 systolic blood pressure (SBP). In this respect data concerning diastolic blood
pressure (DBP) are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its
hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable
to that of substances representative of other classes of antihypertensive medicinal products
(demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril,
hydrochlorothiazide, and lisinopril).
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.
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
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.
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.
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.
30
Telmisartan/Amlodipine
In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study
in 1461 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
diastolic and systolic blood pressure reductions and higher control rates compared to the respective
monotherapy components.
TWYNSTA showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic
dose range of
−
21.8/
−
16.5 mmHg (40 mg/5 mg),
−
22.1/
−
18.2 mmHg (80 mg/5 mg),
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 adjusted for baseline and country.
24.7/
−
20.2 mmHg (40 mg/10 mg) and
−
26.4/
−
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 in systolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg
(
−
22.2/
−
17.2 mmHg with 40 mg/5 mg;
−
22.5/
−
17.6 mmHg) and associated with significant
lower oedema rates (1.4% with 40 mg/5 mg; 0.5% with 80 mg/5 mg; 17.6% with amlodipine 10 mg).
−
21.0/
−
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, randomised, double-blind, active-controlled, parallel group study, a total of
1097 patients with mild to severe hypertension who were not adequately controlled on amlodipine 5
mg received TWYNSTA (40 mg/5 mg or 80 mg/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 (
−
13.6/
−
9.4 mmHg,
8.0 mmHg with
amlodipine 5 mg and 10 mg and higher diastolic blood pressure control rates compared to the
respective monotherapies 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 and 80 mg/5 mg compared to amlodipine 10 mg (4.4% versus 24.9%, respectively).
15.0/
−
10.6 mmHg with 40 mg/5 mg, 80 mg/5 mg versus
−
6.2/
−
5.7 mmHg,
−
11.1/
−
In another multicentre, randomised, double-blind, active-controlled, parallel group study, a total of
947 patients with mild to severe hypertension who were not adequately controlled on amlodipine
10 mg received TWYNSTA (40 mg/10 mg or 80 mg/10 mg) or amlodipine alone (10 mg). After 8
weeks of treatment, each of the combination treatments was statistically significantly superior to
amlodipine monotherapy in reducing diastolic and systolic blood pressures (
−
11.1/
−
9.2 mmHg,
−
11.3/
6.5 mmHg with amlodipine 10 mg) and
higher diastolic blood pressure normalisation rates compared to monotherapy were achieved (63.7%,
66.5% with 40 mg/10 mg, 80 mg/10 mg versus 51.1% with amlodipine 10 mg).
9.3 mmHg with 40 mg/10 mg, 80 mg/10 mg versus
−
7.4/
−
In two corresponding open-label long-term follow up studies performed over a further 6 months the
effect of TWYNSTA was maintained over the trial period. Furthermore it was shown that some
patients not adequately controlled with TWYNSTA 40 mg/10 mg had additional blood pressure
reduction by up-titration to TWYNSTA 80 mg/10 mg.
The overall incidence of adverse reactions with TWYNSTA in the clinical trial programme was low
with only 12.7% of patients on treatment experiencing adverse reactions. The most common adverse
reactions were peripheral oedema and dizziness, see also section 4.8. The adverse reactions reported
were in agreement 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
31
−
19.1 mmHg with 80 mg/5 mg) were comparable to or
greater than those seen with amlodipine 10 mg (
−
−
received TWYNSTA as compared to 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% for 40 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
in patients with and without diabetes.
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.
The European Medicines Agency has waived the obligation to submit the results of studies with
TWYNSTA in all subsets of the paediatric population in hypertension (see section 4.2 for information
on paediatric use).
5.2 Pharmacokinetic properties
Pharmacokinetic of the fixed dose combination (FDC)
The rate and extent of absorption of TWYNSTA are equivalent to the bioavailability of telmisartan
and amlodipine when administered as individual tablets.
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
0-∞
) 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.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels
between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
Amlodipine bioavailability is not affected by food ingestion.
Linearity/non-linearity
The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeutic
efficacy. There is no linear relationship between doses and plasma levels. C
max
and to a lesser extent
AUC increase disproportionately at doses above 40 mg.
Amlodipine exhibits linear pharmacokinetics.
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 (V
dss
) is approximately 500 l.
The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown that
approximately 97.5% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Biotransformation
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
32
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, the area
under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no
evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma
concentrations were 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 (Cl
tot
) 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
approximately 30 to 50 hours consistent with once daily dosing. Steady-state plasma levels are
reached after continuous administration for 7–8 days. Ten per cent of original amlodipine and 60% of
amlodipine metabolites are excreted in urine.
