ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Tolura 20 mg tablets
Each tablet contains 20 mg telmisartan.
Excipients:
Each tablet contains 74.9 mg sorbitol (E420) and 28.5 mg lactose.
For a full list of excipients, see section 6.1.
3.
Tablet.
20 mg: white to almost white, round tablets
4.
Treatment of essential hypertension in adults.
The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of
20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be
increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination
with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive
blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne
in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the
start of treatment (see section 5.1).
Telmisartan may be taken with or without food.
Renal impairment
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. A lower starting
dose of 20 mg is recommended in these patients (see section 4.4).
Hepatic impairment
In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg once
daily (see section 4.4).
No dose adjustment is necessary for elderly patients.
Tolura is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy.
2
Elderly
Paediatric patients
-
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
-
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
-
Severe hepatic impairment
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 anti-hypertensive 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 sections 4.3 and
4.6).
Hepatic impairment
Tolura is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic
impairment (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can be
expected to have reduced hepatic clearance for telmisartan. Tolura should be used only with caution in
patients with mild to moderate hepatic impairment.
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 Tolura is used in patients with impaired renal function, periodic monitoring of potassium and
creatinine serum levels is recommended. There is no experience regarding the administration of Tolura
in patients with recent kidney transplantation.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose of Tolura, may occur in patients who are
volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, or
vomiting. Such conditions should be corrected before the administration of Tolura. Volume and/or
sodium depletion should be corrected prior to administration of Tolura.
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. Dual blockade of the renin-angiotensin-
aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) is
therefore not recommended in patients with already controlled blood pressure and should 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 such
as telmisartan 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
3
-
Biliary obstructive disorders
Pregnancy
Renovascular hypertension
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.
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia.
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, hyperkalaemia may be fatal.
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).
Close monitoring of serum potassium in at risk patients is recommended (see section 4.5).
Sorbitol
Tolura tablets contain sorbitol (E420). Patients with rare hereditary problems of fructose intolerance
should not take Tolura.
Lactose
Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take Tolura.
Ethnic differences
As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin II
receptor antagonists are apparently less effective in lowering blood pressure in black people than in
non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive
population.
Other
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Interaction studies have only been performed in adults.
As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may
provoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination with
other medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-
4
inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).
The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of
the above-mentioned treatment combinations. The risk is particularly high in combination with
potassium sparing-diuretics, and when combined with salt substitutes containing potassium. A
combination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided that
precautions for use are strictly followed.
Concomitant use not recommended
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
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 agents
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.
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.
Diuretics (thiazide or loop diuretics)
Prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide
(thiazide diuretic) may result in volume depletion and in a risk of hypotension when initiating therapy
with telmisartan.
To be taken into account with concomitant use
The blood pressure lowering effect of telmisartan can be increased by concomitant use of other
antihypertensive medicinal products.
Based on their pharmacological properties it can be expected that the following medicinal products
may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen,
amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics
or antidepressants.
5
Potassium sparing diuretics or potassium supplements
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.
Other antihypertensive agents
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
Pregnancy
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 trimester of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of Tolura in pregnant women. Studies 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 drugs. Unless continued angiotensin II
receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to
alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
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).
Because no information is available regarding the use of Tolura during breast-feeding, Tolura is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machinery it should be taken into account that dizziness or
drowsiness may occasionally occur when taking antihypertensive therapy.
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The incidence of adverse events was not dose related and
showed no correlation with gender, age or race of the patients.
The adverse drug reactions listed below have been accumulated from all clinical trials in patients
treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular
events.
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.
6
Lactation
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infections and infestations
Rare:
Upper respiratory tract infection including pharyngitis and sinusitis, urinary
tract infection including cystitis
Sepsis including fatal outcome*
Not known:
Blood and the lymphatic system disorders
Rare:
Anaemia, thrombocytopenia
Not known: Eosinophilia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon: Hyperkalaemia
Psychiatric disorders
Anxiety, depression
Nervous system disorders
Uncommon: Syncope, insomnia
Eye disorders
Rare:
Abnormal vision
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Tachycardia
Not known: Bradycardia
Vascular disorders
Hypotension
Orthostatic hypotension
Rare:
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Uncommon:
Abdominal pain, diarrhoea, dry mouth, dyspepsia, flatulence
Stomach upset, vomiting
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal/liver disorder
Skin and subcutaneous tissue disorders
Hyperhidrosis, pruritus
Erythema, angioedema, urticaria
Drug eruption, toxic skin eruption, rash, eczema
Rare:
Not known:
7
Rare:
Rare:
Uncommon:
Uncommon: Dyspnoea
Uncommon:
Muscoloskeletal and connective tissue disorders
Uncommon:
Myalgia
Arthralgia, back pain (e.g. sciatica), muscle cramps, pain in limb, weakness
Tendonitis
Not known:
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Uncommon:
Chest pain
Influenza-like illness
Drug ineffective
Not known:
Investigations
Blood uric acid increased, blood creatinine increased, hepatic enzyme
increased, blood creatine phosphokinase increased
Haemoglobin decreased
* In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with
placebo. The event may be a chance finding or related to a mechanism currently not known (see
section 5.1).
Rare:
Not known:
There is limited information available with regard to overdose in humans.
Symptoms
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia;
bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported.
Telmisartan is not removed by haemodialysis. 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 overdosage. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacement given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC Code: C09CA07.
Mechanism of action:
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 effects.
8
Rare:
Rare:
Treatment
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.
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 agents 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.
In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients 50
years and older, who recently experienced stroke, an increased incidence of sepsis was noted for
telmisartan compared with placebo, 0,70 % vs. 0,49 % [RR 1,43 (95 % confidence interval 1,00 –
2,06)]; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0,33 %) vs.
patients taking placebo (0,16 %) [RR 2,07 (95 % confidence interval 1,14 – 3,76)]. The observed
increased occurrence rate of sepsis associated with the use of telmisartan may be either a chance
finding or related to a mechanism not currently known.
Beneficial effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
5.2 Pharmacokinetic properties
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.
The small reduction in AUC 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.
Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid
9
Clinical efficacy and safety
Absorption
Linearity/non-linearity
Distribution
glycoprotein. The mean steady state apparent volume of distribution (V
dss
) is approximately 500 l.
Metabolism
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
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).
Special Populations
Differences in plasma concentrations 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 between the elderly and those younger than
65 years.
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations 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 patients and
cannot be removed by dialysis. The elimination half-life is not changed in patients with renal
impairment.
Patients with hepatic impairment
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute
bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic
impairment.
5.3 Preclinical safety data
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.
10
Gender effects
Patients with renal impairment
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.
6.
6.1 List of excipients
Povidone (K30)
Meglumine
Sodium hydroxide
Lactose monohydrate
Sorbitol (E420)
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5
Nature and contents of container
OPA/Al/PVC Al blister. Each blister contains 7 or 10 tablets.
Pack sizes: 14, 28, 30, 56, 84, 90 and 98 tablets in a box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
9.
Date of first authorisation:
11
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
12
1.
Tolura 40 mg tablets
Each tablet contains 40 mg telmisartan.
Excipients:
Each tablet contains 149.8 mg sorbitol (E420) and 57 mg lactose.
For a full list of excipients, see section 6.1.
3.
Tablet.
40 mg: white to almost white, biconvex, oval tablets
4.
Treatment of essential hypertension in adults.
The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of
20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be
increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination
with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive
blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne
in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the
start of treatment (see section 5.1).
Telmisartan may be taken with or without food.
Renal impairment
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. A lower starting
dose of 20 mg is recommended in these patients (see section 4.4).
Hepatic impairment
In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg once
daily (see section 4.4).
No dose adjustment is necessary for elderly patients.
Tolura is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy.
13
Elderly
Paediatric patients
-
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
-
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
-
Severe hepatic impairment
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 anti-hypertensive 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 sections 4.3 and
4.6).
Hepatic impairment
Tolura is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic
impairment (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can be
expected to have reduced hepatic clearance for telmisartan. Tolura should be used only with caution in
patients with mild to moderate hepatic impairment.
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 Tolura is used in patients with impaired renal function, periodic monitoring of potassium and
creatinine serum levels is recommended. There is no experience regarding the administration of Tolura
in patients with recent kidney transplantation.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose of Tolura, may occur in patients who are
volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, or
vomiting. Such conditions should be corrected before the administration of Tolura. Volume and/or
sodium depletion should be corrected prior to administration of Tolura.
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. Dual blockade of the renin-angiotensin-
aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) is
therefore not recommended in patients with already controlled blood pressure and should 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 such
as telmisartan 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
14
-
Biliary obstructive disorders
Pregnancy
Renovascular hypertension
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.
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia.
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, hyperkalaemia may be fatal.
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).
Close monitoring of serum potassium in at risk patients is recommended (see section 4.5).
Sorbitol
Tolura tablets contain sorbitol (E420). Patients with rare hereditary problems of fructose intolerance
should not take Tolura.
Lactose
Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take Tolura.
Ethnic differences
As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin II
receptor antagonists are apparently less effective in lowering blood pressure in black people than in
non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive
population.
Other
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Interaction studies have only been performed in adults.
As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may
provoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination with
other medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-
15
inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).
The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of
the above-mentioned treatment combinations. The risk is particularly high in combination with
potassium sparing-diuretics, and when combined with salt substitutes containing potassium. A
combination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided that
precautions for use are strictly followed.
Concomitant use not recommended
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
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 agents
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.
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.
Diuretics (thiazide or loop diuretics)
Prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide
(thiazide diuretic) may result in volume depletion and in a risk of hypotension when initiating therapy
with telmisartan.
To be taken into account with concomitant use
The blood pressure lowering effect of telmisartan can be increased by concomitant use of other
antihypertensive medicinal products.
Based on their pharmacological properties it can be expected that the following medicinal products
may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen,
amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics
or antidepressants.
16
Potassium sparing diuretics or potassium supplements
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.
Other antihypertensive agents
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
Pregnancy
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 trimester of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of Tolura in pregnant women. Studies 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 drugs. Unless continued angiotensin II
receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to
alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
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).
Because no information is available regarding the use of Tolura during breast-feeding, Tolura is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machinery it should be taken into account that dizziness or
drowsiness may occasionally occur when taking antihypertensive therapy.
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The incidence of adverse events was not dose related and
showed no correlation with gender, age or race of the patients.
The adverse drug reactions listed below have been accumulated from all clinical trials in patients
treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular
events.
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.
17
Lactation
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infections and infestations
Rare:
Upper respiratory tract infection including pharyngitis and sinusitis, urinary
tract infection including cystitis
Sepsis including fatal outcome*
Not known:
Blood and the lymphatic system disorders
Rare:
Anaemia, thrombocytopenia
Not known: Eosinophilia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon: Hyperkalaemia
Psychiatric disorders
Anxiety, depression
Nervous system disorders
Uncommon: Syncope, insomnia
Eye disorders
Rare:
Abnormal vision
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Tachycardia
Not known: Bradycardia
Vascular disorders
Hypotension
Orthostatic hypotension
Rare:
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Uncommon:
Abdominal pain, diarrhoea, dry mouth, dyspepsia, flatulence
Stomach upset, vomiting
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal/liver disorder
Skin and subcutaneous tissue disorders
Hyperhidrosis, pruritus
Erythema, angioedema, urticaria
Drug eruption, toxic skin eruption, rash, eczema
Rare:
Not known:
18
Rare:
Rare:
Uncommon:
Uncommon: Dyspnoea
Uncommon:
Muscoloskeletal and connective tissue disorders
Uncommon:
Myalgia
Arthralgia, back pain (e.g. sciatica), muscle cramps, pain in limb, weakness
Tendonitis
Not known:
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Uncommon:
Chest pain
Influenza-like illness
Drug ineffective
Not known:
Investigations
Blood uric acid increased, blood creatinine increased, hepatic enzyme
increased, blood creatine phosphokinase increased
Haemoglobin decreased
* In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with
placebo. The event may be a chance finding or related to a mechanism currently not known (see
section 5.1).
