Active ingredients: Telmisartan, Hydrochlorothiazide
MicardisPlus 40 mg / 12.5 mg tablets
MicardisPlus package inserts are available for pack sizes:- MicardisPlus 40 mg / 12.5 mg tablets
- MicardisPlus 80 mg / 12.5 mg tablets
- MicardisPlus 80 mg / 25 mg tablets
Indications Why is MicardisPlus used? What is it for?
MicardisPlus is a "combination of two active ingredients, telmisartan and" hydrochlorothiazide in a single tablet. Each of these substances facilitates the control of high blood pressure.
- Telmisartan belongs to a group of medicines known as angiotensin II receptor antagonists. Angiotensin II is a substance in the body that causes blood vessels to constrict, thereby increasing blood pressure. Telmisartan blocks this effect of angiotensin II, causing the blood vessels to relax and thus lowering blood pressure.
- Hydrochlorothiazide belongs to a group of medicines known as thiazide diuretics which cause an increase in the flow of urine, thus helping to lower blood pressure.
If left untreated, hypertension can damage blood vessels in many organs, which can sometimes lead to heart attack, heart or kidney failure, stroke, or blindness. Hypertension usually has no symptoms before such damage occurs. Therefore it is important to take regular blood pressure measurements to see if it is average.
MicardisPlus is used to treat high blood pressure (essential hypertension) in adults whose blood pressure is not controlled sufficiently by telmisartan used alone.
Contraindications When MicardisPlus should not be used
Do not take MicardisPlus
- if you are allergic to telmisartan or any of the other ingredients of this medicine
- if you are allergic to hydrochlorothiazide or any other sulphonamide derivative 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 the drainage of bile from the liver and gallbladder) or any other severe liver disease.
- if you have severe kidney disease.
- if your doctor determines that your blood potassium levels are low or your calcium levels are high and do not improve following treatment.
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
If you have any of these conditions, tell your doctor or pharmacist before taking MicardisPlus
Precautions for use What you need to know before taking MicardisPlus
Talk to your doctor if you have or have ever suffered from any of the following conditions or illnesses:
- Low blood pressure (hypotension), which is more likely to occur if you are dehydrated (excessive loss of water from the body) or have a salt deficiency due to diuretic therapy (diuretics), low salt diet, diarrhea, vomiting or hemodialysis.
- Kidney disease or kidney transplant.
- Renal artery stenosis (narrowing of the blood vessels of one or both kidneys).
- Liver disease.
- Heart problems.
- Diabetes.
- Gout.
- Increased aldosterone levels (water and salt retention in the body with imbalance of several minerals in the blood).
- Systemic lupus erythematosus (also called "lupus" or "SLE") a disease in which the body's immune system attacks the body.
- The active substance hydrochlorothiazide can cause an uncommon reaction, resulting in decreased vision and eye pain. These could be symptoms of increased pressure in your eye and can occur hours to weeks after taking MicardisPlus. This condition can lead to permanent vision impairment if left untreated
Talk to your doctor before taking MicardisPlus:
- if you are taking any of the following medicines used to treat high blood pressure:
- an ACE inhibitor (for example enalapril, lisinopril, ramipril), particularly if you have diabetes-related kidney problems.
- aliskiren. Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals. See also information under the heading "Do not take MicardisPlus".
- if you are taking digoxin.
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming 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 can cause an electrolyte imbalance in the body. Typical symptoms of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, sleepiness, restlessness, muscle pain or cramps, nausea (feeling sick), vomiting, tiredness muscle and abnormally fast heartbeat (greater than 100 beats per minute) If you get any of these symptoms, tell your doctor
You should also tell your doctor if you have experienced increased skin sensitivity to the sun, resulting in sunburn symptoms (such as redness, itching, swelling, blistering) onset faster than normal.
In case of surgery or administration of anesthetics, you should tell your doctor that you are taking MicardisPlus.
MicardisPlus may be less effective in lowering blood pressure in ethnic African patients.