Special populations
Paediatric population (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
Gender effects
Differences in plasma concentrations of telmisartan were observed, with C
max
and AUC being
approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly patients
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.
In elderly patients, amlodipine clearance tends to decline with resulting increases in AUC and
elimination half-life.
Patients with renal impairment
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of
telmisartan was observed. However, lower plasma concentrations 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.
Patients with 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 of telmisartan 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.
5.3 Preclinical safety data
Since the non-clinical toxicity profiles of telmisartan and amlodipine are not overlapping, no
exacerbation of 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 and amlodipine were tested.
Preclinical data available for the components of this fixed dose combination are reported below.
33
Telmisartan
: In preclinical safety studies, doses producing exposure comparable to that in the clinical
therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit),
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 undesirable effects, known from preclinical studies with both angiotensin
converting enzyme inhibitors and angiotensin II receptor 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 angiotensin converting
enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical
significance.
There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential of
telmisartan to the postnatal development of the offspring such as lower body weight, delayed eye
opening, and higher mortality.
There was no evidence of mutagenicity and relevant clastogenic activity in
in vitro
studies and no
evidence of carcinogenicity in rats and mice.
Amlodipine:
Preclinical 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 Maximum Recommended Human Dose of 10 mg/day on
an mg/m
2
basis).
6.
6.1 List of excipients
Colloidal anhydrous silica
Brilliant blue FCF (E 133)
Ferric oxide black (E172)
Ferric oxide yellow (E172)
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone K25
Pregelatinised starch
Sodium hydroxide
Sorbitol (E420)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light and moisture.
34
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al) in a carton containing 14, 28, 56, 98 tablets or
aluminium/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.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
35
1.
TWYNSTA 80 mg/5 mg tablets
2.
Each tablet contains 80 mg telmisartan and 5 mg amlodipine (as amlodipine besilate).
Excipient(s): Each tablet contains 337.28 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet
Blue and white oval shaped two layer tablet engraved with the product code A3.
4.
Treatment of essential hypertension in adults:
Add on therapy
TWYNSTA is indicated in adults whose blood pressure is not adequately controlled on amlodipine.
Replacement therapy
Adult patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses.
Posology
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 for long term treatment.
Add on therapy
TWYNSTA 80 mg/5 mg may be administered in patients whose blood pressure is not adequately
controlled with TWYNSTA 40 mg/5 mg.
Individual dose titration with the components (i.e. amlodipine and telmisartan) is recommended before
changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy
to the fixed combination may be considered.
Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such as
oedema, may be switched to TWYNSTA 40 mg/5 mg once daily, reducing the dose of amlodipine
without reducing the overall expected antihypertensive response.
36
Replacement therapy
Patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of
TWYNSTA containing the same component doses in one tablet once daily, e.g. to enhance
convenience or compliance
Special population
Elderly
No dose adjustment is necessary for elderly patients. Little information is available in the very elderly
patients.
Renal impairment (see also section 4.4)
No posology adjustment is required for patients with mild to moderate renal impairment. Limited
experience is available in patients with severe renal impairment or haemodialysis. Caution is advised
when using TWYNSTA in such patients as amlodipine and telmisartan are not dialysable.
Hepatic impairment
In patients with mild to moderate hepatic impairment TWYNSTA should be administered with
caution. For telmisartan the posology should not exceed 40 mg once daily (see section 4.4).
TWYNSTA is contraindicated in patients with severe hepatic impairment (see section 4.3).
Paediatric population
The safety and efficacy of TWYNSTA in children aged below 18 years have not been established. No
data are available.
Methods of administration
TWYNSTA can be taken with or without food. It is recommended to take TWYNSTA with some
liquid.
•
Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the
excipients (see 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)
•
Severe hypotension
•
Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)
•
Haemodynamically unstable heart failure after acute myocardial infarction
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see section 4.3 and
4.6).
Hepatic impairment
Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic
insufficiency can be expected to have reduced clearance. Furthermore as with all calcium antagonists,
amlodipine half-life is prolonged in patients with impaired liver function and dose recommendations
have not been established. TWYNSTA should therefore be used with caution in these patients.
37
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.