Rare:
Not known:
There is limited information available with regard to overdose in humans.
Symptoms
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia;
bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported.
Telmisartan is not removed by haemodialysis. 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 overdosage. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacement given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC Code: C09CA07.
Mechanism of action:
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 effects.
19
Rare:
Rare:
Treatment
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.
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 agents 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.
In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients 50
years and older, who recently experienced stroke, an increased incidence of sepsis was noted for
telmisartan compared with placebo, 0,70 % vs. 0,49 % [RR 1,43 (95 % confidence interval 1,00 –
2,06)]; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0,33 %) vs.
patients taking placebo (0,16 %) [RR 2,07 (95 % confidence interval 1,14 – 3,76)]. The observed
increased occurrence rate of sepsis associated with the use of telmisartan may be either a chance
finding or related to a mechanism not currently known.
Beneficial effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
5.2 Pharmacokinetic properties
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.
The small reduction in AUC 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.
Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid
20
Clinical efficacy and safety
Absorption
Linearity/non-linearity
Distribution
glycoprotein. The mean steady state apparent volume of distribution (V
dss
) is approximately 500 l.
Metabolism
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
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).
Special Populations
Differences in plasma concentrations 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 between the elderly and those younger than
65 years.
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations 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 patients and
cannot be removed by dialysis. The elimination half-life is not changed in patients with renal
impairment.
Patients with hepatic impairment
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute
bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic
impairment.
5.3 Preclinical safety data
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.
21
Gender effects
Patients with renal impairment
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.
6.
6.1 List of excipients
Povidone (K30)
Meglumine
Sodium hydroxide
Lactose monohydrate
Sorbitol (E420)
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
OPA/Al/PVC Al blister. Each blister contains 7 or 10 tablets.
Pack sizes: 14, 28, 30, 56, 84, 90 and 98 tablets in a box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
9.
Date of first authorisation:
22
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
23
Tolura 80 mg tablets
Each tablet contains 80 mg telmisartan.
Excipients:
Each tablet contains 299.7 mg sorbitol (E420) and 114 mg lactose.
For a full list of excipients, see section 6.1.
3.
Tablet.
80 mg: white to almost white, biconvex, capsule shape tablets
4.
Treatment of essential hypertension in adults.
The usually effective dose is 40 mg once daily. Some patients may already benefit at a daily dose of
20 mg. In cases where the target blood pressure is not achieved, the dose of telmisartan can be
increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination
with thiazide-type diuretics such as hydrochlorothiazide, which has been shown to have an additive
blood pressure lowering effect with telmisartan. When considering raising the dose, it must be borne
in mind that the maximum antihypertensive effect is generally attained four to eight weeks after the
start of treatment (see section 5.1).
Telmisartan may be taken with or without food.
Renal impairment
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. A lower starting
dose of 20 mg is recommended in these patients (see section 4.4).
Hepatic impairment
In patients with mild to moderate hepatic impairment the posology should not exceed 40 mg once
daily (see section 4.4).
No dose adjustment is necessary for elderly patients.
Tolura is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy.
24
Elderly
Paediatric patients
-
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
-
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
-
Severe hepatic impairment
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 anti-hypertensive 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 sections 4.3 and
4.6).
Hepatic impairment
Tolura is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic
impairment (see section 4.3) since telmisartan is mostly eliminated with the bile. These patients can be
expected to have reduced hepatic clearance for telmisartan. Tolura should be used only with caution in
patients with mild to moderate hepatic impairment.
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 Tolura is used in patients with impaired renal function, periodic monitoring of potassium and
creatinine serum levels is recommended. There is no experience regarding the administration of Tolura
in patients with recent kidney transplantation.
Intravascular hypovolaemia
Symptomatic hypotension, especially after the first dose of Tolura, may occur in patients who are
volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, or
vomiting. Such conditions should be corrected before the administration of Tolura. Volume and/or
sodium depletion should be corrected prior to administration of Tolura.
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. Dual blockade of the renin-angiotensin-
aldosterone system (e.g. by adding an ACE-inhibitor to an angiotensin II receptor antagonist) is
therefore not recommended in patients with already controlled blood pressure and should 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 such
as telmisartan 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
25
-
Biliary obstructive disorders
Pregnancy
Renovascular hypertension
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.
Hyperkalaemia
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause
hyperkalaemia.
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, hyperkalaemia may be fatal.
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).
Close monitoring of serum potassium in at risk patients is recommended (see section 4.5).
Sorbitol
Tolura tablets contain sorbitol (E420). Patients with rare hereditary problems of fructose intolerance
should not take Tolura.
Lactose
Tolura tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take Tolura.
Ethnic differences
As observed for angiotensin converting enzyme inhibitors, telmisartan and the other angiotensin II
receptor antagonists are apparently less effective in lowering blood pressure in black people than in
non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive
population.
Other
As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Interaction studies have only been performed in adults.
As with other medicinal products acting on the renin-angiotensin-aldosterone system, telmisartan may
provoke hyperkalaemia (see section 4.4). The risk may increase in case of treatment combination with
other medicinal products that may also provoke hyperkalaemia (salt substitutes containing potassium,
potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non steroidal anti-
26
inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin,
immunosuppressives (cyclosporin or tacrolimus), and trimethoprim).
The occurrence of hyperkalaemia depends on associated risk factors. The risk is increased in case of
the above-mentioned treatment combinations. The risk is particularly high in combination with
potassium sparing-diuretics, and when combined with salt substitutes containing potassium. A
combination with ACE inhibitors or NSAIDs, for example, presents a lesser risk provided that
precautions for use are strictly followed.
Concomitant use not recommended
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
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 agents
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.
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.
Diuretics (thiazide or loop diuretics)
Prior treatment with high dose diuretics such as furosemide (loop diuretic) and hydrochlorothiazide
(thiazide diuretic) may result in volume depletion and in a risk of hypotension when initiating therapy
with telmisartan.
To be taken into account with concomitant use
The blood pressure lowering effect of telmisartan can be increased by concomitant use of other
antihypertensive medicinal products.
