ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
MicardisPlus 40 mg/12.5 mg tablets
2.
Each tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide.
Excipients: Each tablet contains 112 mg of lactose monohydrate and 169 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet.
Red and white oval shaped two layer tablet engraved with the company logo and the code 'H4'.
4.
Treatment of essential hypertension.
MicardisPlus fixed dose combination (40 mg telmisartan/12.5 mg hydrochlorothiazide) is indicated in
patients whose blood pressure is not adequately controlled on telmisartan alone.
Adults
MicardisPlus should be taken once daily with liquid, with or without food in patients whose blood
pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the
two components is recommended before changing to the fixed dose combination. When clinically
appropriate, direct change from monotherapy to the fixed combination may be considered.
•
MicardisPlus 40 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled by Micardis 40 mg
•
MicardisPlus 80 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled by Micardis 80 mg
Renal impairment
: Periodic monitoring of renal function is advised (see section 4.4).
Hepatic impairment
: In patients with mild to moderate hepatic impairment the posology should not
exceed MicardisPlus 40 mg/12.5 mg once daily. MicardisPlus is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function
(see section 4.4).
Elderly:
No dosage adjustment is necessary.
Children and adolescents
: MicardisPlus is not recommended for use in children below 18 years due to
a lack of data on safety and efficacy.
•
Hypersensitivity to any of the active substances or to any of the excipients (see section 6.1).
2
•
Hypersensitivity to other sulphonamide-derived substances (since hydrochlorothiazide is a
sulphonamide-derived medicinal product).
•
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
•
Cholestasis and biliary obstructive disorders.
•
Severe hepatic impairment.
•
Severe renal impairment (creatinine clearance < 30 ml/min).
•
Refractory hypokalaemia, hypercalcaemia.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should
be changed to alternative antihypertensive treatments which have an established safety profile for use
in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and
4.6).
Hepatic impairment:
MicardisPlus should not be given to patients with cholestasis, biliary obstructive
disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated with
the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.
In addition, MicardisPlus should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with MicardisPlus in patients with hepatic impairment.
Renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation:
MicardisPlus should not be used in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see section 4.3). There is no experience regarding
the administration of MicardisPlus in patients with recent kidney transplantation. Experience with
MicardisPlus is modest in the patients with mild to moderate renal impairment, therefore periodic
monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-
associated azotaemia may occur in patients with impaired renal function.
Intravascular hypovolaemia:
Symptomatic hypotension, especially after the first dose, 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 MicardisPlus.
Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-
angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia, 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 has been
associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section
4.8).
3
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 MicardisPlus is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
As with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy;
however, at the 12.5 mg dose contained in MicardisPlus, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide
therapy.
Electrolyte imbalance:
As for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including
hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte
imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or
cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as
nausea or vomiting (see section 4.8).
- Hypokalaemia
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate
oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or
Adrenocorticotropic hormone (ACTH) (see section 4.5).
- Hyperkalaemia
Conversely, due to the antagonism of the angiotensin II (AT
1
) receptors by the telmisartan component
of MicardisPlus, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not
been documented with MicardisPlus, risk factors for the development of hyperkalaemia include renal
insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium
supplements or potassium-containing salt substitutes should be co-administered cautiously with
MicardisPlus (see section 4.5).
- Hyponatraemia and hypochloraemic alkalosis
There is no evidence that MicardisPlus would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
- Hypercalcaemia
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
- Hypomagnesaemia
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see section 4.5).
Sorbitol and Lactose Monohydrate:
This medicinal product contains lactose monohydrate and sorbitol.
Patients with rare hereditary problems of fructose intolerance and/or with rare hereditary problems of
4
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Ethnic differences:
As with all other angiotensin II receptor antagonists, telmisartan is apparently less
effective in lowering blood pressure in black patients 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.
General:
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a
history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the
sun or to artificial UVA.
Interaction studies have only been performed in adults.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have
also been reported with angiotensin II receptor antagonists (including MicardisPlus). Co-
administration of lithium and MicardisPlus is not recommended (see section 4.4). If this combination
proves essential, careful monitoring of serum lithium level is recommended during concomitant use.
Medicinal products associated with potassium loss and hypokalaemia
(e.g. other kaliuretic diuretics,
laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and
derivatives): If these substances are to be prescribed with the hydrochlorothiazide-telmisartan
combination, monitoring of potassium plasma levels is advised. These medicinal products may
potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
Medicinal products that may increase potassium levels or induce hyperkalaemia
(e.g. ACE inhibitors,
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin
or other medicinal products such as heparin sodium): If these medicinal products are to be prescribed
with the hydrochlorothiazide-telmisartan combination, monitoring of potassium plasma levels is
advised. Based on the experience with the use of other medicinal products that blunt the renin-
angiotensin system, concomitant use of the above medicinal products may lead to increases in serum
potassium and is, therefore, not recommended (see section 4.4).
Medicinal products affected by serum potassium disturbances:
Periodic monitoring of serum
potassium and ECG is recommended when MicardisPlus is administered with these medicinal
products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the
following torsades de pointes inducing medicinal products (which include some antiarrhythmics),
hypokalaemia being a predisposing factor to torsades de pointes.
-
class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)
-
some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,
cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
-
others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,
pentamidine, sparfloxacine, terfenadine, vincamine IV.)
5
-
class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of
digitalis-induced arrhythmia (see section 4.4).
Other antihypertensive agents:
Telmisartan may increase the hypotensive effect of other
antihypertensive agents.
Antidiabetic medicinal products (oral agents and insulin):
Dosage adjustment of the antidiabetic
medicinal products may be required (see section 4.4).
Metformin:
Metformin should be used with precaution: risk of lactic acidosis induced by a possible
functional renal failure linked to hydrochlorothiazide.
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins.
Non-steroidal anti-inflammatory medicinal products:
NSAIDs (i.e. acetylsalicylic acid at anti-
inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic,
natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of
angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with
compromised renal function) the co-administration of angiotensin II receptor antagonists and 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.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
The effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide.
Medicinal products used in the treatment for gout
(e.g. probenecid, sulfinpyrazone and allopurinol):
Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the
level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-
administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If
calcium supplements must be prescribed, serum calcium levels should be monitored and calcium
dosage adjusted accordingly.
Beta-blockers and diazoxide:
The hyperglycaemic effect of beta-blockers and diazoxide may be
enhanced by thiazides.
Anticholinergic agents
(e.g. atropine, biperiden) may increase the bioavailability of thiazide-type
diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Amantadine:
Thiazides may increase the risk of adverse effects caused by amantadine.
Cytotoxic agents
(e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of
cytotoxic medicinal products and potentiate their myelosuppressive effects.
6
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.
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 trimesters of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of MicardisPlus 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 antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped
immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known
to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification
retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for
hypotension (see sections 4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte
disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal
thrombocytopenia, of foetal or neonatal jaundice have been reported with maternal thiazide therapy.
Lactation
:
Because no information is available regarding the use of MicardisPlus during breast-feeding,
MicardisPlus is not recommended and alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Thiazides
appear in human milk and may inhibit lactation.
No studies on the effect 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.
Fixed Dose Combination
The overall incidence of adverse events reported with MicardisPlus was comparable to those reported
with telmisartan alone in randomised controlled trials involving 1471 patients randomised to receive
telmisartan plus hydrochlorothiazide (835) or telmisartan alone (636). Dose-relationship of
7
undesirable effects was not established and they showed no correlation with gender, age or race of the
patients.
0.05) with
telmisartan plus hydrochlorothiazide than with placebo are shown below according to system organ
class. Adverse reactions known to occur with each component given singly but which have not been
seen in clinical trials may occur during treatment with MicardisPlus.
≤
Adverse reactions have been ranked under headings of frequency using the following convention:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Bronchitis
Pharyngitis, sinusitis
Metabolism and nutrition disorders
Not known:
Uncommon:
Hypokalaemia,
Hyperuricaemia, hyponatraemia
Rare:
Psychiatric disorders
Uncommon:
Anxiety
Depression
Dizziness
Syncope, paraesthesia
Insomnia, sleep disorders
Eye disorders
Rare: Visual disturbance, vision blurred
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Uncommon: Tachycardia, arrhythmias
Vascular disorders
Uncommon: Hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon:
Rare:
Uncommon:
Dyspnoea
Respiratory distress (including pneumonitis and pulmonary
oedema)
Rare:
Gastrointestinal disorders
Diarrhoea, dry mouth, flatulence,
Abdominal pain, constipation, dyspepsia, vomiting
Gastritis
Rare:
Not known:
Hepatobiliary disorders
Rare:
Abnormal hepatic function/liver disorder
8
Adverse reactions reported in all clinical trials and occurring more frequently (p
Infections and infestations
Rare:
Rare:
Nervous system disorders
Common:
Uncommon:
Back pain, muscle spasms, myalgia
Arthralgia, muscle cramps, pain in limb
Reproductive system and breast disorders
Uncommon: Erectile dysfunction
General disorders and administration site conditions
Rare:
Uncommon:
Chest pain
Influenza-like illness, pain
Rare:
Investigations
Uncommon:
Blood uric acid increased
Blood creatinine increased, blood creatine phosphokinase
increased, hepatic enzyme increased
Additional information on individual components
undesirable effects with MicardisPlus, even if not observed in clinical trials with this product.
Telmisartan:
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The following 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 of unknown frequency reported with the use of telmisartan alone include:
Infections and infestations
Not known: Upper respiratory tract infection, urinary tract infection including
cystitis, sepsis including fatal outcome*
Blood and lymphatic system disorders
Not known: Eosinophilia, anaemia, thrombocytopenia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reactions
Metabolism and nutrition disorders
Not known: Hyperkalaemia
Cardiac disorders
Not known: Bradycardia
Gastrointestinal disorders
Not known: Stomach discomfort
Skin and subcutaneous tissue disorders
Eczema, drug eruption, toxic skin eruption
9
Skin and subcutaneous tissue disorders
Rare: Angioedema, erythema, pruritus, rash, hyperhidrosis, urticaria
Muscoloskeletal, connective tissue and bone disorders
Uncommon:
Rare:
Not known:
Arthrosis, tendon pain
Renal and urinary disorders
Not known: Renal dysfunction, renal impairment (including acute renal
failure)
General disorders and administration site conditions
Not known: Asthenia
Investigations
Not known: 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).
Hydrochlorothiazide:
Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance
(see section 4.4).