Renal impairment and kidney transplantation
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 and amlodipine are not dialysable.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or
sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such
conditions should be corrected before the administration of telmisartan. If hypotension occurs with
TWYNSTA, the patient should be placed in the supine position and, if necessary, given an intravenous
infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
Dual blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, hypotension and changes in
renal function (including acute renal failure) have been reported in susceptible individuals, especially
if combining medicinal products that affect this system. TWYNSTA can be administered with other
antihypertensive medicinal products, however dual blockade of the renin-angiotensin-aldosterone
system (e.g. by adding an angiotensin converting enzyme (ACE)-inhibitor to an angiotensin II receptor
antagonist) is not recommended in patients with already controlled blood pressure and should
therefore be limited to individually defined cases with close monitoring of renal function.
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 medicinal products that affect this system has
been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see
section 4.8).
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 telmisartan is not
recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
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 TWYNSTA in unstable angina pectoris and during or within
one month of a myocardial infarction.
Heart failure
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV
heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of
pulmonary oedema despite no significant difference in the incidence of worsening heart failure as
compared to placebo (see section 5.1).
38
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in
diabetic patients, in patients concomitantly treated with other medicinal products that may increase
potassium levels, and/or in patients with intercurrent events,.
Before considering the concomitant use of medicinal products that affect the renin-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 the renin-angiotensin-
aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes of
medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal
anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.
-
Intercurrent events, in particular dehydratation, 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, extend trauma).
Serum potassium should be monitored closely in these patients (see section 4.5).
Sorbitol
This medicinal product contains sorbitol (E420). Patients with rare hereditary problems of fructose
intolerance should not take TWYNSTA.
Other
As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with
ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction
or stroke.
No interactions between the two components of this fixed dose combinations have been observed in
clinical studies.
Interactions common to the combination
No drugs interaction studies have been performed.
To be taken into account with concomitant use
Other antihypertensive medicinal products
The blood pressure lowering effect of TWYNSTA can be increased by concomitant use of other
antihypertensive medicinal products.
Medicinal products 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 all antihypertensives including TWYNSTA, e.g. baclofen,
amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated
by alcohol.
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
39
Interactions linked to telmisartan
Concomitant use not recommended
Potassium sparing diuretics or potassium supplements
Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss.
Potassium sparing diuretics e.g. spirinolactone, eplerenone, triamterene, or amiloride, potassium
supplements, or potassium-containing salt substitutes may lead to a significant increase in serum
potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used
with caution and with frequent monitoring of serum potassium.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with
angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary,
careful monitoring of serum lithium levels is recommended.
Concomitant use requiring caution
Non-steroidal anti-inflammatory medicinal products
NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-
selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with
compromised renal function), the co-administration of angiotensin II receptor antagonists and
medicinal products that inhibit cyclo-oxygenase may result in further deterioration of renal function,
including possible acute renal failure, which is usually reversible. Therefore, the combination should
be administered with caution, especially in the elderly. Patients should be adequately hydrated and
consideration should be given to monitoring of renal function after initiation of concomitant therapy
and periodically thereafter.
Ramipril
In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the
AUC
0-24
and C
max
of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Interactions linked to amlodipine
Concomitant use requiring caution
CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients
and diltiazem in elderly patients respectively, the plasma concentration of amlodipine increased by
22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be
ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the
plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used
with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such
interaction have been reported.
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine.
The concomitant use of CYP3A4 inducers (i.e. rifampicin,
Hypericum perforatum
) may lead to a
lower plasma concentration of amlodipine.
Concomitant use to be taken into account
Others
Amlodipine has been safely administered with digoxin, warfarin, atorvastatin, sildenafil, anti-acid
medicinal products (aluminium hydroxide, magnesium hydroxide, simeticone), cimetidine,
40
ciclosporin, antibiotics and oral hypoglycaemic medicinal products. When amlodipine and sildenafil
were used in combination, each agent independently exerted its own blood pressure lowering effect.
Additional information
Concomitant administration of 240 ml of grapefruit juice with a single oral dose of 10 mg amlodipine
in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of
amlodipine.
Pregnancy
There are no adequate data from the use of TWYNSTA in pregnant women. Animal reproductive
toxicity studies with TWYNSTA have not been performed.
Telmisartan
The use of angiotensin II receptor antagonists is not recommended during the first trimester of
pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during
the second and third 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 inhibitors
during the first trimester of pregnancy has not been conclusive; however a small increase in risk
cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II
receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued
angiotensin II receptor antagonist therapy is considered essential, 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 angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy 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) (see section 5.3).
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 (see sections 4.3 and 4.4).
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.
Breastfeeding
Because no information is available regarding the use of telmisartan and/or amlodipine during
breastfeeding, TWYNSTA is not recommended and alternative treatments with better established
safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or
preterm infant.