Based on their pharmacological properties it can be expected that the following medicinal products
may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen,
amifostine. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics
or antidepressants.
27
Potassium sparing diuretics or potassium supplements
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.
Other antihypertensive agents
Corticosteroids (systemic route)
Reduction of the antihypertensive effect.
Pregnancy
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 trimester of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of Tolura in pregnant women. Studies 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 drugs. Unless continued angiotensin II
receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to
alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
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).
Because no information is available regarding the use of Tolura during breast-feeding, Tolura is not
recommended and alternative treatments with better established safety profiles during breast-feeding
are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machinery it should be taken into account that dizziness or
drowsiness may occasionally occur when taking antihypertensive therapy.
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The incidence of adverse events was not dose related and
showed no correlation with gender, age or race of the patients.
The adverse drug reactions listed below have been accumulated from all clinical trials in patients
treated with telmisartan for hypertension or in patients 50 years or older at high risk of cardiovascular
events.
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.
28
Lactation
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infections and infestations
Rare:
Upper respiratory tract infection including pharyngitis and sinusitis, urinary
tract infection including cystitis
Sepsis including fatal outcome*
Not known:
Blood and the lymphatic system disorders
Rare:
Anaemia, thrombocytopenia
Not known: Eosinophilia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reaction
Metabolism and nutrition disorders
Uncommon: Hyperkalaemia
Psychiatric disorders
Anxiety, depression
Nervous system disorders
Uncommon: Syncope, insomnia
Eye disorders
Rare:
Abnormal vision
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Tachycardia
Not known: Bradycardia
Vascular disorders
Hypotension
Orthostatic hypotension
Rare:
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Uncommon:
Abdominal pain, diarrhoea, dry mouth, dyspepsia, flatulence
Stomach upset, vomiting
Rare:
Hepato-biliary disorders
Rare:
Hepatic function abnormal/liver disorder
Skin and subcutaneous tissue disorders
Hyperhidrosis, pruritus
Erythema, angioedema, urticaria
Drug eruption, toxic skin eruption, rash, eczema
Rare:
Not known:
29
Rare:
Rare:
Uncommon:
Uncommon: Dyspnoea
Uncommon:
Muscoloskeletal and connective tissue disorders
Uncommon:
Myalgia
Arthralgia, back pain (e.g. sciatica), muscle cramps, pain in limb, weakness
Tendonitis
Not known:
Renal and urinary disorders
Uncommon: Renal impairment including acute renal failure
General disorders and administration site conditions
Uncommon:
Chest pain
Influenza-like illness
Drug ineffective
Not known:
Investigations
Blood uric acid increased, blood creatinine increased, hepatic enzyme
increased, blood creatine phosphokinase increased
Haemoglobin decreased
* In the PRoFESS trial, an increased incidence of sepsis was observed with telmisartan compared with
placebo. The event may be a chance finding or related to a mechanism currently not known (see
section 5.1).
Rare:
Not known:
There is limited information available with regard to overdose in humans.
Symptoms
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia;
bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported.
Telmisartan is not removed by haemodialysis. 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 overdosage. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacement given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC Code: C09CA07.
Mechanism of action:
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 effects.
30
Rare:
Rare:
Treatment
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.
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 agents 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.
In the “Prevention Regimen For Effectively avoiding Second Strokes” (PRoFESS) trial in patients 50
years and older, who recently experienced stroke, an increased incidence of sepsis was noted for
telmisartan compared with placebo, 0,70 % vs. 0,49 % [RR 1,43 (95 % confidence interval 1,00 –
2,06)]; the incidence of fatal sepsis cases was increased for patients taking telmisartan (0,33 %) vs.
patients taking placebo (0,16 %) [RR 2,07 (95 % confidence interval 1,14 – 3,76)]. The observed
increased occurrence rate of sepsis associated with the use of telmisartan may be either a chance
finding or related to a mechanism not currently known.
Beneficial effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
5.2 Pharmacokinetic properties
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.
The small reduction in AUC 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.
Telmisartan is largely bound to plasma protein (>99.5 %), mainly albumin and alpha-1 acid
31
Clinical efficacy and safety
Absorption
Linearity/non-linearity
Distribution
glycoprotein. The mean steady state apparent volume of distribution (V
dss
) is approximately 500 l.
Metabolism
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No
pharmacological activity has been shown for the conjugate.
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).
Special Populations
Differences in plasma concentrations 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 between the elderly and those younger than
65 years.
In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations 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 patients and
cannot be removed by dialysis. The elimination half-life is not changed in patients with renal
impairment.
Patients with hepatic impairment
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute
bioavailability up to nearly 100 %. The elimination half-life is not changed in patients with hepatic
impairment.
5.3 Preclinical safety data
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.
32
Gender effects
Patients with renal impairment
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.
6.
6.1 List of excipients
Povidone (K30)
Meglumine
Sodium hydroxide
Lactose monohydrate
Sorbitol (E420)
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.6
Nature and contents of container
OPA/Al/PVC Al blister. Each blister contains 7 or 10 tablets.
Pack sizes: 14, 28, 30, 56, 84, 90 and 98 tablets in a box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
9.
Date of first authorisation:
33
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
34
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
35
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Krka, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia
Krka Polska Sp. z o.o.
Ul. Równoległa 5
Warszawa
Poland
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version
DescPhSys000001/17 2.12.2006 updated 29.01.2009 presented in Module 1.8.1. of the Marketing
Authorisation Application, is in place and functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product. Thus, the
MAH will have to submit PSURs on a yearly basis, unless otherwise specified by the CHMP.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON/BOX
1.
Tolura 20 mg tablets
telmisartan
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 20 mg telmisartan.
3. LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420). Read the package leaflet for further information.
14 tablets
28 tablets
30 tablets
56 tablets
84 tablets
90 tablets
98 tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
39
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tolura 20 mg
40
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
BLISTER/OPA/Al/PVC Al
1.
Tolura 20 mg tablets
telmisartan
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Only on blisters containing 7 tablets
MON
TUE
WED
THU
FRI
SAT
SUN
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON/BOX
1.
Tolura 40 mg tablets
telmisartan
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 40 mg telmisartan.
3. LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420). Read the package leaflet for further information.
14 tablets
28 tablets
30 tablets
56 tablets
84 tablets
90 tablets
98 tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
42
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tolura 40 mg
43
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
BLISTER/OPA/Al/PVC Al
1.
Tolura 40 mg tablets
telmisartan
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Only on blisters containing 7 tablets
MON
TUE
WED
THU
FRI
SAT
SUN
44
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON/BOX
1.
Tolura 80 mg tablets
telmisartan
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 80 mg telmisartan.
3. LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420). Read the package leaflet for further information.
14 tablets
28 tablets
30 tablets
56 tablets
84 tablets
90 tablets
98 tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
45
9. SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Tolura 80 mg
46
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
BLISTER/OPA/Al/PVC Al
1.
Tolura 80 mg tablets
telmisartan
2.
KRKA
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
Only on blisters containing 7 tablets
MON
TUE
WED
THU
FRI
SAT
SUN
47
B. PACKAGE LEAFLET
48
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tolura 20 mg tablets
Telmisartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Tolura is and what it is used for
2. Before you take Tolura
3. How to take Tolura
4. Possible side effects
4.
How to store Tolura
6. Further information
1.
WHAT TOLURA IS AND WHAT IT IS USED FOR
Tolura belongs to a class of medicines known as angiotensin II receptor antagonists. Angiotensin II is
a substance produced in your body which causes your blood vessels to narrow, thus increasing your
blood pressure. Tolura blocks the effect of angiotensin II so that the blood vessels relax, and your
blood pressure is lowered.
Tolura is used to
treat essential hypertension (high blood pressure). ‘Essential’ means that the high
blood pressure is not caused by any other condition.
High blood pressure, if not treated, can damage blood vessels in several organs, which could lead
sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms
of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure
to verify if it is within the normal range.
2.
BEFORE YOU TAKE TOLURA
Do not take Tolura
-
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in Tolura
tablets (see section Further information for a list of other ingredients).
-
if you are more than 3 months pregnant. (It is also better to avoid Tolura in early pregnancy –
see pregnancy section.)
-
if you have severe liver problems such as cholestasis or biliary obstruction (problems with the
drainage of the bile from the liver and gall bladder) or any other severe liver disease.
If any of the above applies to you, tell your doctor or pharmacist before taking Tolura.
Take special care with Tolura
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
49
-
If you have any further questions, ask your doctor or pharmacist.
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body
water) or have salt deficiency due to diuretic therapy ('water tablets'), low-salt diet, diarrhoea, or
vomiting.
-
Elevated potassium levels in your blood.
-
Diabetes.
You must tell your doctor if you think you are (or might become) pregnant. Tolura is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
In case of surgery or anaesthesia, you should tell your doctor that you are taking Tolura.
The use of Tolura in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, Tolura may be less effective in lowering the
blood pressure in black patients.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose of
these other medicines or take other precautions. In some cases you may have to stop taking one of the
medicines. This applies especially to the medicines listed below taken at the same time with Tolura:
-
Lithium containing medicines to treat some types of depression.
-
Medicines that may increase blood potassium levels such as salt substitutes containing
potassium, potassium-sparing diuretics (certain 'water tablets'), ACE inhibitors, angiotensin II
receptor antagonists, NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or
ibuprofen), heparin, immunosuppressives (e.g. cyclosporin or tacrolimus), and the antibiotic
trimethoprim.
-
Diuretics ('water tablets'), especially if taken in high doses together with Tolura, may lead to
excessive loss of body water and low blood pressure (hypotension).
As with other blood pressure lowering medicines, the effect of Tolura may be reduced when you take
NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen) or corticosteroids.
Tolura may increase the blood pressure lowering effect of other medicines used to treat high blood
pressure.
Taking Tolura with food and drink
You can take Tolura with or without food.
50
-
Heart trouble.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Tolura before you become pregnant or as soon as you know you are pregnant
and will advise you to take another medicine instead of Tolura. Tolura is not recommended in early
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to
your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Tolura is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No information is available on the effect of Tolura on the ability to drive or operate machinery. Some
people feel dizzy or tired when they are treated for high blood pressure. If you feel dizzy or tired, do
not drive or operate machinery.
Important information about some of the ingredients of Tolura
Tolura contains lactose and sorbitol (E420).
If you are intolerant to some sugars, consult your doctor before taking Tolura.
3.
HOW TO TAKE TOLURA
Always take Tolura exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of Tolura is one tablet a day. Try to take the tablet at the same time each day. You can
take Tolura with or without food. The tablets should be swallowed with some water or other non-
alcoholic drink. It is important that you take Tolura every day until your doctor tells you otherwise. If
you have the impression that the effect of Tolura is too strong or too weak, talk to your doctor or
pharmacist.
The usual dose of Tolura for most patients is one 40 mg tablet once a day to control blood pressure
over the 24 hour period. Your doctor has recommended a lower dose of one 20 mg tablet daily. Tolura
may also be used in combination with diuretics ('water tablets') such as hydrochlorothiazide which has
been shown to have an additive blood pressure lowering effect with Tolura.
If your liver is not working properly, the usual dose should not exceed 40 mg once daily.
If you take more Tolura than you should
If you accidentally take too many tablets, contact your doctor, pharmacist, or your nearest hospital
emergency department immediately.
If you forget to take Tolura
If you forget to take a dose, do not worry. Take it as soon as you remember then carry on as before. If
you do not take your tablet on one day, take your normal dose on the next day.
Do not
take a double
dose to make up for forgotten individual doses.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
51
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tolura can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
Very common:
Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from available data
Uncommon side effects
High potassium levels, fainting (syncope), difficulty falling asleep, feeling of spinning (vertigo), low
blood pressure (hypotension), shortness of breath, abdominal pain, diarrhoea, dry mouth, discomfort in
the abdomen, bloating, increased sweating, itching, muscle pain (myalgia), kidney impairment
including acute kidney failure, and pain in the chest.