Adverse reactions of unknown frequency reported with the use of hydrochlorothiazide alone include:
Infections and infestations
Not known: Sialoadenitis
Blood and lymphatic system disorders
Not known:
Anaemia aplastic, haemolytic anaemia, bone marrow failure,
leukopenia, neutropenia, agranulocytosis, thrombocytopenia
Immune system disorders
Anaphylactic reactions, hypersensitivity
Endocrine disorders
Diabetes mellitus inadequate control
Metabolism and nutrition disorders
Anorexia, appetite decreased, electrolyte imbalance,
hypercholesterolaemia, hyperglycaemia, hypovolaemia
Psychiatric disorders
Not known:
Restlessness
Nervous system disorders
Not known:
Light-headedness
Eye disorders
Not known
Xanthopsia
Vascular disorders
Not known:
Vasculitis necrotizing
Gastrointestinal disorders
Not known:
Pancreatitis, stomach discomfort
Hepatobiliary disorders
Not known:
Jaundice hepatocellular, jaundice cholestatic
10
Musculoskeletal, connective tissue and bone disorders
Not known:
Not known:
Not known:
Not known:
Skin and subcutaneous tissue disorders
Not known: Lupus-like syndrome, photosensitivity reactions, skin
vasculitis, toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders
Not known: Weakness
Renal and urinary disorders
Not known: Nephritis interstitial, renal dysfunction, glycosuria
General disorders and administration site conditions
Not known:
Pyrexia
Investigations
Not known:
Triglycerides increased
There is limited information available for telmisartan with regard to overdose in humans. The degree
to which hydrochlorothiazide is removed by haemodialysis has not been established.
Symptoms:
The most prominent manifestations of telmisartan overdose were hypotension and
tachycardia; bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure
(hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Treatment:
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 overdose. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacements given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II receptor antagonists and diuretics, ATC code: C09DA07
MicardisPlus is a combination of an angiotensin II receptor antagonist, telmisartan, and a thiazide
diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive
effect, reducing blood pressure to a greater degree than either component alone. MicardisPlus once
daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (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
11
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.
An 80 mg dose of telmisartan administered to healthy volunteers 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 4-8 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 measurements made at the point of maximum
effect and immediately prior to the next dose (through to peak ratios consistently above 80 % after
doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies).
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents
representative of other classes of antihypertensive 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.
The effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide
diuretics is not fully known. Thiazides have an effect on the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin
activity, increases aldosterone secretion, with consequent increases in urinary potassium and
bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-
angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium loss
associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak
effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the
risk of cardiovascular mortality and morbidity.
The effects of Fixed Dose Combination of telmisartan/HCTZ on mortality and cardiovascular
morbidity are currently unknown.
5.2. Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect the
pharmacokinetics of either substance in healthy subjects.
12
Absorption:
Telmisartan: Following oral administration peak concentrations of telmisartan are reached
in 0.5 – 1.5 h after dosing. The absolute bioavailability of telmisartan at 40 mg and 160 mg was 42 %
and 58 %, respectively. Food slightly reduces the bioavailability of telmisartan with a reduction in the
area under the plasma concentration time curve (AUC) of about 6 % with the 40 mg tablet and about
19 % after a 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. The pharmacokinetics of orally administered telmisartan are non-
linear over doses from 20 – 160 mg with greater than proportional increases of plasma concentrations
(C
max
and AUC) with increasing doses. Telmisartan does not accumulate significantly in plasma on
repeated administration.
Hydrochlorothiazide: Following oral administration of MicardisPlus peak concentrations of
hydrochlorothiazide are reached in approximately 1.0 – 3.0 hours after dosing. Based on cumulative
renal excretion of hydrochlorothiazide the absolute bioavailability was about 60 %.
Distribution:
Telmisartan is highly bound to plasma proteins (>99.5 %) mainly albumin and alpha l-
acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 litres
indicating additional tissue binding.
Hydrochlorothiazide is 68 % protein bound in the plasma and its apparent volume of distribution is
0.83 – 1.14 l/kg.
Biotransformation and elimination:
Telmisartan: Following either intravenous or oral administration of
14
C-labelled telmisartan most of the administered dose (>97 %) was eliminated in faeces via biliary
excretion. Only minute amounts were found in urine. Telmisartan is metabolised by conjugation to
form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the
only metabolite that has been identified in humans. After a single dose of
14
C-labelled telmisartan the
glucuronide represents approximately 11 % of the measured radioactivity in plasma. The cytochrome
P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of
telmisartan after oral administration is >1500 ml/min. Terminal elimination half-life was >20 hours.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as
unchanged substance in urine. About 60 % of the oral dose is eliminated as unchanged substance
within 48 hours. Renal clearance is about 250 – 300 ml/min. The terminal elimination half-life of
hydrochlorothiazide is 10 – 15 hours.
Special populations
Elderly patients:
Pharmacokinetics of telmisartan do not differ between the elderly and those younger
than 65 years.
Gender:
Plasma concentrations of telmisartan are generally 2 – 3 times higher in females than in
males. In clinical trials however, no significant increases in blood pressure response or in the
incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There
was a trend towards higher plasma concentrations of hydrochlorothiazide in female than in male
subjects. This is not considered to be of clinical relevance.
Patients with renal impairment:
Renal excretion does not contribute to the clearance of telmisartan.
Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance
of 30 – 60 ml/min, mean about 50 ml/min) no dosage adjustment is necessary in patients with
decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with
impaired renal function the rate of hydrochlorothiazide elimination is reduced. In a typical study in
patients with a mean creatinine clearance of 90 ml/min the elimination half-life of hydrochlorothiazide
was increased. In functionally anephric patients the elimination half-life is about 34 hours.
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.
13
5.3 Preclinical safety data
In preclinical safety studies performed with co-administration of telmisartan and hydrochlorothiazide
in normotensive rats and dogs, doses producing exposure comparable to that in the clinical
therapeutic range caused no additional findings not already observed with administration of either
substance alone. The toxicological findings observed appear to have no relevance to human
therapeutic use.
Toxicological findings also well known from preclinical studies with angiotensin converting enzyme
inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters
(erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea
nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the
juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented/ameliorated by
oral saline supplementation and group housing of animals. In dogs renal tubular dilation and atrophy
were observed. These findings are considered to be due to the pharmacological activity of telmisartan.
Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies
and no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shown
equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the
extensive human experience with hydrochlorothiazide has failed to show an association between its
use and an increase in neoplasms.
For the foetotoxic potential of the telmisartan/hydrochlorothiazide combination see section 4.6.
6.
6.1 List of excipients
Lactose monohydrate
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone (K25)
Red ferric oxide (E172)
Sodium hydroxide
Sodium starch glycollate (type A)
Sorbitol (E420).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. Store in the original package
in order to protect from moisture.
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al or PA/PA/Al/PVC/Al). One blister contains 7 or 10
tablets.
14
Pack sizes: Blister with 14, 28, 56, 84, or 98 tablets or perforated unit dose blisters with 28 x 1, 30 x 1
or 90 x 1 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Occasionally, the outer layer of the blister pack has been observed to separate from the inner layer
between the blister pockets. No action needs to be taken if this is observed.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/02/213/001-005
EU/1/02/213/011
EU/1/02/213/013-014
9.
Date of first authorisation:19 April 2002
Date of last renewal: 19 April 2007
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu
/
.
15
1.
MicardisPlus 80 mg/12.5 mg tablets
2.
Each tablet contains 80 mg telmisartan and 12.5 mg hydrochlorothiazide.
Excipients: Each tablet contains 112 mg of lactose monohydrate and 338 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet.
Red and white oval shaped two layer tablet engraved with the company logo and the code 'H8'.
4.
Treatment of essential hypertension.
MicardisPlus fixed dose combination (80 mg telmisartan/12.5 mg hydrochlorothiazide) is indicated in
patients whose blood pressure is not adequately controlled on telmisartan alone.
Adults
MicardisPlus should be taken once daily with liquid, with or without food in patients whose blood
pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the
two components is recommended before changing to the fixed dose combination. When clinically
appropriate, direct change from monotherapy to the fixed combination may be considered
•
MicardisPlus 40 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled by Micardis 40 mg
•
MicardisPlus 80 mg/12.5 mg may be administered in patients whose blood pressure is not
adequately controlled by Micardis 80 mg
Renal impairment
: Periodic monitoring of renal function is advised (see section 4.4).
Hepatic impairment:
In patients with mild to moderate hepatic impairment the posology should not
exceed MicardisPlus 40 mg/12.5 mg once daily. MicardisPlus is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function
(see section 4.4).
Elderly:
No dosage adjustment is necessary.
Children and adolescents:
MicardisPlus is not recommended for use in children below 18 years due to
a lack of data on safety and efficacy.
•
Hypersensitivity to any of the active substances or to any of the excipients (see section 6.1).
16
•
Hypersensitivity to other sulphonamide-derived substances (since hydrochlorothiazide is a
sulphonamide-derived medicinal product).
•
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
•
Cholestasis and biliary obstructive disorders.
•
Severe hepatic impairment.
•
Severe renal impairment (creatinine clearance <30 ml/min).
•
Refractory hypokalaemia, hypercalcaemia.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should
be changed to alternative antihypertensive treatments which have an established safety profile for use
in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and
4.6).
Hepatic impairment:
MicardisPlus should not be given to patients with cholestasis, biliary obstructive
disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated with
the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.
In addition, MicardisPlus should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with MicardisPlus in patients with hepatic impairment.
Renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation:
MicardisPlus should not be used in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see section 4.3). There is no experience regarding
the administration of MicardisPlus in patients with recent kidney transplantation. Experience with
MicardisPlus is modest in the patients with mild to moderate renal impairment, therefore periodic
monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-
associated azotaemia may occur in patients with impaired renal function.
Intravascular hypovolaemia:
Symptomatic hypotension, especially after the first dose, 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 MicardisPlus.
Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-
angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia, 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 has been
associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section
4.8).
17
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 MicardisPlus is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
As with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy;
however, at the 12.5 mg dose contained in MicardisPlus, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide
therapy.
Electrolyte imbalance:
As for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including
hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte
imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or
cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as
nausea or vomiting (see section 4.8).
- Hypokalaemia
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate
oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or
Adrenocorticotropic hormone (ACTH) (see section 4.5).
- Hyperkalaemia
Conversely, due to the antagonism of the angiotensin II (AT
1
) receptors by the telmisartan component
of MicardisPlus, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not
been documented with MicardisPlus, risk factors for the development of hyperkalaemia include renal
insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium
supplements or potassium-containing salt substitutes should be co-administered cautiously with
MicardisPlus (see section 4.5).
- Hyponatraemia and hypochloraemic alkalosis
There is no evidence that MicardisPlus would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
- Hypercalcaemia
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
- Hypomagnesaemia
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see section 4.5).
Sorbitol and Lactose Monohydrate:
This medicinal product contains lactose monohydrate and sorbitol.
Patients with rare hereditary problems of fructose intolerance and/or with rare hereditary problems of
18
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Ethnic differences:
As with all other angiotensin II receptor antagonists telmisartan is apparently less
effective in lowering blood pressure in black patients 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.
General:
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a
history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the
sun or to artificial UVA.