41
Fertility
Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been
observed for calcium channel blockers in preclinical and
in vitro
studies. No clinical relevance has
been established.
No studies on the effects on the ability to drive and use machines have been performed. However,
patients should be advised that they may experience adverse reactions such as syncope, somnolence,
dizziness, or vertigo during treatment (see section 4.8). Therefore, caution should be recommended
when driving a car or using machines. If patients experience these adverse reactions, they should avoid
potentially hazardous tasks such as driving or using machines.
Fixed dose combination
The most common adverse reactions include dizziness and peripheral oedema. Serious syncope may
occur rarely (less than 1 case per 1,000 patients).
The safety and tolerability of TWYNSTA has been evaluated in five controlled clinical studies with
over 3500 patients, over 2500 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.
42
System Organ
Class
Common
Uncommon
Rare
Infections and
infestations
cystitis
Psychiatric disorders
depression,
anxiety,
insomnia
Nervous system
disorders
dizziness
somnolence,
migraine,
headache paraesthesia
syncope,
peripheral neuropathy,
hypoaesthesia,
dysgeusia,
tremor
Ear and labyrinth
disorders
vertigo
Cardiac disorders
bradycardia,
palpitations
Vascular disorders
hypotension,
orthostatic
hypotension, flushing
Respiratory, thoracic
and mediastinal
disorders
cough
Gastro-intestinal
disorders
abdominal pain,
diarrhoea,
nausea
vomiting,
gingival hypertrophy,
dyspepsia,
dry mouth
Skin and subcutaneous
tissue disorders
pruritus
eczema, erythema,
rash
Musculoskeletal and
connective tissue
disorders
arthralgia,
muscle spasms
(cramps in legs),
myalgia
back pain,
pain in extremity (leg
pain)
Renal and urinary
disorders
nocturia
Reproductive system,
and breast disorders
erectile dysfunction
General disorders and
administration site
conditions
peripheral oedema
asthenia,
chest pain, fatigue,
oedema
malaise
Investigations
hepatic enzymes
increased
blood uric acid
increased
Additional information on individual components
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 during the post-marketing period.
Telmisartan
Infections and infestations
Uncommon:
Upper respiratory tract infection including pharyngitis and
sinusitis, urinary tract infection including cystitis
43
Rare: Sepsis including fatal outcome
1
Blood and lymphatic system disorders
Uncommon:
Anaemia
Rare:
Thrombocytopenia, eosinophilia
Immune system disorders
Rare: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon:
Hyperkalaemia
Eye disorders
Rare: Visual disturbance
Cardiac disorders
Rare: Tachycardia
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea
Gastrointestinal disorders
Uncommon:
Flatulence
Stomach discomfort
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal, liver disorder
Skin and subcutaneous tissue disorders
Uncommon:
Hyperhidrosis
Angioedema, drug eruption, toxic skin eruption, urticaria
Rare:
Muscoloskeletal and connective tissue disorders
Rare:
Tendon pain (tendinitis like symptoms)
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Rare:
Influenza-like illness
Investigations
Uncommon:
Blood creatinine increased
Blood creatine phosphokinase increased, haemoglobin decreased
1
: the event may be a chance finding or related to a mechanism currently not known
Amlodipine
Blood and lymphatic system disorders
Very rare:
Leukocytopenia, thrombocytopenia
Immune system disorders
Very rare:
Hypersensitivity
Metabolism and nutrition disorders
44
Rare:
Very rare:
Hyperglycaemia
Psychiatric disorders
Uncommon:
Mood change
Rare:
Confusion
Nervous system disorders
Uncommon:
Paraesthesia
Very rare:
Peripheral neuropathy, extrapyramidal syndrome
Eye disorders
Uncommon:
Visual impairment
Ear and labyrinth disorders
Uncommon:
Tinnitus
Cardiac disorders
Very rare:
Myocardial infarction, arrhythmia, ventricular tachycardia, atrial
fibrillation
Vascular disorders
Very rare:
Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon:
Dyspnoea, rhinitis
Gastrointestinal disorders
Uncommon:
Change of bowel habit
Very rare:
Pancreatitis, gastritis
Hepatobiliary disorders
Very rare:
Hepatitis, jaundice, hepatic enzyme elevations (mostly consistent
with cholestasis
Skin and subcutaneous tissue disorders
Uncommon:
Alopecia, purpura, skin discolouration, hyperhidrosis
Very rare:
Angioedema, erythema multiforme, urticaria, exfoliative dermatitis,
Stevens-Johnson syndrome, photosensitivity
Renal and urinary disorders
Uncommon:
Micturition disorder, pollakiuria
Reproductive system and breast disorders
Uncommon:
Gynaecomastia
General disorders and administration site conditions
Uncommon:
Pain
Investigations
Uncommon:
Weight increased, weight decreased
45
Symptoms
: Signs and symptoms of overdose are expected to be in line with exaggerated
pharmacological effects. The most 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.
tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with
fatal outcome have been reported.