Children and adolescents
The use of MicardisPlus is not recommended in children and adolescents up to 18 years
Interactions Which drugs or foods may change the effect of MicardisPlus
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may decide to change the dose of these other medicines or take other precautions. In some cases it may be necessary to stop taking one of these medicines. This mainly applies to the medicines listed below, taken at the same time as MicardisPlus:
- Medicines containing lithium to treat some types of depression.
- Medicines associated with low blood potassium levels (hypokalaemia) such as other diuretics, laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone), amphotericin (antifungal medicine), carbenoxolone (used for the treatment of mouth ulcers), penicillin G sodium (antibiotic), salicylic acid and its derivatives.
- Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, ACE inhibitors which may increase blood potassium levels.
- Medicines for the heart (eg digoxin) or medicines to control the rhythm of the heart (eg quinidine, disopyramide).
- Medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine).
- Other substances used to treat high blood pressure, steroids, pain relievers, medicines to treat cancer, gout or arthritis, and vitamin D supplements.
- If you are taking an ACE inhibitor or aliskiren (see also information under the headings: "Do not take MicardisPlus" and "Warnings and precautions").
- Digoxin.
MicardisPlus may increase the effect of other medicines used to lower blood pressure or medicines that have the potential to lower blood pressure (eg baclofen, amifostine). In addition, the lowering of blood pressure may be aggravated by alcohol, barbiturates, narcotics or antidepressants. You may feel this drop in blood pressure as dizziness on standing up. Consult your doctor if you need to change the dose of your other medicines while taking MicardisPlus.
The effect of MicardisPlus may be reduced when taking NSAIDs (non-steroidal anti-inflammatory medicines, eg aspirin and ibuprofen)
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Your doctor will usually advise you to stop taking MicardisPlus before becoming 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 during pregnancy. pregnant and should not be taken if you are more than 3 months pregnant as it may cause serious harm to your baby if taken after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding. MicardisPlus is not recommended for women who are breastfeeding and your doctor may choose another treatment for you if you wish to breastfeed.
Driving and using machines
Some patients may feel dizzy or sleepy when taking MicardisPlus. If these effects occur, do not drive or use machines.
MicardisPlus contains milk sugar (lactose) and sorbitol.
If you are intolerant to any sugars, consult your doctor before taking MicardisPlus.
Dosage and method of use How to use MicardisPlus: Dosage
Always take MicardisPlus exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose of MicardisPlus is one tablet per 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 another non-alcoholic drink. It is important to take MicardisPlus every day until your doctor tells you otherwise.
If your liver is not functioning properly, the usual dose of 40 mg / 12.5 mg once daily should not be exceeded.
Overdose What to do if you have taken an overdose of MicardisPlus
If you take more MicardisPlus than you should
If you have taken too many tablets by mistake, contact your doctor or pharmacist, or the nearest hospital emergency department immediately.
If you forget to take MicardisPlus
If you forget to take your medicine, don't worry. Take it as soon as you remember, then continue as before.
If you miss the dose on one day, take your normal dose the next day. Do not take a double dose to make up for a forgotten dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Side Effects What are the side effects of MicardisPlus
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be serious and need immediate medical attention:
You should see your doctor immediately if you experience any of the following symptoms:
Sepsis * (often called "blood infection") is a serious infection with a whole body inflammatory response, rapid swelling of the skin and mucous membranes (angioedema); these side effects are rare (may affect up to 1 in 1,000 people), but extremely serious and patients should stop taking the medicine and consult their doctor immediately. If left untreated, they can be fatal. The increased incidence of sepsis has been observed with telmisartan alone, however it cannot be excluded for MicardisPlus.
Possible side effects of MicardisPlus:
Common side effects (may affect up to 1 in 10 people):
Dizziness.
Uncommon side effects (may affect up to 1 in 100 people):
Low blood potassium levels, anxiety, fainting (syncope), feeling numb, tingling sensation (paraesthesia), spinning sensation (dizziness), fast heart beat (tachycardia), heart rhythm disorder, low blood pressure , sudden drop in blood pressure when standing up, shortness of breath (dyspnoea), diarrhea, dry mouth, flatulence, back pain, muscle spasm, muscle pain, erectile dysfunction (inability to get or maintain an erection), pain in the chest, increased blood uric acid levels.