Interaction studies have only been performed in adults.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have
also been reported with angiotensin II receptor antagonists (including MicardisPlus). Co-
administration of lithium and MicardisPlus is not recommended (see section 4.4). If this combination
proves essential, careful monitoring of serum lithium level is recommended during concomitant use.
Medicinal products associated with potassium loss and hypokalaemia
(e.g. other kaliuretic diuretics,
laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and
derivatives): If these substances are to be prescribed with the hydrochlorothiazide-telmisartan
combination, monitoring of potassium plasma levels is advised. These medicinal products may
potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
Medicinal products that may increase potassium levels or induce hyperkalaemia
(e.g. ACE inhibitors,
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin
or other medicinal products such as heparin sodium): If these medicinal products are to be prescribed
with the hydrochlorothiazide-telmisartan combination, monitoring of potassium plasma levels is
advised. Based on the experience with the use of other medicinal products that blunt the renin-
angiotensin system, concomitant use of the above medicinal products may lead to increases in serum
potassium and is, therefore, not recommended (see section 4.4).
Medicinal products affected by serum potassium disturbances:
Periodic monitoring of serum
potassium and ECG is recommended when MicardisPlus is administered with medicinal products
affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following
torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia
being a predisposing factor to torsades de pointes.
-
class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)
-
some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,
cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
-
others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,
pentamidine, sparfloxacine, terfenadine, vincamine IV.)
19
-
class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of
digitalis-induced arrhythmia (see section 4.4).
Other antihypertensive agents:
Telmisartan may increase the hypotensive effect of other
antihypertensive agents.
Antidiabetic medicinal products (oral agents and insulin):
Dosage adjustment of the antidiabetic
medicinal products may be required (see section 4.4).
Metformin:
Metformin should be used with precaution: risk of lactic acidosis induced by a possible
functional renal failure linked to hydrochlorothiazide.
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins.
Non-steroidal anti-inflammatory medicinal products:
NSAIDs (i.e. acetylsalicylic acid at anti-
inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic,
natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of
angiotensin II receptor antagonists.
In some patients with compromised renal function (eg 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.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
The effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide.
Medicinal products used in the treatment for gout
(e.g. probenecid, sulfinpyrazone and allopurinol):
Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the
level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-
administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If
calcium supplements must be prescribed, serum calcium levels should be monitored and calcium
dosage adjusted accordingly.
Beta-blockers and diazoxide:
The hyperglycaemic effect of beta-blockers and diazoxide may be
enhanced by thiazides.
Anticholinergic agents
(e.g. atropine, biperiden) may increase the bioavailability of thiazide-type
diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Amantadine:
Thiazides may increase the risk of adverse effects caused by amantadine.
Cytotoxic agents
(e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of
cytotoxic medicinal products and potentiate their myelosuppressive effects.
20
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.
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 trimesters of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of MicardisPlus 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 antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped
immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known
to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification
retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for
hypotension (see sections 4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte
disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal
thrombocytopenia, of foetal or neonatal jaundice have been reported with maternal thiazide therapy.
Lactation:
Because no information is available regarding the use of MicardisPlus during breast-feeding,
MicardisPlus is not recommended and alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Thiazides
appear in human milk and may inhibit lactation.
No studies on the effect 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.
Fixed Dose Combination
The overall incidence of adverse events reported with MicardisPlus was comparable to those reported
with telmisartan alone in randomised controlled trials involving 1471 patients randomised to receive
telmisartan plus hydrochlorothiazide (835) or telmisartan alone (636). Dose-relationship of
21
undesirable effects was not established and they showed no correlation with gender, age or race of the
patients.
0.05) with
telmisartan plus hydrochlorothiazide than with placebo are shown below according to system organ
class. Adverse reactions known to occur with each component given singly but which have not been
seen in clinical trials may occur during treatment with MicardisPlus.
≤
Adverse reactions have been ranked under headings of frequency using the following convention:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Bronchitis
Pharyngitis, sinusitis
Metabolism and nutrition disorders
Not known:
Uncommon:
Hypokalaemia,
Hyperuricaemia, hyponatraemia
Rare:
Psychiatric disorders
Uncommon:
Anxiety
Depression
Dizziness
Syncope, paraesthesia
Insomnia, sleep disorders
Eye disorders
Rare: Visual disturbance, vision blurred
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Uncommon: Tachycardia, arrhythmias
Vascular disorders
Uncommon: Hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon:
Rare:
Uncommon:
Dyspnoea
Respiratory distress (including pneumonitis and pulmonary
oedema)
Rare:
Gastrointestinal disorders
Diarrhoea, dry mouth, flatulence,
Abdominal pain, constipation,dyspepsia, vomiting
Gastritis
Rare:
Not known:
Hepatobiliary disorders
Rare:
Abnormal hepatic function/liver disorder
22
Adverse reactions reported in all clinical trials and occurring more frequently (p
Infections and infestations
Rare:
Rare:
Nervous system disorders
Common:
Uncommon:
Back pain, muscle spasms, myalgia
Arthralgia, muscle cramps, pain in limb
Reproductive system and breast disorders
Uncommon: Erectile dysfunction
General disorders and administration site conditions
Rare:
Uncommon:
Chest pain
Influenza-like illness, pain
Rare:
Investigations
Uncommon:
Blood uric acid increased
Blood creatinine increased, blood creatine phosphokinase
increased, hepatic enzyme increased
Additional information on individual components
undesirable effects with MicardisPlus, even if not observed in clinical trials with this product.
Telmisartan:
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The following 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 of unknown frequency reported with the use of telmisartan alone include:
Infections and infestations
Not known: Upper respiratory tract infection, urinary tract infection including
cystitis, sepsis including fatal outcome*
Blood and lymphatic system disorders
Not known: Eosinophilia, anaemia, thrombocytopenia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reactions
Metabolism and nutrition disorders
Not known:
Hyperkalaemia
Cardiac disorders
Not known:
Bradycardia
Gastrointestinal disorders
Stomach discomfort
23
Skin and subcutaneous tissue disorders
Rare: Angioedema, erythema, pruritus, rash, hyperhidrosis, urticaria
Muscoloskeletal, connective tissue and bone disorders
Uncommon:
Rare:
Not known:
Eczema, drug eruption, toxic skin eruption
Musculoskeletal, connective tissue and bone disorders
Not known: Arthrosis, tendon pain
Renal and urinary disorders
Not known: Renal dysfunction, renal impairment (including acute renal
failure)
General disorders and administration site conditions
Not known: Asthenia
Investigations
Not known: 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).
Hydrochlorothiazide:
Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance
(see section 4.4).
Adverse reactions of unknown frequency reported with the use of hydrochlorothiazide alone include:
Infections and infestations
Not known: Sialoadenitis
Blood and lymphatic system disorders
Anaemia aplastic, haemolytic anaemia, bone marrow failure,
leukopenia, neutropenia, agranulocytosis, thrombocytopenia
Immune system disorders
Not known:
Anaphylactic reactions, hypersensitivity
Endocrine disorders
Not known:
Diabetes mellitus inadequate control
Metabolism and nutrition disorders
Not known:
Anorexia, appetite decreased, electrolyte imbalance,
hypercholesterolaemia, hyperglycaemia, hypovolaemia
Psychiatric disorders
Restlessness
Nervous system disorders
Light-headedness
Eye disorders
Xanthopsia
Vascular disorders
Vasculitis necrotizing
Gastrointestinal disorders
Pancreatitis, stomach discomfort
24
Skin and subcutaneous tissue disorders
Not known:
Not known:
Not known:
Not known:
Not known
Not known:
Not known:
Hepatobiliary disorders
Not known: Jaundice hepatocellular, jaundice cholestatic
Skin and subcutaneous tissue disorders
Not known: Lupus-like syndrome, photosensitivity reactions, skin
vasculitis, toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders
Not known: Weakness
Renal and urinary disorders
Not known: Nephritis interstitial, renal dysfunction, glycosuria
General disorders and administration site conditions
Not known:
Pyrexia
Investigations
Not known:
Triglycerides increased
There is limited information available for telmisartan with regard to overdose in humans. The degree
to which hydrochlorothiazide is removed by haemodialysis has not been established.
Symptoms:
The most prominent manifestations of telmisartan overdose were hypotension and
tachycardia; bradycardia dizziness, vomiting, increase in serum creatinine, and acute renal failure have
(hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Treatment:
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 overdose. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacements given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II receptor antagonists and diuretics, ATC code: C09DA07
MicardisPlus is a combination of an angiotensin II receptor antagonist, telmisartan, and a thiazide
diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive
effect, reducing blood pressure to a greater degree than either component alone. MicardisPlus once
daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (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
25
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.
An 80
mg dose of telmisartan administered to healthy volunteers 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 4-8 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 measurements made at the point of maximum
effect and immediately prior to the next dose (through to peak ratios consistently above 80 % after
doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies).
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents
representative of other classes of antihypertensive 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.
The effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide
diuretics is not fully known. Thiazides have an effect on the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin
activity, increases aldosterone secretion, with consequent increases in urinary potassium and
bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-
angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium loss
associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak
effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the
risk of cardiovascular mortality and morbidity.
The effects of Fixed Dose Combination of telmisartan/HCTZ on mortality and cardiovascular
morbidity are currently unknown.
26
5.2. Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect the
pharmacokinetics of either substance in healthy subjects.
Absorption:
Telmisartan: Following oral administration peak concentrations of telmisartan are reached
in 0.5 – 1.5 h after dosing. The absolute bioavailability of telmisartan at 40 mg and 160 mg was 42 %
and 58 %, respectively. Food slightly reduces the bioavailability of telmisartan with a reduction in the
area under the plasma concentration time curve (AUC) of about 6 % with the 40 mg tablet and about
19 % after a 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. The pharmacokinetics of orally administered telmisartan are non-
linear over doses from 20 – 160 mg with greater than proportional increases of plasma concentrations
(C
max
and AUC) with increasing doses. Telmisartan does not accumulate significantly in plasma on
repeated administration.
Hydrochlorothiazide: Following oral administration of MicardisPlus peak concentrations of
hydrochlorothiazide are reached in approximately 1.0 – 3.0 hours after dosing. Based on cumulative
renal excretion of hydrochlorothiazide the absolute bioavailability was about 60 %.
Distribution:
Telmisartan is highly bound to plasma proteins (>99.5 %) mainly albumin and alpha l-
acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 litres
indicating additional tissue binding.
Hydrochlorothiazide is 68 % protein bound in the plasma and its apparent volume of distribution is
0.83 – 1.14 1/kg.
Biotransformation and elimination:
Telmisartan: Following either intravenous or oral administration of
14
C-labelled telmisartan most of the administered dose (>97 %) was eliminated in faeces via biliary
excretion. Only minute amounts were found in urine. Telmisartan is metabolised by conjugation to
form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the
only metabolite that has been identified in humans. After a single dose of
14
C-labelled telmisartan the
glucuronide represents approximately 11 % of the measured radioactivity in plasma. The cytochrome
P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of
telmisartan after oral administration is >1500 ml/min. Terminal elimination half-life was >20 hours.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as
unchanged substance in urine. About 60 % of the oral dose is eliminated as unchanged substance
within 48 hours. Renal clearance is about 250 – 300 ml/min. The terminal elimination half-life of
hydrochlorothiazide is 10 – 15 hours.