Treatment:
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 measures include induction of emesis and / or gastric lavage. Activated charcoal may be
useful in the treatment of overdose of both telmisartan and amlodipine.
Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient
should be placed in a supine position with elevation of extremities, with salt and volume replacement
given quickly. Supportive treatment should be instituted. Intravenous calcium gluconate may be
beneficial in reversing the effects of calcium channel blockade. Telmisartan and Amlodipine are not
removed by haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists
and calcium channel blockers; ATC Code: C09DB04.
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.
TWYNSTA once daily produces effective and consistent reductions in blood pressure across the 24-
hour therapeutic dose range.
Telmisartan
Telmisartan is an orally active and specific angiotensin II receptor (type AT
1
) antagonist. Telmisartan
displaces angiotensin II with very high affinity from its binding site at the AT
1
receptor subtype,
which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial
agonist activity at the AT
1
receptor. Telmisartan selectively binds the AT
1
receptor. The binding is
long-lasting. Telmisartan does not show affinity for other receptors, including AT
2
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 reactions.
In human, 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.
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
treatment and is sustained during long-term therapy.
46
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 systolic blood pressure (SBP). In this respect data concerning diastolic blood
pressure (DBP) are inconsistent.
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its
hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable
to that of substances representative of other classes of antihypertensive medicinal products
(demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril,
hydrochlorothiazide, and lisinopril).
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.
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
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.
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.
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.
47
Telmisartan/Amlodipine
In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study
in 1461 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
diastolic and systolic blood pressure reductions and higher control rates compared to the respective
monotherapy components.
TWYNSTA showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic
dose range of
−
21.8/
−
16.5 mmHg (40 mg/5 mg),
−
22.1/
−
18.2 mmHg (80 mg/5 mg),
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 adjusted for baseline and country.
24.7/
−
20.2 mmHg (40 mg/10 mg) and
−
26.4/
−
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 in systolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg
(
−
22.2/
−
17.2 mmHg with 40 mg/5 mg;
−
22.5/
−
17.6 mmHg) and associated with significant
lower oedema rates (1.4% with 40 mg/5 mg; 0.5% with 80 mg/5 mg; 17.6% with amlodipine 10 mg).
−
21.0/
−
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, randomised, double-blind, active-controlled, parallel group study, a total of
1097 patients with mild to severe hypertension who were not adequately controlled on amlodipine 5
mg received TWYNSTA (40 mg/5 mg or 80 mg/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 (
−
13.6/
−
9.4 mmHg,
8.0 mmHg with
amlodipine 5 mg and 10 mg and higher diastolic blood pressure control rates compared to the
respective monotherapies 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 and 80 mg/5 mg compared to amlodipine 10 mg (4.4% versus 24.9%, respectively).
15.0/
−
10.6 mmHg with 40 mg/5 mg, 80 mg/5 mg versus
−
6.2/
−
5.7 mmHg,
−
11.1/
−
In another multicentre, randomised, double-blind, active-controlled, parallel group study, a total of
947 patients with mild to severe hypertension who were not adequately controlled on amlodipine
10 mg received TWYNSTA (40 mg/10 mg or 80 mg/10 mg) or amlodipine alone (10 mg). After 8
weeks of treatment, each of the combination treatments was statistically significantly superior to
amlodipine monotherapy in reducing diastolic and systolic blood pressures (
−
11.1/
−
9.2 mmHg,
−
11.3/
6.5 mmHg with amlodipine 10 mg) and
higher diastolic blood pressure normalisation rates compared to monotherapy were achieved (63.7%,
66.5% with 40 mg/10 mg, 80 mg/10 mg versus 51.1% with amlodipine 10 mg).
9.3 mmHg with 40 mg/10 mg, 80 mg/10 mg versus
−
7.4/
−
In two corresponding open-label long-term follow up studies performed over a further 6 months the
effect of TWYNSTA was maintained over the trial period. Furthermore it was shown that some
patients not adequately controlled with TWYNSTA 40 mg/10 mg had additional blood pressure
reduction by up-titration to TWYNSTA 80 mg/10 mg.