:
Rare side effects
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), deficiency in red
blood cells (anaemia), low platelet count (thrombocytopenia), feeling anxious, feeling sad
(depression), impaired vision, fast heart beat (tachycardia), dizziness on standing up (orthostatic
hypotension), upset stomach, vomiting, abnormal liver function, redness of skin, rapid swelling of the
skin and mucosa (angioedema), hives (urticaria), joint pain (arthralgia), back pain, muscle cramps,
pain in extremity, symptoms of weakness, flu-like-illness, increased levels of uric acid, creatinine,
hepatic enzymes or creatine phosphokinase in the blood.
:
Side effects of unknown frequency
Urinary tract infections, increase in certain white blood cells (eosinophilia), allergic reaction (e.g. rash,
itching, difficulty breathing, wheezing, swelling of the face or low blood pressure), slow heart rate
(bradycardia), drug rash, eczema (a skin disorder), inflammation of the tendons, ineffectiveness of
Tolura, decreased haemoglobin (a blood protein), sepsis* (often called “blood poisoning”, is a severe
infection with whole-body inflammatory response which can lead to death).
:
* In a long-term study involving more than 20,000 patients, more patients treated with telmisartan
experienced sepsis compared with patients who received no telmisartan. The event may have
happened by chance or could be related to a mechanism currently not known.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TOLURA
Keep out of the reach and sight of children.
Do not use Tolura after the expiry date which is stated on the carton and blister after “EXP”. The
expiry date refers to the last day of that month.
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
52
6. FURTHER INFORMATION
What Tolura contains
-
The active substance is telmisartan. Each tablet contains 20 mg telmisartan.
-
The other ingredients are povidone, meglumine, sodium hydroxide, lactose monohydrate,
sorbitol (E420) and magnesium stearate.
What Tolura looks like and contents of the pack
Tolura 20 mg tablets are white to almost white, round tablets.
Tolura is available in blister packs containing 14, 28, 30, 56, 84, 90 and 98 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Manufacturers
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
KRKA Polska Sp. z o.o., Ul. Równoległa 5, 02-235 Warsaw, Poland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 597 365
Österreich
KRKA Pharma GmbH, Wien
Tel:
+
43 (0)1 66 24 300
53
Ελλάδα
QUALIA PHARMA S.A.
Τηλ:
+30 (0)210 2832941
Polska
KRKA Polska Sp.z.o.o
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA Romania S.R.L., Bucharest
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
Κύπρος
Kipa Pharmacal Ltd.
Τηλ:
+
357 24 651 882
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 (0)733 8610
United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0)2089562310
Lietuva
KRKA, d.d., Novo mesto
Tel:
+
370 5 236 27 40
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
(EMA)
http://www.ema.europa.eu/
.
54
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tolura 40 mg tablets
Telmisartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Tolura is and what it is used for
2. Before you take Tolura
3. How to take Tolura
4. Possible side effects
5.
How to store Tolura
6. Further information
1
WHAT TOLURA IS AND WHAT IT IS USED FOR
Tolura belongs to a class of medicines known as angiotensin II receptor antagonists. Angiotensin II is
a substance produced in your body which causes your blood vessels to narrow, thus increasing your
blood pressure. Tolura blocks the effect of angiotensin II so that the blood vessels relax, and your
blood pressure is lowered.
Tolura is used to
treat essential hypertension (high blood pressure). ‘Essential’ means that the high
blood pressure is not caused by any other condition.
High blood pressure, if not treated, can damage blood vessels in several organs, which could lead
sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms
of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure
to verify if it is within the normal range.
2
BEFORE YOU TAKE TOLURA
Do not take Tolura
-
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in Tolura
tablets (see section Further information for a list of other ingredients).
-
if you are more than 3 months pregnant. (It is also better to avoid Tolura in early pregnancy –
see pregnancy section.)
-
if you have severe liver problems such as cholestasis or biliary obstruction (problems with the
drainage of the bile from the liver and gall bladder) or any other severe liver disease.
If any of the above applies to you, tell your doctor or pharmacist before taking Tolura.
Take special care with Tolura
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
55
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body
water) or have salt deficiency due to diuretic therapy ('water tablets'), low-salt diet, diarrhoea, or
vomiting.
-
Elevated potassium levels in your blood.
-
Diabetes.
You must tell your doctor if you think you are (or might become) pregnant. Tolura is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
In case of surgery or anaesthesia, you should tell your doctor that you are taking Tolura.
The use of Tolura in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, Tolura may be less effective in lowering the
blood pressure in black patients.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose of
these other medicines or take other precautions. In some cases you may have to stop taking one of the
medicines. This applies especially to the medicines listed below taken at the same time with Tolura:
-
Lithium containing medicines to treat some types of depression.
-
Medicines that may increase blood potassium levels such as salt substitutes containing
potassium, potassium-sparing diuretics (certain 'water tablets'), ACE inhibitors, angiotensin II
receptor antagonists, NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or
ibuprofen), heparin, immunosuppressives (e.g. cyclosporin or tacrolimus), and the antibiotic
trimethoprim.
-
Diuretics ('water tablets'), especially if taken in high doses together with Tolura, may lead to
excessive loss of body water and low blood pressure (hypotension).
As with other blood pressure lowering medicines, the effect of Tolura may be reduced when you take
NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen) or corticosteroids.
Tolura may increase the blood pressure lowering effect of other medicines used to treat high blood
pressure.
Taking Tolura with food and drink
You can take Tolura with or without food.
56
-
Heart trouble.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Tolura before you become pregnant or as soon as you know you are pregnant
and will advise you to take another medicine instead of Tolura. Tolura is not recommended in early
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to
your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Tolura is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No information is available on the effect of Tolura on the ability to drive or operate machinery. Some
people feel dizzy or tired when they are treated for high blood pressure. If you feel dizzy or tired, do
not drive or operate machinery.
Important information about some of the ingredients of Tolura
Tolura contains lactose and sorbitol (E420).
If you are intolerant to some sugars, consult your doctor before taking Tolura.
3
HOW TO TAKE TOLURA
Always take Tolura exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of Tolura is one tablet a day. Try to take the tablet at the same time each day. You can
take Tolura with or without food. The tablets should be swallowed with some water or other non-
alcoholic drink. It is important that you take Tolura every day until your doctor tells you otherwise. If
you have the impression that the effect of Tolura is too strong or too weak, talk to your doctor or
pharmacist.