Special populations
Elderly patients:
Pharmacokinetics of telmisartan do not differ between the elderly and those younger
than 65 years.
Gender:
Plasma concentrations of telmisartan are generally 2 – 3 times higher in females than in
males. In clinical trials however, no significant increases in blood pressure response or in the
incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There
was a trend towards higher plasma concentrations of hydrochlorothiazide in female than in male
subjects. This is not considered to be of clinical relevance.
Patients with renal impairment:
Renal excretion does not contribute to the clearance of telmisartan.
Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance
of 30 – 60 ml/min, mean about 50 ml/min) no dosage adjustment is necessary in patients with
decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with
impaired renal function the rate of hydrochlorothiazide elimination is reduced. In a typical study in
patients with a mean creatinine clearance of 90 ml/min the elimination half-life of hydrochlorothiazide
was increased. In functionally anephric patients the elimination half-life is about 34 hours.
27
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 performed with co-administration of telmisartan and hydrochlorothiazide
in normotensive rats and dogs, doses producing exposure comparable to that in the clinical
therapeutic range caused no additional findings not already observed with administration of either
substance alone. The toxicological findings observed appear to have no relevance to human
therapeutic use.
Toxicological findings also well known from preclinical studies with angiotensin converting enzyme
inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters
(erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea
nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the
juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented/ameliorated by
oral saline supplementation and group housing of animals. In dogs renal tubular dilation and atrophy
were observed. These findings are considered to be due to the pharmacological activity of telmisartan.
Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies
and no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shown
equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the
extensive human experience with hydrochlorothiazide has failed to show an association between its
use and an increase in neoplasms.
For the foetotoxic potential of the telmisartan/hydrochlorothiazide combination see section 4.6.
6.
6.1 List of excipients
Lactose monohydrate
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone (K25)
Red ferric oxide (E172)
Sodium hydroxide
Sodium starch glycollate (type A)
Sorbitol (E420).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. Store in the original package
in order to protect from moisture.
28
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al or PA/PA/Al/PVC/Al). One blister contains 7 or 10
tablets.
Pack sizes: Blister with 14, 28, 56, 84, or 98 tablets or perforated unit dose blisters with 28 x 1, 30 x 1
or 90 x 1 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Occasionally, the outer layer of the blister pack has been observed to separate from the inner layer
between the blister pockets. No action needs to be taken if this is observed.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/02/213/006-010
EU/1/02/213/012
EU/1/02/213/015-016
9.
Date of first authorisation:19 April 2002
Date of last renewal: 19 April 2007
10.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
29
1.
MicardisPlus 80 mg/25 mg tablets
2.
Each tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.
Excipients: Each tablet contains 99 mg of lactose monohydrate and 338 mg sorbitol (E420).
For a full list of excipients, see section 6.1.
3.
Tablet.
Yellow and white oval shaped tablet engraved with the company logo and the code 'H9'.
4.
Treatment of essential hypertension.
MicardisPlus fixed dose combination (80 mg telmisartan/25 mg hydrochlorothiazide) is indicated in
patients whose blood pressure is not adequately controlled on MicardisPlus 80 mg/12.5 mg (80 mg
telmisartan/12.5 mg hydrochlorothiazide) or patients who have been previously stabilised on
telmisartan and hydrochlorothiazide given separately.
Adults
MicardisPlus should be taken once daily with liquid, with or without food in patients whose blood
pressure is not adequately controlled by telmisartan alone. Individual dose titration with each of the
two components is recommended before changing to the fixed dose combination. When clinically
appropriate, direct change from monotherapy to the fixed combination may be considered
MicardisPlus 80 mg/25 mg may be administered in patients whose blood pressure is not
adequately controlled by MicardisPlus 80 mg/12.5 mg or in patients who have been previously
stabilised on telmisartan and hydrochlorothiazide given separately.
MicardisPlus is also available at the dose strengths 40 mg/12.5 mg and 80 mg/ 12.5 mg
Renal impairment
: Periodic monitoring of renal function is advised (see section 4.4).
Hepatic impairment:
In patients with mild to moderate hepatic impairment the posology should not
exceed MicardisPlus 40 mg/12.5 mg once daily. MicardisPlus is not indicated in patients with severe
hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function
(see section 4.4).
Elderly:
No dosage adjustment is necessary.
Children and adolescents:
MicardisPlus is not recommended for use in children below 18 years due to
a lack of data on safety and efficacy.
30
•
Hypersensitivity to any of the active substances or to any of the excipients (see section 6.1).
•
Hypersensitivity to other sulphonamide-derived substances (since hydrochlorothiazide is a
sulphonamide-derived medicinal product).
•
Second and third trimesters of pregnancy (see section
s 4.4 and 4.6).
•
Cholestasis and biliary obstructive disorders.
•
Severe hepatic impairment.
•
Severe renal impairment (creatinine clearance <30 ml/min).
•
Refractory hypokalaemia, hypercalcaemia.
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued
angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should
be changed to alternative antihypertensive treatments which have an established safety profile for use
in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should
be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and
4.6).
Hepatic impairment:
MicardisPlus should not be given to patients with cholestasis, biliary obstructive
disorders or severe hepatic insufficiency (see section 4.3) since telmisartan is mostly eliminated with
the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.
In addition, MicardisPlus should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma. There is no clinical experience with MicardisPlus in patients with hepatic impairment.
Renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation:
MicardisPlus should not be used in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see section 4.3). There is no experience regarding
the administration of MicardisPlus in patients with recent kidney transplantation. Experience with
MicardisPlus is modest in the patients with mild to moderate renal impairment, therefore periodic
monitoring of potassium, creatinine and uric acid serum levels is recommended. Thiazide diuretic-
associated azotaemia may occur in patients with impaired renal function.
Intravascular hypovolaemia:
Symptomatic hypotension, especially after the first dose, 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 MicardisPlus.
Dual blockade of the renin-angiotensin-aldosterone system: As a consequence of inhibiting the renin-
angiotensin-aldosterone system, hypotension, syncope, hyperkalaemia, 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 has been
31
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 MicardisPlus is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
As with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. In diabetic patients
dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus
may become manifest during thiazide therapy.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy;
however, at the 12.5 mg dose contained in MicardisPlus, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide
therapy.
Electrolyte imbalance:
As for any patient receiving diuretic therapy, periodic determination of serum
electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including
hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte
imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or
cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as
nausea or vomiting (see section 4.8).
- Hypokalaemia
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with
telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients
with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate
oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or
Adrenocorticotropic hormone (ACTH) (see section 4.5).
- Hyperkalaemia
Conversely, due to the antagonism of the angiotensin II (AT
1
) receptors by the telmisartan component
of MicardisPlus, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not
been documented with MicardisPlus, risk factors for the development of hyperkalaemia include renal
insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium
supplements or potassium-containing salt substitutes should be co-administered cautiously with
MicardisPlus (see section 4.5).
- Hyponatraemia and hypochloraemic alkalosis
There is no evidence that MicardisPlus would reduce or prevent diuretic-induced hyponatraemia.
Chloride deficit is generally mild and usually does not require treatment.
- Hypercalcaemia
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia
may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out
tests for parathyroid function.
- Hypomagnesaemia
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see section 4.5).
32
Sorbitol and Lactose Monohydrate:
This medicinal product contains lactose monohydrate and sorbitol.
Patients with rare hereditary problems of fructose intolerance and/or with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
Ethnic differences:
As with all other angiotensin II receptor antagonists, telmisartan is apparently less
effective in lowering blood pressure in black patients 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.
General:
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a
history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide
diuretics.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a
photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-
administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the
sun or to artificial UVA.
Interaction studies have only been performed in adults.
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have
also been reported with angiotensin II receptor antagonists (including MicardisPlus). Co-
administration of lithium and MicardisPlus is not recommended (see section 4.4). If this combination
proves essential, careful monitoring of serum lithium level is recommended during concomitant use.
Medicinal products associated with potassium loss and hypokalaemia
(e.g. other kaliuretic diuretics,
laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and
derivatives): If these substances are to be prescribed with the hydrochlorothiazide-telmisartan
combination, monitoring of potassium plasma levels is advised. These medicinal products may
potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
Medicinal products that may increase potassium levels or induce hyperkalaemia
(e.g. ACE inhibitors,
potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporin
or other medicinal products such as heparin sodium): If these medicinal products are to be prescribed
with the hydrochlorothiazide-telmisartan combination, monitoring of potassium plasma levels is
advised. Based on the experience with the use of other medicinal products that blunt the renin-
angiotensin system, concomitant use of the above medicinal products may lead to increases in serum
potassium and is, therefore, not recommended (see section 4.4).
Medicinal products affected by serum potassium disturbances:
Periodic monitoring of serum
potassium and ECG is recommended when MicardisPlus is administered with medicinal products
affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following
torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalaemia
being a predisposing factor to torsades de pointes.
-
class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)
-
class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
-
some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,
cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
-
others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,
pentamidine, sparfloxacine, terfenadine, vincamine IV.)
33
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of
digitalis-induced arrhythmia (see section 4.4).
Other antihypertensive agents:
Telmisartan may increase the hypotensive effect of other
antihypertensive agents.
Antidiabetic medicinal products (oral agents and insulin):
Dosage adjustment of the antidiabetic
medicinal products may be required (see section 4.4).
Metformin:
Metformin should be used with precaution: risk of lactic acidosis induced by a possible
functional renal failure linked to hydrochlorothiazide.
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence of
anionic exchange resins.
Non-steroidal anti-inflammatory medicinal products:
NSAIDs (i.e. acetylsalicylic acid at anti-
inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic,
natriuretic and antihypertensive effects of thiazide diuretics and the antihypertensive effects of
angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with
compromised renal function) the co-administration of angiotensin II receptor antagonists and 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.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine):
The effect of nondepolarizing skeletal
muscle relaxants may be potentiated by hydrochlorothiazide.
Medicinal products used in the treatment for gout
(e.g. probenecid, sulfinpyrazone and allopurinol):
Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the
level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-
administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If
calcium supplements must be prescribed, serum calcium levels should be monitored and calcium
dosage adjusted accordingly.
Beta-blockers and diazoxide:
The hyperglycaemic effect of beta-blockers and diazoxide may be
enhanced by thiazides.
Anticholinergic agents
(e.g. atropine, biperiden) may increase the bioavailability of thiazide-type
diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Amantadine:
Thiazides may increase the risk of adverse effects caused by amantadine.
Cytotoxic agents
(e.g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of
cytotoxic medicinal products and potentiate their myelosuppressive effects.