The overall incidence of adverse reactions with TWYNSTA in the clinical trial programme was low
with only 12.7% of patients on treatment experiencing adverse reactions. The most common adverse
reactions were peripheral oedema and dizziness, see also section 4.8. The adverse reactions reported
were in agreement 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
48
−
19.1 mmHg with 80 mg/5 mg) were comparable to or
greater than those seen with amlodipine 10 mg (
−
−
received TWYNSTA as compared to 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% for 40 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
in patients with and without diabetes.
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.
The European Medicines Agency has waived the obligation to submit the results of studies with
TWYNSTA in all subsets of the paediatric population in hypertension (see section 4.2 for information
on paediatric use).
5.2 Pharmacokinetic properties
Pharmacokinetic of the fixed dose combination (FDC)
The rate and extent of absorption of TWYNSTA are equivalent to the bioavailability of telmisartan
and amlodipine when administered as individual tablets.
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
0-∞
) 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.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels
between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
Amlodipine bioavailability is not affected by food ingestion.
Linearity/non-linearity
The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeutic
efficacy. There is no linear relationship between doses and plasma levels. C
max
and to a lesser extent
AUC increase disproportionately at doses above 40 mg.
Amlodipine exhibits linear pharmacokinetics.
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 (V
dss
) is approximately 500 l.
The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown that
approximately 97.5% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Biotransformation
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
49
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, the area
under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no
evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma
concentrations were 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 (Cl
tot
) 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
approximately 30 to 50 hours consistent with once daily dosing. Steady-state plasma levels are
reached after continuous administration for 7–8 days. Ten per cent of original amlodipine and 60% of
amlodipine metabolites are excreted in urine.
Special populations
Paediatric population (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
Gender effects
Differences in plasma concentrations of telmisartan were observed, with C
max
and AUC being
approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly patients
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.
In elderly patients, amlodipine clearance tends to decline with resulting increases in AUC and
elimination half-life.
Patients with renal impairment
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of
telmisartan was observed. However, lower plasma concentrations 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.
Patients with 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 of telmisartan 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.
5.3 Preclinical safety data
Since the non-clinical toxicity profiles of telmisartan and amlodipine are not overlapping, no
exacerbation of 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 and amlodipine were tested.
Preclinical data available for the components of this fixed dose combination are reported below.
50
Telmisartan
: In preclinical safety studies, doses producing exposure comparable to that in the clinical
therapeutic range caused reduced red cell parameters (erythrocytes, haemoglobin, haematocrit),
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 undesirable effects, known from preclinical studies with both angiotensin
converting enzyme inhibitors and angiotensin II receptor 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 angiotensin converting
enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical
significance.
There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential of
telmisartan to the postnatal development of the offspring such as lower body weight, delayed eye
opening, and higher mortality.
There was no evidence of mutagenicity and relevant clastogenic activity in
in vitro
studies and no
evidence of carcinogenicity in rats and mice.
Amlodipine:
Preclinical 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 Maximum Recommended Human Dose of 10 mg/day on
an mg/m
2
basis).
6.
6.1 List of excipients
Colloidal anhydrous silica
Brilliant blue FCF (E 133)
Ferric oxide black (E172)
Ferric oxide yellow (E172)
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone K25
Pregelatinised starch
Sodium hydroxide
Sorbitol (E420)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from light and moisture.
51
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al) in a carton containing 14, 28, 56, 98 tablets or
aluminium/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.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
52
1.
FURTHER INFORMATION
What TWYNSTA contains
The active substances are telmisartan and amlodipine. Each tablet contains 80 mg telmisartan and
10 mg amlodipine.
135
The other ingredients are colloidal anhydrous silica, brilliant blue FCF (E 133), ferric oxide black
(E172), ferric oxide yellow (E172), magnesium stearate, maize starch, meglumine, microcrystalline
cellulose, povidone K25, pregelatinized starch, sodium hydroxide, sorbitol (E420).
What TWYNSTA looks like and contents of the pack
TWYNSTA 80 mg/10 mg tablets are blue and white oval shaped two layer tablet engraved with the
product code A4.
TWYNSTA is available in folding box containing 14, 28, 56, 98 tablets in aluminium/aluminium
blisters and in folding box containing 30 x 1, 90 x 1, 360 (4 x 90) tablets in aluminium/aluminium
perforated unit dose blisters.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Manufacturer
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
136
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 89 00
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti Filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
137
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
138
Source: European Medicines Agency
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