The usual dose of Tolura for most patients is one 40 mg tablet once a day to control blood pressure
over the 24 hour period. However, sometimes your doctor may recommend a lower dose of 20 mg or a
higher dose of 80 mg. Tolura may also be used in combination with diuretics ('water tablets') such as
hydrochlorothiazide which has been shown to have an additive blood pressure lowering effect with
Tolura.
If your liver is not working properly, the usual dose should not exceed 40 mg once daily.
If you take more Tolura than you should
If you accidentally take too many tablets, contact your doctor, pharmacist, or your nearest hospital
emergency department immediately.
If you forget to take Tolura
If you forget to take a dose, do not worry. Take it as soon as you remember then carry on as before. If
you do not take your tablet on one day, take your normal dose on the next day.
Do not
take a double
dose to make up for forgotten individual doses.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
57
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tolura can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
Very common:
Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from available data
Uncommon side effects
High potassium levels, fainting (syncope), difficulty falling asleep, feeling of spinning (vertigo), low
blood pressure (hypotension), shortness of breath, abdominal pain, diarrhoea, dry mouth, discomfort in
the abdomen, bloating, increased sweating, itching, muscle pain (myalgia), kidney impairment
including acute kidney failure, and pain in the chest.
:
Rare side effects
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), deficiency in red
blood cells (anaemia), low platelet count (thrombocytopenia), feeling anxious, feeling sad
(depression), impaired vision, fast heart beat (tachycardia), dizziness on standing up (orthostatic
hypotension), upset stomach, vomiting, abnormal liver function, redness of skin, rapid swelling of the
skin and mucosa (angioedema), hives (urticaria), joint pain (arthralgia), back pain, muscle cramps,
pain in extremity, symptoms of weakness, flu-like-illness, increased levels of uric acid, creatinine,
hepatic enzymes or creatine phosphokinase in the blood.
:
Side effects of unknown frequency
Urinary tract infections, increase in certain white blood cells (eosinophilia), allergic reaction (e.g. rash,
itching, difficulty breathing, wheezing, swelling of the face or low blood pressure), slow heart rate
(bradycardia), drug rash, eczema (a skin disorder), inflammation of the tendons, ineffectiveness of
Tolura, decreased haemoglobin (a blood protein), sepsis* (often called “blood poisoning”, is a severe
infection with whole-body inflammatory response which can lead to death).
:
* In a long-term study involving more than 20,000 patients, more patients treated with telmisartan
experienced sepsis compared with patients who received no telmisartan. The event may have
happened by chance or could be related to a mechanism currently not known.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TOLURA
Keep out of the reach and sight of children.
Do not use Tolura after the expiry date which is stated on the carton and blister after “EXP”. The
expiry date refers to the last day of that month.
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
58
6. FURTHER INFORMATION
What Tolura contains
-
The active substance is telmisartan. Each tablet contains 40 mg telmisartan.
-
The other ingredients are povidone, meglumine, sodium hydroxide, lactose monohydrate,
sorbitol (E420) and magnesium stearate.
What Tolura looks like and contents of the pack
Tolura 40 mg tablets are white to almost white, biconvex, oval tablets.
Tolura is available in blister packs containing 14, 28, 30, 56, 84, 90 and 98 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Manufacturers
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
KRKA Polska Sp. z o.o., Ul. Równoległa 5, 02-235 Warsaw, Poland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 597 365
Österreich
KRKA Pharma GmbH, Wien
Tel:
+
43 (0)1 66 24 300
59
Ελλάδα
QUALIA PHARMA S.A.
Τηλ:
+30 (0)210 2832941
Polska
KRKA Polska Sp.z.o.o
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA Romania S.R.L., Bucharest
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
Κύπρος
Kipa Pharmacal Ltd.
Τηλ:
+
357 24 651 882
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 (0)733 8610
United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0)2089562310
Lietuva
KRKA, d.d., Novo mesto
Tel:
+
370 5 236 27 40
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
(EMA)
http://www.ema.europa.eu/
.
60
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tolura 80 mg tablets
Telmisartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Tolura is and what it is used for
2. Before you take Tolura
3. How to take Tolura
4. Possible side effects
6.
How to store Tolura
6. Further information
1
WHAT TOLURA IS AND WHAT IT IS USED FOR
Tolura belongs to a class of medicines known as angiotensin II receptor antagonists. Angiotensin II is
a substance produced in your body which causes your blood vessels to narrow, thus increasing your
blood pressure. Tolura blocks the effect of angiotensin II so that the blood vessels relax, and your
blood pressure is lowered.
Tolura is used to
treat essential hypertension (high blood pressure). ‘Essential’ means that the high
blood pressure is not caused by any other condition.
High blood pressure, if not treated, can damage blood vessels in several organs, which could lead
sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms
of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure
to verify if it is within the normal range.
2
BEFORE YOU TAKE TOLURA
Do not take Tolura
-
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in Tolura
tablets (see section Further information for a list of other ingredients).
-
if you are more than 3 months pregnant. (It is also better to avoid Tolura in early pregnancy –
see pregnancy section.)
-
if you have severe liver problems such as cholestasis or biliary obstruction (problems with the
drainage of the bile from the liver and gall bladder) or any other severe liver disease.
If any of the above applies to you, tell your doctor or pharmacist before taking Tolura.
Take special care with Tolura
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
61
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body
water) or have salt deficiency due to diuretic therapy ('water tablets'), low-salt diet, diarrhoea, or
vomiting.
-
Elevated potassium levels in your blood.
-
Diabetes.
You must tell your doctor if you think you are (or might become) pregnant. Tolura is not
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
In case of surgery or anaesthesia, you should tell your doctor that you are taking Tolura.
The use of Tolura in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, Tolura may be less effective in lowering the
blood pressure in black patients.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. Your doctor may need to change the dose of
these other medicines or take other precautions. In some cases you may have to stop taking one of the
medicines. This applies especially to the medicines listed below taken at the same time with Tolura:
-
Lithium containing medicines to treat some types of depression.