34
Based on their pharmacological properties it can be expected that the following medicinal product may
potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine.
Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or
antidepressants.
4.6
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 trimesters of pregnancy (see sections 4.3 and 4.4).
There are no adequate data from the use of MicardisPlus 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 antihypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped
immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known
to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification
retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for
hypotension (see sections 4.3 and 4.4).
Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte
disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal
thrombocytopenia, of foetal or neonatal jaundice have been reported with maternal thiazide therapy.
Lactation:
Because no information is available regarding the use of MicardisPlus during breast-feeding,
MicardisPlus is not recommended and alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Thiazides
appear in human milk and may inhibit lactation.
No studies on the effect 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.
Fixed Dose Combination
The overall incidence and pattern of adverse events reported with MicardisPlus 80 mg/25 mg was
comparable with MicardisPlus 80 mg/12.5 mg. A dose-relationship of undesirable effects was not
established and they showed no correlation with gender, age or race of the patients.
35
0.05) with
telmisartan plus hydrochlorothiazide than with placebo are shown below according to system organ
class. Adverse reactions known to occur with each component given singly but which have not been
seen in clinical trials may occur during treatment with MicardisPlus.
≤
Adverse reactions have been ranked under headings of frequency using the following convention:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000
to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Bronchitis
Pharyngitis, sinusitis
Metabolism and nutrition disorders
Not known:
Uncommon:
Hypokalaemia,
Hyperuricaemia, hyponatraemia
Rare:
Psychiatric disorders
Uncommon:
Anxiety
Depression
Dizziness
Syncope, paraesthesia
Insomnia, sleep disorders
Eye disorders
Rare: Visual disturbance, vision blurred
Ear and labyrinth disorders
Uncommon: Vertigo
Cardiac disorders
Uncommon: Tachycardia, arrhythmias
Vascular disorders
Uncommon: Hypotension, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon:
Rare:
Uncommon:
Dyspnoea
Respiratory distress (including pneumonitis and pulmonary
oedema)
Rare:
Diarrhoea, dry mouth, flatulence
Abdominal pain, constipation, dyspepsia, vomiting
Gastritis
Hepatobiliary disorders
Rare: Abnormal hepatic function/liver disorder
Skin and subcutaneous tissue disorders
Rare:
Not known:
Rare:
Angioedema, erythema, pruritus, rash, hyperhidrosis, urticaria
36
Adverse reactions reported in all clinical trials and occurring more frequently (p
Infections and infestations
Rare:
Rare:
Nervous system disorders
Common:
Gastrointestinal disorders
Uncommon:
Back pain, muscle spasms, myalgia
Arthralgia, muscle cramps, pain in limb
Reproductive system and breast disorders
Uncommon: Erectile dysfunction
General disorders and administration site conditions
Rare:
Uncommon:
Chest pain
Influenza-like illness, pain
Rare:
Investigations
Uncommon:
Blood uric acid increased
Blood creatinine increased, blood creatine phosphokinase
increased, hepatic enzyme increased
Additional information on individual components
undesirable effects with MicardisPlus, even if not observed in clinical trials with this product.
Telmisartan:
The overall incidence of adverse events reported with telmisartan (41.4 %) was usually comparable to
placebo (43.9 %) in placebo controlled trials. The following 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 of unknown frequency reported with the use of telmisartan alone include:
Infections and infestations
Not known: Upper respiratory tract infection, urinary tract infection including
cystitis, sepsis including fatal outcome*
Blood and lymphatic system disorders
Not known: Eosinophilia, anaemia, thrombocytopenia
Immune system disorders
Not known: Hypersensitivity, anaphylactic reactions
Metabolism and nutrition disorders
Not known:
Hyperkalaemia
Cardiac disorders
Not known:
Bradycardia
Gastrointestinal disorders
Stomach discomfort
37
Muscoloskeletal, connective tissue and bone disorders
Uncommon:
Rare:
Not known:
Eczema, drug eruption, toxic skin eruption
Musculoskeletal, connective tissue and bone disorders
Arthrosis, tendon pain
Renal and urinary disorders
Not known: Renal dysfunction, renal impairment (including acute renal
failure)
General disorders and administration site conditions
Not known: Asthenia
Investigations
Not known: 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).
Hydrochlorothiazide:
Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance
(see section 4.4).
Adverse reactions of unknown frequency reported with the use of hydrochlorothiazide alone include:
Infections and infestations
Not known: Sialoadenitis
Blood and lymphatic system disorders
Not known: Anaemia aplastic, haemolytic anaemia, bone marrow failure,
leukopenia, neutropenia, agranulocytosis, thrombocytopenia
Immune system disorders
Not known: Anaphylactic reactions, hypersensitivity
Endocrine disorders
Not known: Diabetes mellitus inadequate control
Metabolism and nutrition disorders
Not known:
Anorexia, appetite decreased, electrolyte imbalance,
hypercholesterolaemia, hyperglycaemia, hypovolaemia
Psychiatric disorders
Not known:
Restlessness
Nervous system disorders
Not known:
Light-headedness
Eye disorders
Not known:
Xanthopsia
Vascular disorders
Vasculitis necrotizing
Gastrointestinal disorders
Pancreatitis, stomach discomfort
38
Skin and subcutaneous tissue disorders
Not known:
Not known:
Not known:
Not known:
Hepatobiliary disorders
Not known: Jaundice hepatocellular, jaundice cholestatic
Skin and subcutaneous tissue disorders
Not known: Lupus-like syndrome, photosensitivity reactions, skin vasculitis,
toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders
Not known: Weakness
Renal and urinary disorders
Not known: Nephritis interstitial, renal dysfunction, glycosuria
General disorders and administration site conditions
Not known:
Pyrexia
Investigations
Not known:
Triglycerides increased
There is limited information available for telmisartan with regard to overdose in humans. The degree
to which hydrochlorothiazide is removed by haemodialysis has not been established.
Symptoms
: The most prominent manifestations of telmisartan overdose were hypotension and
tachycardia; bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure
(hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most
common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in
muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis
glycosides or certain anti-arrhythmic medicinal products.
Treatment:
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 overdose. Serum electrolytes and
creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a
supine position, with salt and volume replacements given quickly.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II receptor antagonists and diuretics, ATC code: C09DA07
MicardisPlus is a combination of an angiotensin II receptor antagonist, telmisartan, and a thiazide
diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive
effect, reducing blood pressure to a greater degree than either component alone. MicardisPlus once
daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (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
39
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.
An 80 mg dose of telmisartan administered to healthy volunteers 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 4-8 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 measurements made at the point of maximum
effect and immediately prior to the next dose (through to peak ratios consistently above 80 % after
doses of 40 and 80 mg of telmisartan in placebo controlled clinical studies).
In patients with hypertension telmisartan reduces both systolic and diastolic blood pressure without
affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents
representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials
comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
In a double-blind controlled clinical trial (n=687 patients evaluated for efficacy) in non-responders to
the 80 mg/12.5 mg combination, an incremental blood pressure lowering effect of the 80 mg/25 mg
combination compared to continued treatment with the 80 mg/12.5 mg combination of 2.7/1.6 mm Hg
(SBP/DBP) was demonstrated (difference in adjusted mean changes from baseline). In a follow-up
trial with the 80 mg/25 mg combination, blood pressure was further decreased (resulting in an overall
reduction of 11.5/9.9 mm Hg (SBP/DBP).
In a pooled analysis of two similar 8 week double-blind placebo-controlled clinical trials vs.
valsartan/hydrochlorothiazide 160 mg/25 mg (n=2121 patients evaluated for efficacy) a significantly
greater blood pressure lowering effect of 2.2/1.2 mm Hg (SBP/DBP) was demonstrated (difference in
adjusted mean changes from baseline, respectively) in favour of telmisartan/hydrochlorothiazide
80 mg/25 mg combination.
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.
The effects of telmisartan on mortality and cardiovascular morbidity are currently unknown.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide
diuretics is not fully known. Thiazides have an effect on the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent
amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin
40
activity, increases aldosterone secretion, with consequent increases in urinary potassium and
bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-
angiotensin-aldosterone system, co-administration of telmisartan tends to reverse the potassium loss
associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak
effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the
risk of cardiovascular mortality and morbidity.
The effects of Fixed Dose Combination of telmisartan/HCTZ on mortality and cardiovascular
morbidity are currently unknown.
5.2. Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and telmisartan does not appear to affect the
pharmacokinetics of either substance in healthy subjects.
Absorption:
Telmisartan: Following oral administration peak concentrations of telmisartan are reached
in 0.5 – 1.5 h after dosing. The absolute bioavailability of telmisartan at 40 mg and 160 mg was 42 %
and 58 %, respectively. Food slightly reduces the bioavailability of telmisartan with a reduction in the
area under the plasma concentration time curve (AUC) of about 6 % with the 40 mg tablet and about
19 % after a 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. The pharmacokinetics of orally administered telmisartan are non-
linear over doses from 20 – 160 mg with greater than proportional increases of plasma concentrations
(C
max
and AUC) with increasing doses. Telmisartan does not accumulate significantly in plasma on
repeated administration.
Hydrochlorothiazide: Following oral administration of MicardisPlus peak concentrations of
hydrochlorothiazide are reached in approximately 1.0 – 3.0 hours after dosing. Based on cumulative
renal excretion of hydrochlorothiazide the absolute bioavailability was about 60 %.
Distribution:
Telmisartan is highly bound to plasma proteins (>99.5 %) mainly albumin and alpha l-
acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 litres
indicating additional tissue binding.
Hydrochlorothiazide is 68 % protein bound in the plasma and its apparent volume of distribution is
0.83 – 1.14 1/kg.
Biotransformation and elimination:
Telmisartan: Following either intravenous or oral administration of
14
C-labelled telmisartan most of the administered dose (>97 %) was eliminated in faeces via biliary
excretion. Only minute amounts were found in urine. Telmisartan is metabolised by conjugation to
form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the
only metabolite that has been identified in humans. After a single dose of
14
C-labelled telmisartan the
glucuronide represents approximately 11 % of the measured radioactivity in plasma. The cytochrome
P450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of
telmisartan after oral administration is >1500 ml/min. Terminal elimination half-life was >20 hours.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as
unchanged substance in urine. About 60 % of the oral dose is eliminated as unchanged substance
within 48 hours. Renal clearance is about 250 – 300 ml/min. The terminal elimination half-life of
hydrochlorothiazide is 10 – 15 hours.
Special populations
Elderly patients:
Pharmacokinetics of telmisartan do not differ between the elderly and those younger
than 65 years.
41
Gender:
Plasma concentrations of telmisartan are generally 2 – 3 times higher in females than in
males. In clinical trials however, no significant increases in blood pressure response or in the
incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There
was a trend towards higher plasma concentrations of hydrochlorothiazide in female than in male
subjects. This is not considered to be of clinical relevance.
Patients with renal impairment:
Renal excretion does not contribute to the clearance of telmisartan.
Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance
of 30 – 60 ml/min, mean about 50 ml/min) no dosage adjustment is necessary in patients with
decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with
impaired renal function the rate of hydrochlorothiazide elimination is reduced. In a typical study in
patients with a mean creatinine clearance of 90 ml/min the elimination half-life of hydrochlorothiazide
was increased. In functionally anephric patients the elimination half-life is about 34 hours.
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
No additional preclinical studies have been performed with the Fixed Dose Combination product
80 mg/25 mg. Previous preclinical safety studies performed with co-administration of telmisartan
and hydrochlorothiazide in normotensive rats and dogs, in doses producing exposure comparable to
that in the clinical therapeutic range, caused no additional findings not already observed with
administration of either substance alone. The toxicological findings observed appear to have no
relevance to human therapeutic use.
Toxicological findings also well known from preclinical studies with angiotensin converting enzyme
inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters
(erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea
nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the
juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented/ameliorated by
oral saline supplementation and group housing of animals. In dogs renal tubular dilation and atrophy
were observed. These findings are considered to be due to the pharmacological activity of telmisartan.
Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies
and no evidence of carcinogenicity in rats and mice. Studies with hydrochlorothiazide have shown
equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the
extensive human experience with hydrochlorothiazide has failed to show an association between its
use and an increase in neoplasms.
For the foetotoxic potential of the telmisartan/hydrochlorothiazide combination see section 4.6.
6.
6.1 List of excipients
Lactose monohydrate
Magnesium stearate
Maize starch
Meglumine
Microcrystalline cellulose
Povidone (K25)
Yellow ferric oxide (E172)
Sodium hydroxide
Sodium starch glycollate (type A)
Sorbitol (E420).
42
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. Store in the original package
in order to protect from moisture.
6.5 Nature and contents of container
Aluminium/aluminium blisters (PA/Al/PVC/Al or PA/PA/Al/PVC/Al). One blister contains 7 or 10
tablets.
Pack sizes: blister with 14, 28, 56, or 98 tablets or perforated unit dose blisters with 28 x 1, 30 x 1 or
90 x 1 tablets.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Occasionally, the outer layer of the blister pack has been observed to separate from the inner layer
between the blister pockets. No action needs to be taken if this is observed.
7.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/02/213/017-023
9.
Date of first authorisation:19 April 2002
Date of last renewal: 19 April 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA)
http://www.ema.europa.eu/
.
43
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
44
A
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Boehringer Ingelheim Pharma GmbH & Co. KG
D-55216 Ingelheim am Rhein
Germany
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 5.2, 09 April 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.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 1.0, 30 March 2007 of the Risk Management Plan (RMP)
presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated
RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
•
At the request of the EMA
45
•
ANNEX III
LABELLING AND PACKAGE LEAFLET
46
A. LABELLING
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
MicardisPlus 40 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420).
Read the package leaflet for further information.
4.
14 tablets
28 tablets
30 x 1 tablets
56 tablets
84 tablets
90 x 1 tablets
98 tablets
28 x 1 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
48
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
This medicinal product does not require any special storage conditions.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/02/213/001
14 tablets
EU/1/02/213/003
28 x 1 tablets
EU/1/02/213/013
30 x 1 tablets
EU/1/02/213/004
56 tablets
EU/1/02/213/011
84 tablets
EU/1/02/213/014
90 x 1 tablets
EU/1/02/213/005
98 tablets
13. BATCH NUMBER
<Batch> {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
MicardisPlus 40 mg/12.5 mg
49
EU/1/02/213/002
28 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister of 7 tablets
1.
MicardisPlus 40 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
MON
TUE
WED
THU
FRI
SAT
SUN
50
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Unit dose blister 7 or 10-count or any non 7 count blister
1.
MicardisPlus 40 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
51
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
MicardisPlus 80 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 80 mg telmisartan and 12.5 mg hydrochlorothiazide.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420).
Read the package leaflet for further information.
4.
14 tablets
28 tablets
30 x 1 tablets
56 tablets
84 tablets
90 x 1 tablets
98 tablets
28 x 1 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:
52
9.
SPECIAL STORAGE CONDITIONS
This medicinal product does not require any special storage conditions.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/02/213/006
14 tablets
EU/1/02/213/007
28 x 1 tablets
EU/1/02/213/015
30 x 1 tablets
EU/1/02/213/009
56 tablets
EU/1/02/213/012
84 tablets
EU/1/02/213/016
90 x 1 tablets
EU/1/02/213/010
98 tablets
13. BATCH NUMBER
<Batch> {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
MicardisPlus 80 mg/12.5 mg
53
EU/1/02/213/008
28 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister of 7 tablets
1.
MicardisPlus 80 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
MON
TUE
WED
THU
FRI
SAT
SUN
54
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Unit dose blister 7 or 10-count or any non 7 count blister
1.
MicardisPlus 80 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
55
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
MicardisPlus 80 mg/25 mg tablets
telmisartan/hydrochlorothiazide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate and sorbitol (E420).
Read the package leaflet for further information.
4.
14 tablets
28 tablets
30 x 1 tablets
56 tablets
90 x 1 tablets
98 tablets
28 x 1 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:
56
9.
SPECIAL STORAGE CONDITIONS
This medicinal product does not require any special storage conditions.
Store in the original package in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
EU/1/02/213/017
14 tablets
EU/1/02/213/018
28 tablets
EU/1/02/213/019
28 x 1 tablets
EU/1/02/213/021
56 tablets
EU/1/02/213/022
90 x 1tablets
EU/1/02/213/023
98 tablets
13. BATCH NUMBER
<Batch> {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
MicardisPlus 80 mg/25 mg
57
EU/1/02/213/020
30 x 1 tablets
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Blister of 7 tablets
1.
MicardisPlus 80 mg/25 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
MON
TUE
WED
THU
FRI
SAT
SUN
58
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
Unit dose blister 7 or 10-count or any non 7 count blister
1.
MicardisPlus 80 mg/25 mg tablets
telmisartan/hydrochlorothiazide
2.
Boehringer Ingelheim (Logo)
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
<Lot>{number}
5.
OTHER
59
B. PACKAGE LEAFLET
60
PACKAGE LEAFLET: INFORMATION FOR THE USER
MicardisPlus 40 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
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 MicardisPlus is and what it is used for
2.
Before you take MicardisPlus
3.
How to take MicardisPlus
4.
Possible side effects
5.
How to store MicardisPlus
6.
Further information
1.
WHAT MICARDISPLUS IS AND WHAT IT IS USED FOR
MicardisPlus is a combination of two active substances, telmisartan and hydrochlorothiazide in one
tablet. Both of these substances help to control high blood pressure.
-
Telmisartan belongs to a group of medicines called 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. Telmisartan blocks the effect of angiotensin II so
that the blood vessels relax, and your blood pressure is lowered.
-
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics, which cause
your urine output to increase, leading to a lowering of your blood pressure.
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.
MicardisPlus is used to
treat high blood pressure (essential hypertension) in patients whose blood
pressure is not controlled enough when either telmisartan or hydrochlorothiazide is used alone.
2.
BEFORE YOU TAKE MICARDISPLUS
Do not take MicardisPlus
•
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in
MicardisPlus tablets (see "Further information" for a list of other ingredients).
•
if you are allergic (hypersensitive) to hydrochlorothiazide or to any other sulfonamide-derived
medicines.
•
if you are more than 3 months pregnant. (It is also better to avoid MicardisPlus in early
pregnancy – see pregnancy section.)
•
if you have severe liver problems such as cholestasis or biliary obstruction (problems with
drainage of the bile from the gall bladder) or any other severe liver disease.
61
-
Keep this leaflet. You may need to read it again.
•
if you have severe kidney disease.
•
if your doctor determines that you have low potassium levels or high calcium levels in your
blood that do not get better with treatment.
If any of the above applies to you, tell your doctor or pharmacist before taking MicardisPlus.
Take special care with MicardisPlus
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
-
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,
vomiting, or haemodialysis.
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Heart trouble.
-
Diabetes.
-
Gout.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Lupus erythematosus (also called “lupus” or “SLE”) a disease where the body’s immune system
attacks the body.
You must tell your doctor if you think you are (or might become) pregnant. MicardisPlus 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).
Treatment with hydrochlorothiazide may cause electrolyte imbalance in your body. Typical symptoms
of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, drowsiness, restlessness,
muscle pain or cramps, nausea (feeling sick), vomiting, tired muscles, and an abnormally fast heart
rate (faster than 100 beats per minute). If you experience any of these you should tell your doctor.
You should also tell your doctor, if you experience an increased sensitivity of the skin to the sun with
symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than
normal.
In case of surgery or anaesthetics, you should tell your doctor that you are taking MicardisPlus.
The use of MicardisPlus in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, telmisartan 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 medications 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
MicardisPlus:
-
Medicines associated with low blood potassium (hypokalaemia) such as other diuretics, ('water
tablets'), laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone),
62
-
Lithium containing medicines to treat some types of depression.
amphotericin (an antifungal medicine), carbenoxolone (used to treat mouth ulcers), penicillin G
sodium (an antibiotic), and salicylic acid and derivatives.
-
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium,
ACE inhibitors that may increase blood potassium levels.
-
Heart medicines (e.g. digoxin) or medicines to control the rhythm of your heart (e.g. quinidine,
disopyramide).
-
Other medicines used to treat high blood pressure, steroids, painkillers, medicines to treat
cancer, gout, or arthritis, and vitamin D supplements.
MicardisPlus may increase the blood pressure lowering effect of other medicines and you should
consult with your doctor if you need to adjust the dose of your other medicine while taking
MicardisPlus.
As with other blood pressure lowering medicines, the effect of MicardisPlus may be reduced when
you take NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen).
Taking MicardisPlus with food and drink
You can take MicardisPlus with or without food.
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 MicardisPlus before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of MicardisPlus. MicardisPlus 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. MicardisPlus 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 MicardisPlus 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 MicardisPlus
MicardisPlus contains milk sugar (lactose) and sorbitol.
If you are intolerant to some sugars, consult your doctor before taking MicardisPlus.
3.
HOW TO TAKE MICARDISPLUS
Always take MicardisPlus exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of MicardisPlus is one tablet a day. Try to take a tablet at the same time each day. You
can take MicardisPlus with or without food. The tablets should be swallowed with some water or other
non-alcoholic drink. It is important that you take MicardisPlus every day until your doctor tells you
otherwise.
63
-
Medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine).
If your liver is not working properly, the usual dose should not exceed 40 mg/12.5 mg once a day.
If you take more MicardisPlus 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 MicardisPlus
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 further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, MicardisPlus 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 the available data.