-
Medicines that may increase blood potassium levels such as salt substitutes containing
potassium, potassium-sparing diuretics (certain 'water tablets'), ACE inhibitors, angiotensin II
receptor antagonists, NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or
ibuprofen), heparin, immunosuppressives (e.g. cyclosporin or tacrolimus), and the antibiotic
trimethoprim.
-
Diuretics ('water tablets'), especially if taken in high doses together with Tolura, may lead to
excessive loss of body water and low blood pressure (hypotension).
As with other blood pressure lowering medicines, the effect of Tolura may be reduced when you take
NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen) or corticosteroids.
Tolura may increase the blood pressure lowering effect of other medicines used to treat high blood
pressure.
Taking Tolura with food and drink
You can take Tolura with or without food.
62
-
Heart trouble.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally
advise you to stop taking Tolura before you become pregnant or as soon as you know you are pregnant
and will advise you to take another medicine instead of Tolura. Tolura is not recommended in early
pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to
your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Tolura is not recommended
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish
to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No information is available on the effect of Tolura on the ability to drive or operate machinery. Some
people feel dizzy or tired when they are treated for high blood pressure. If you feel dizzy or tired, do
not drive or operate machinery.
Important information about some of the ingredients of Tolura
Tolura contains lactose and sorbitol (E420).
If you are intolerant to some sugars, consult your doctor before taking Tolura.
3
HOW TO TAKE TOLURA
Always take Tolura exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of Tolura is one tablet a day. Try to take the tablet at the same time each day. You can
take Tolura with or without food. The tablets should be swallowed with some water or other non-
alcoholic drink. It is important that you take Tolura every day until your doctor tells you otherwise. If
you have the impression that the effect of Tolura is too strong or too weak, talk to your doctor or
pharmacist.
The usual dose of Tolura for most patients is one 40 mg tablet once a day to control blood pressure
over the 24 hour period. However, sometimes your doctor may recommend a lower dose of 20 mg or a
higher dose of 80 mg. Tolura may also be used in combination with diuretics ('water tablets') such as
hydrochlorothiazide which has been shown to have an additive blood pressure lowering effect with
Tolura.
If your liver is not working properly, the usual dose should not exceed 40 mg once daily.
If you take more Tolura than you should
If you accidentally take too many tablets, contact your doctor, pharmacist, or your nearest hospital
emergency department immediately.
If you forget to take Tolura
If you forget to take a dose, do not worry. Take it as soon as you remember then carry on as before. If
you do not take your tablet on one day, take your normal dose on the next day.
Do not
take a double
dose to make up for forgotten individual doses.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
63
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Tolura can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
Very common:
Affects more than 1 user in 10
Common:
Affects 1 to 10 users in 100
Uncommon:
Affects 1 to 10 users in 1,000
Rare:
Affects 1 to 10 users in 10,000
Very rare:
Affects less than 1 user in 10,000
Not known:
Frequency cannot be estimated from available data
Uncommon side effects
High potassium levels, fainting (syncope), difficulty falling asleep, feeling of spinning (vertigo), low
blood pressure (hypotension), shortness of breath, abdominal pain, diarrhoea, dry mouth, discomfort in
the abdomen, bloating, increased sweating, itching, muscle pain (myalgia), kidney impairment
including acute kidney failure, and pain in the chest.
:
Rare side effects
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), deficiency in red
blood cells (anaemia), low platelet count (thrombocytopenia), feeling anxious, feeling sad
(depression), impaired vision, fast heart beat (tachycardia), dizziness on standing up (orthostatic
hypotension), upset stomach, vomiting, abnormal liver function, redness of skin, rapid swelling of the
skin and mucosa (angioedema), hives (urticaria), joint pain (arthralgia), back pain, muscle cramps,
pain in extremity, symptoms of weakness, flu-like-illness, increased levels of uric acid, creatinine,
hepatic enzymes or creatine phosphokinase in the blood.
:
Side effects of unknown frequency
Urinary tract infections, increase in certain white blood cells (eosinophilia), allergic reaction (e.g. rash,
itching, difficulty breathing, wheezing, swelling of the face or low blood pressure), slow heart rate
(bradycardia), drug rash, eczema (a skin disorder), inflammation of the tendons, ineffectiveness of
Tolura, decreased haemoglobin (a blood protein), sepsis* (often called “blood poisoning”, is a severe
infection with whole-body inflammatory response which can lead to death).
:
* In a long-term study involving more than 20,000 patients, more patients treated with telmisartan
experienced sepsis compared with patients who received no telmisartan. The event may have
happened by chance or could be related to a mechanism currently not known.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TOLURA
Keep out of the reach and sight of children.
Do not use Tolura after the expiry date which is stated on the carton and blister after “EXP”. The
expiry date refers to the last day of that month.
Store in the original package in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
64
6. FURTHER INFORMATION
What Tolura contains
-
The active substance is telmisartan. Each tablet contains 80 mg telmisartan.
-
The other ingredients are povidone, meglumine, sodium hydroxide, lactose monohydrate,
sorbitol (E420) and magnesium stearate.
What Tolura looks like and contents of the pack
Tolura 80 mg tablets are white to almost white, biconvex, capsule shape tablets.
Tolura is available in blister packs containing 14, 28, 30, 56, 84, 90 and 98 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
Manufacturers
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
KRKA Polska Sp. z o.o., Ul. Równoległa 5, 02-235 Warsaw, Poland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 597 365
Österreich
KRKA Pharma GmbH, Wien
Tel:
+
43 (0)1 66 24 300
65
Ελλάδα
QUALIA PHARMA S.A.
Τηλ:
+30 (0)210 2832941
Polska
KRKA Polska Sp.z.o.o
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA Romania S.R.L., Bucharest
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
Κύπρος
Kipa Pharmacal Ltd.
Τηλ:
+
357 24 651 882
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 (0)733 8610
United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0)2089562310
Lietuva
KRKA, d.d., Novo mesto
Tel:
+
370 5 236 27 40
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
(EMA)
http://www.ema.europa.eu/
.
66
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/tolura.html
Copyright © 1995-2021 ITA all rights reserved.