Common side effects
may include:
Dizziness
Uncommon side effects
may include:
Decreased blood potassium levels; anxiety; fainting (syncope); sensation of tingling, pins and needles
(paraesthesia); feeling of spinning (vertigo); fast heart beat (tachycardia), heart rhythm disorders, low
blood pressure, a sudden fall in blood pressure when you stand up; shortness of breath (dyspnoea);
symptoms of an upset stomach such as diarrhoea; dry mouth, flatulence; back pain, muscle spasm,
muscle pain; erectile dysfunction (inability to get or keep an erection); chest pain, increased blood uric
acid levels.
Rare side effects
may include:
Inflammation of the lung (bronchitis); feeling sad (depression); difficulty falling asleep (insomnia);
impaired vision; difficulty breathing; abdominal pain, constipation, bloating (dyspepsia), feeling sick;
abnormal liver function; rapid swelling of the skin and mucosa (angioedema), redness of the skin
(erythema); allergic reactions such as itching or rash; increased sweating, hives (urticaria); joint pain
(arthralgia) and pain in extremities, muscle cramps; flu-like-illness; pain; increased levels of uric acid,
low levels of sodium, increased levels of creatinine, hepatic enzymes or creatine phosphokinase in the
blood.
Side effects of unknown frequency
may include:
Sore throat, inflamed sinuses; inflammation of the stomach (gastritis)
Telmisartan
In patients taking telmisartan alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), urinary tract
infections; increase in certain white blood cells (eosinophilia), deficiency in red blood cells (anaemia),
low platelet count (thrombocytopenia); serious allergic reaction (e.g. hypersensitivity, anaphylactic
reaction, drug rash); high potassium levels; slow heart rate (bradycardia); upset stomach; eczema (a
skin disorder); inflammation of the tendons; kidney impairment including acute kidney failure;
64
weakness; 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.
Hydrochlorothiazide
In patients taking hydrochlorothiazide alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Inflammation of the salivary gland; decreases in the number of cells in the blood, including low red
and white blood cell count, low platelet count (thrombocytopenia); serious allergic reactions (e.g.
hypersensitivity, anaphylactic reaction), inflammation of blood vessels (vasculitis necrotising),
decreased or loss of appetite; restlessness, weakness, light-headedness, blurred or yellowing of vision;
inflamed pancreas, upset stomach; yellowing of the skin or eyes (jaundice); skin disorders such as
inflamed blood vessels in the skin; increased sensitivity to sunlight, or blistering and peeling of the top
layer of skin (toxic epidermal necrolysis); kidney inflammation or impaired kidney function; fever;
impaired electrolyte balance, high blood cholesterol levels, decreased blood volume, glucose in the
urine (glycosuria), increased levels of glucose, or fat in the blood.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE MICARDISPLUS
Keep out of the reach and sight of children.
Do not use MicardisPlus after the expiry date which is stated on the carton after “EXP”. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions. You should store your medicine in the
original package in order to protect the tablets from moisture.
Occasionally, the outer layer of the blister pack separates from the inner layer between the blister
pockets. You do not need to take any action if this happens.
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.
6.
FURTHER INFORMATION
What MicardisPlus contains
The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 40 mg telmisartan
and 12.5 mg hydrochlorothiazide.
The other ingredients are lactose monohydrate, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, povidone, red iron oxide (E172), sodium hydroxide, sodium starch
glycollate (type A), sorbitol (E420)
What MicardisPlus looks like and contents of the pack
MicardisPlus 40 mg/12.5 mg tablets are red and white, oval-shaped two-layer tablets engraved with
the company logo and the code 'H4'.
65
MicardisPlus is available in blisters packs containing 14, 28, 56, 84, or 98 tablets, or unit dose blister
packs containing 28 x 1, 30 x 1 or 90 x 1 tablets.
Not all pack sizes may be available in your country.
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
66
Marketing Authorisation Holder
Manufacturer
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 49
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 / 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
MERCK Gesellschaft mbH
Tel: +43 1 57 6000
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
SímiTel: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
67
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
68
PACKAGE LEAFLET: INFORMATION FOR THE USER
MicardisPlus 80 mg/12.5 mg tablets
telmisartan/hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
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 MicardisPlus is and what it is used for
3.
How to take MicardisPlus
4.
Possible side effects
5.
How to store MicardisPlus
6.
Further information
1.
WHAT MICARDISPLUS IS AND WHAT IT IS USED FOR
MicardisPlus is a combination of two active substances, telmisartan and hydrochlorothiazide in one
tablet. Both substances help to control high blood pressure.
-
Telmisartan belongs to a group of medicines called 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. Telmisartan blocks the effect of angiotensin II so
that the blood vessels relax, and your blood pressure is lowered.
-
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics, which cause
your urine output to increase leading to a lowering of your blood pressure.
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.
MicardisPlus is used to
treat high blood pressure (essential hypertension) in patients whose blood
pressure is not controlled enough when either telmisartan or hydrochlorothiazide is used alone.
2.
BEFORE YOU TAKE MICARDISPLUS
Do not take MicardisPlus
•
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in
MicardisPlus tablets (see "Further Information" for a list of other ingredients).
•
if you are allergic (hypersensitive) to hydrochlorothiazide or to any other sulfonamide-derived
medicines.
•
if you are more than 3 months pregnant. (It is also better to avoid MicardisPlus in early
pregnancy – see pregnancy section.)
•
if you have severe liver problems such as cholestasis or biliary obstruction (problems with
drainage of the bile from the gall bladder) or any other severe liver disease.
69
-
Keep this leaflet. You may need to read it again.
2.
Before you take MicardisPlus
•
if you have severe kidney disease.
•
if your doctor determines that you have low potassium levels or high calcium levels in your
blood that do not get better with treatment.
If any of the above applies to you, tell your doctor or pharmacist before taking MicardisPlus.
Take special care with MicardisPlus
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
-
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,
vomiting, or haemodialysis.
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Heart trouble.
-
Diabetes.
-
Gout.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Lupus erythematosus (also called “lupus” or “SLE”) a disease where the body’s immune system
attacks the body.
You must tell your doctor if you think you are (or might become) pregnant. MicardisPlus 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).
Treatment with hydrochlorothiazide may cause electrolyte imbalance in your body. Typical symptoms
of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, drowsiness, restlessness,
muscle pain or cramps, nausea (feeling sick), vomiting, tired muscles, and an abnormally fast heart
rate (faster than 100 beats per minute). If you experience any of these you should tell your doctor.
You should also tell your doctor, if you experience an increased sensitivity of the skin to the sun with
symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than
normal.
In case of surgery or anaesthetics, you should tell your doctor that you are taking MicardisPlus.
The use of MicardisPlus in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, telmisartan 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 medications 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
MicardisPlus:
-
Medicines associated with low blood potassium (hypokalaemia) such as other diuretics, ('water
tablets'), laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone),
70
-
Lithium containing medicines to treat some types of depression.
amphotericin (an antifungal medicine), carbenoxolone (used to treat mouth ulcers), penicillin G
sodium (an antibiotic), and salicylic acid and derivatives.
-
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium,
ACE inhibitors that may increase blood potassium levels.
-
Heart medicines (e.g. digoxin) or medicines to control the rhythm of your heart (e.g. quinidine,
disopyramide).
-
Other medicines used to treat high blood pressure, steroids, painkillers, medicines to treat
cancer, gout, or arthritis, and vitamin D supplements.
MicardisPlus may increase the blood pressure lowering effect of other medicines and you should
consult with your doctor if you need to adjust the dose of your other medicine while taking
MicardisPlus.
As with other blood pressure lowering medicines, the effect of MicardisPlus may be reduced when
you take NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen).
Taking MicardisPlus with food and drink
You can take MicardisPlus tablets with or without food.
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 MicardisPlus before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of MicardisPlus. MicardisPlus 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. MicardisPlus 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 MicardisPlus 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 MicardisPlus
MicardisPlus contains milk sugar (lactose) and sorbitol.
If you are intolerant to some sugars, consult your doctor before taking MicardisPlus.
3.
HOW TO TAKE MICARDISPLUS
Always take MicardisPlus exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of MicardisPlus is one tablet a day. Try to take the tablet at the same time each day.
You can take MicardisPlus with or without food. The tablets should be swallowed with some water or
other non-alcoholic drink. It is important that you take MicardisPlus every day until your doctor tells
you otherwise.
71
-
Medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine).
If your liver is not working properly, the usual dose should not exceed 40 mg/12.5 mg once a day.
If you take more MicardisPlus 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 MicardisPlus
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 further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, MicardisPlus 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 the available data.
Common side effects
may include:
Dizziness
Uncommon side effects
may include:
Decreased blood potassium levels; anxiety; fainting (syncope); sensation of tingling, pins and needles
(paraesthesia); feeling of spinning (vertigo); fast heart beat (tachycardia), heart rhythm disorders, low
blood pressure, a sudden fall in blood pressure when you stand up; shortness of breath (dyspnoea);
symptoms of an upset stomach such as diarrhoea; dry mouth; flatulence; back pain, muscle spasm,
muscle pain; erectile dysfunction (inability to get or keep an erection); chest pain; increased blood uric
acid levels.
Rare side effects
may include:
Inflammation of the lung (bronchitis); feeling sad (depression); difficulty falling asleep (insomnia);
impaired vision; difficulty breathing; abdominal pain, constipation, bloating (dyspepsia), feeling sick;
abnormal liver function; rapid swelling of the skin and mucosa (angioedema), redness of the skin
(erythema); allergic reactions such as itching or rash; increased sweating, hives (urticaria); joint pain
(arthralgia) and pain in extremities, muscle cramps; flu-like-illness; pain; increased levels of uric acid,
low levels of sodium, increased levels of creatinine, hepatic enzymes or creatine phosphokinase in the
blood.
Side effects of unknown frequency
may include:
Sore throat, inflamed sinuses; inflammation of the stomach (gastritis)
Telmisartan
In patients taking telmisartan alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), urinary tract
infections; increase in certain white blood cells (eosinophilia), deficiency in red blood cells (anaemia),
low platelet count (thrombocytopenia); serious allergic reaction (e.g. hypersensitivity, anaphylactic
reaction, drug rash); high potassium levels; slow heart rate (bradycardia); upset stomach; eczema (a
skin disorder); inflammation of the tendons; kidney impairment including acute kidney failure;
72
weakness; 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.
Hydrochlorothiazide
In patients taking hydrochlorothiazide alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Inflammation of the salivary gland; decreases in the number of cells in the blood, including low red
and white blood cell count, low platelet count (thrombocytopenia); serious allergic reactions; (e.g.
hypersensitivity, anaphylactic reaction), inflammation of blood vessels (vasculitis necrotising),
decreased or loss of appetite; restlessness, weakness, light-headedness, blurred or yellowing of vision;
inflamed pancreas, upset stomach; yellowing of the skin or eyes (jaundice); skin disorders such as
inflamed blood vessels in the skin, increased sensitivity to sunlight, or blistering and peeling of the top
layer of skin (toxic epidermal necrolysis); kidney inflammation or impaired kidney function; fever;
impaired electrolyte balance, high blood cholesterol levels, decreased blood volume, glucose in the
urine (glycosuria), increased levels of glucose, or fat in the blood.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE MICARDISPLUS
Keep out of the reach and sight of children.
Do not use MicardisPlus after the expiry date which is stated on the carton after “EXP”. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions. You should store your medicine in the
original package in order to protect the tablets from moisture.
Occasionally, the outer layer of the blister pack separates from the inner layer between the blister
pockets. You do not need to take any action if this happens.
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.
6.
FURTHER INFORMATION
What MicardisPlus contains
The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 80 mg telmisartan
and 12.5 mg hydrochlorothiazide.
The other ingredients are lactose monohydrate, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, povidone, red iron oxide (E172), sodium hydroxide, sodium starch
glycollate (type A), sorbitol (E420)
What MicardisPlus looks like and contents of the pack
MicardisPlus 80 mg/12.5 mg tablets are red and white, oval-shaped, two-layer tablets engraved with
the company logo and the code 'H8'.
73
MicardisPlus is available in blisters packs containing 14, 28, 56, 84, or 98 tablets, or unit dose blister
packs containing 28 x 1, 30 x 1 or 90 x 1 tablets.
Not all pack sizes may be available in your country.
Marketing Authorisation Holder
Manufacturer
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
74
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 49
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 / 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
MERCK Gesellschaft mbH
Tel: +43 1 57 6000
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
SímiTel: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
75
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
76
PACKAGE LEAFLET: INFORMATION FOR THE USER
MicardisPlus 80 mg/25 mg tablets
telmisartan/hydrochlorothiazide
Read all of this leaflet carefully before you start taking this medicine.
-
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 MicardisPlus is and what it is used for
3.
How to take MicardisPlus
4.
Possible side effects
5.
How to store MicardisPlus
6.
Further information
1.
WHAT MICARDISPLUS IS AND WHAT IT IS USED FOR
MicardisPlus is a combination of two active substances, telmisartan and hydrochlorothiazide in one
tablet. Both substances help to control high blood pressure.
-
Telmisartan belongs to a group of medicines called 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. Telmisartan blocks the effect of angiotensin II so
that the blood vessels relax, and your blood pressure is lowered.
-
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics, which cause
your urine output to increase leading to a lowering of your blood pressure.
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.
MicardisPlus is used to
treat high blood pressure (essential hypertension) in patients whose blood
pressure is not controlled enough when either telmisartan or hydrochlorothiazide is used alone.
2.
BEFORE YOU TAKE MICARDISPLUS
Do not take MicardisPlus
•
if you are allergic (hypersensitive) to telmisartan or any other ingredients included in
MicardisPlus tablets (see “Further Information” for a list of other ingredients).
•
if you are allergic (hypersensitive) to hydrochlorothiazide or to any other sulfonamide-derived
medicines.
•
if you are more than 3 months pregnant. (It is also better to avoid MicardisPlus in early
pregnancy – see pregnancy section.)
•
if you have severe liver problems such as cholestasis or biliary obstruction (problems with
drainage of the bile from the gall bladder), or any other severe liver disease.
•
if you have severe kidney disease.
77
-
Keep this leaflet. You may need to read it again.
2.
Before you take MicardisPlus
•
if your doctor determines that you have low potassium levels or high calcium levels in your
blood that do not get better with treatment.
If any of the above applies to you, tell your doctor or pharmacist before taking MicardisPlus.
Take special care with MicardisPlus
Please tell your doctor if you are suffering or have ever suffered from any of the following conditions
or illnesses:
-
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,
vomiting, or haemodialysis.
-
Kidney disease or kidney transplant.
-
Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).
-
Liver disease.
-
Heart trouble.
-
Diabetes.
-
Gout.
-
Raised aldosterone levels (water and salt retention in the body along with imbalance of various
blood minerals).
-
Lupus erythematosus (also called “lupus” or “SLE”) a disease where the body’s immune system
attacks the body.
You must tell your doctor if you think you are (or might become) pregnant. MicardisPlus 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).
Treatment with hydrochlorothiazide may cause electrolyte imbalance in your body. Typical symptoms
of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, drowsiness, restlessness,
muscle pain or cramps, nausea (feeling sick), vomiting, tired muscles, and an abnormally fast heart
rate (faster than 100 beats per minute). If you experience any of these you should tell your doctor.
You should also tell your doctor, if you experience an increased sensitivity of the skin to the sun with
symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than
normal.
In case of surgery or anaesthetics, you should tell your doctor that you are taking MicardisPlus.
The use of MicardisPlus in children and adolescents up to the age of 18 years is not recommended.
As with all other angiotensin II receptor antagonists, telmisartan 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 medications 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
MicardisPlus:
-
Lithium containing medicines to treat some types of depression.
-
Medicines associated with low blood potassium (hypokalaemia) such as other diuretics, ('water
tablets'), laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone),
amphotericin (an antifungal medicine), carbenoxolone (used to treat mouth ulcers), penicillin G
sodium (an antibiotic), and salicylic acid and derivatives.
78
-
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium,
ACE inhibitors that may increase blood potassium levels.
-
Heart medicines (e.g. digoxin) or medicines to control the rhythm of your heart (e.g. quinidine,
disopyramide).
-
Medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine).
-
Other medicines used to treat high blood pressure, steroids, painkillers, medicines to treat
cancer, gout, or arthritis, and vitamin D supplements.
MicardisPlus may increase the blood pressure lowering effect of other medicines and you should
consult with your doctor if you need to adjust the dose of your other medicine while taking
MicardisPlus.
As with other blood pressure lowering medicines, the effect of MicardisPlus may be reduced when
you take NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen).
Taking MicardisPlus with food and drink
You can take MicardisPlus tablets with or without food.
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 MicardisPlus before you become pregnant or as soon as you know you are
pregnant and will advise you to take another medicine instead of MicardisPlus. MicardisPlus 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. MicardisPlus 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 MicardisPlus 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 MicardisPlus
MicardisPlus contains milk sugar (lactose) and sorbitol.
If you are intolerant to some sugars, consult your doctor before taking MicardisPlus.
3.
HOW TO TAKE MICARDISPLUS
Always take MicardisPlus exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of MicardisPlus is one tablet a day. Try to take the tablet at the same time each day.
You can take MicardisPlus with or without food. The tablets should be swallowed with some water or
other non-alcoholic drink. It is important that you take MicardisPlus every day until your doctor tells
you otherwise.
If your liver is not working properly, the usual dose should not exceed 40 mg/12.5 mg once a day.
79
If you take more MicardisPlus 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 MicardisPlus
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 further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, MicardisPlus 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 the available data.
Common side effects
may include:
Dizziness
Uncommon side effects
may include:
Decreased blood potassium levels; anxiety; fainting (syncope); sensation of tingling, pins and needles
(paraesthesia); feeling of spinning (vertigo); fast heart beat (tachycardia), heart rhythm disorders, low
blood pressure, a sudden fall in blood pressure when you stand up; shortness of breath (dyspnoea);
symptoms of an upset stomach such as diarrhoea; dry mouth; flatulence; back pain, muscle spasm,
muscle pain; erectile dysfunction (inability to get or keep an erection); chest pain; increased blood uric
acid levels.
Rare side effects
may include:
Inflammation of the lung (bronchitis); feeling sad (depression); difficulty falling asleep (insomnia);
impaired vision; difficulty breathing; abdominal pain, constipation, bloating (dyspepsia), feeling sick;
abnormal liver function; rapid swelling of the skin and mucosa (angioedema), redness of the skin
(erythema); allergic reactions such as itching or rash; increased sweating, hives (urticaria); joint pain
(arthralgia) and pain in extremities, muscle cramps; flu-like-illness; pain; increased levels of uric acid,
low levels of sodium, increased levels of creatinine, hepatic enzymes or creatine phosphokinase in the
blood.
Side effects of unknown frequency
may include:
Sore throat, inflamed sinuses; inflammation of the stomach (gastritis)
Telmisartan
In patients taking telmisartan alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), urinary tract
infections; increase in certain white blood cells (eosinophilia), deficiency in red blood cells (anaemia),
low platelet count (thrombocytopenia); serious allergic reaction (e.g. hypersensitivity, anaphylactic
reaction, drug rash); high potassium levels; slow heart rate (bradycardia); upset stomach; eczema (a
skin disorder); inflammation of the tendons; kidney impairment including acute kidney failure;
weakness; decreased haemoglobin (a blood protein), sepsis* (often called "blood poisoning", is a
severe infection with whole-body inflammatory response which can lead to death).
80
*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.
Hydrochlorothiazide
In patients taking hydrochlorothiazide alone the following additional side effects have been reported:
Side effects of unknown frequency
may include:
Inflammation of the salivary gland; decreases in the number of cells in the blood, including low red
and white blood cell count , low platelet count (thrombocytopenia); serious allergic reactions (e.g.
hypersensitivity, anaphylactic reaction), inflammation of blood vessels (vasculitis necrotising);
decreased or loss of appetite; restlessness, weakness, light-headedness, blurred or yellowing of vision;
inflamed pancreas, upset stomach; yellowing of the skin or eyes (jaundice); skin disorders such as
inflamed blood vessels in the skin, increased sensitivity to sunlight, or blistering and peeling of the top
layer of skin (toxic epidermal necrolysis); kidney inflammation or impaired kidney function; fever;
impaired electrolyte balance, high blood cholesterol levels, decreased blood volume, glucose in the
urine (glycosuria), increased levels of glucose, or fat in the blood.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE MICARDISPLUS
Keep out of the reach and sight of children.
Do not use MicardisPlus after the expiry date which is stated on the carton after “EXP”. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions. You should store your medicine in the
original package in order to protect the tablets from moisture.
Occasionally, the outer layer of the blister pack separates from the inner layer between the blister
pockets. You do not need to take any action need be taken if this happens.
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.
6.
FURTHER INFORMATION
What MicardisPlus contains
The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 80 mg telmisartan
and 25 mg hydrochlorothiazide.
The other ingredients are lactose monohydrate, magnesium stearate, maize starch, meglumine,
microcrystalline cellulose, povidone, yellow iron oxide (E172), sodium hydroxide, sodium starch
glycollate (type A), sorbitol (E420)
What MicardisPlus looks like and contents of the pack
MicardisPlus 80 mg/25 mg tablets are yellow and white, oval-shaped, two-layer tablets engraved with
the company logo and the code 'H9'.
MicardisPlus is available in blister packs containing 14, 28, 56, or 98 tablets, or unit dose blister packs
containing 28 x 1, 30 x 1 or 90 x 1 tablets
81
Not all pack sizes may be available in your country.
Marketing Authorisation Holder
Manufacturer
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
82
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 49
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 / 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
MERCK Gesellschaft mbH
Tel: +43 1 57 6000
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
SímiTel: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
83
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
84
Source: European Medicines Agency
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