Rare side effects (may affect up to 1 in 1,000 people):
Inflammation of the lungs (bronchitis), activation or worsening of systemic lupus erythematosus (a disease in which the immune system attacks the body itself, which causes joint pain, rash and fever), sore throat, sinusitis, feeling sad (depression), difficulty falling asleep (insomnia), impaired vision, difficulty breathing, abdominal pain, constipation, bloating (dyspepsia), feeling sick, stomach inflammation (gastritis), abnormal liver function (Japanese patients are more likely to have experience this side effect), rapid swelling of the skin and mucous membranes which can also lead to death (angioedema including fatal outcome), redness of the skin (erythema), allergic reactions such as itching or rash, increased sweating, hives, joint pain ( arthralgia) and pain in extremity, muscle cramps, flu-like illness, pain, uric acid levels increased ntates, low sodium levels, increased creatinine levels, liver enzymes or creatine phosphokinase present in the blood.
Adverse reactions reported with any of the individual components may be potential adverse reactions with MicardisPlus, even if not observed in clinical studies with this product.
Telmisartan
The following additional side effects have been reported in patients treated with telmisartan alone:
Uncommon side effects (may affect up to 1 in 100 people):
Upper respiratory tract infection (e.g. sore throat, sinusitis, common cold), urinary tract infections, reduced red blood cells (anemia), high potassium levels, slow heart rate (bradycardia), kidney failure including acute kidney failure , feeling of weakness, cough.
Rare side effects (may affect up to 1 in 1,000 people):
Sepsis * (often called "blood infection" is a severe infection with a whole body inflammatory response that can lead to death), low platelet count (thrombocytopenia), increase in some white blood cells (eosinophilia), severe allergic reaction (eg hypersensitivity, anaphylactic reaction, drug rash), low blood sugar levels (in diabetic patients), stomach upset, eczema (skin disorder), osteoarthritis, inflammation of the tendons, decreased hemoglobin (a blood protein), sleepiness .
Very rare side effects (may affect up to 1 in 10,000 people):
Progressive scarring of lung tissue (interstitial lung disease) **.
* The event may have occurred by chance or could be related to a mechanism currently unknown.
** There have been reports of progressive scarring of lung tissue while taking telmisartan. However, it is not known whether telmisartan was the cause.
Hydrochlorothiazide
The following additional side effects have been reported in patients treated with hydrochlorothiazide alone:
Undesirable effects of unknown frequency (frequency cannot be estimated from the available data):
Inflammation of the salivary glands, decreased number of blood cells, including decreased red and white blood cell counts, low platelet count (thrombocytopenia), severe allergic reactions (eg.hypersensitivity, anaphylactic reaction), decreased or loss of appetite, restlessness, lightheadedness, blurred or yellowish vision, decreased vision and eye pain (possible signs of acute myopia or acute narrow-angle glaucoma), inflammation of the blood vessels (necrotizing vasculitis) , inflammation of the pancreas, stomach upset, yellowing of the skin or eyes (jaundice), lupus-like syndrome (a condition that mimics a disease called systemic lupus erythematosus where the immune system attacks the body itself); skin disorders such as inflammation of the blood vessels in the skin, increased sensitivity to sunlight or blistering and peeling of the outermost layer of the skin (toxic epidermal necrolysis), feeling of weakness, inflammation of the kidneys or impaired kidney function, glucose in the urine ( glycosuria), fever, electrolyte imbalance, high blood cholesterol levels, volume d i reduced blood, increased levels of glucose or fat in the blood.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage temperatures. You must keep the medicine in the original package to keep the tablets away from moisture. Remove the MicardisPlus tablet from the blister only immediately before taking.
Occasionally the outer layer of the blister separates from the inner layer between the blisters. If this happens, you don't need to take any precautions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What MicardisPlus contains
The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 40 mg of telmisartan and 12.5 mg of hydrochlorothiazide.
The other ingredients are lactose monohydrate, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, povidone, red iron oxide (E172), sodium hydroxide, sodium carboxymethyl starch (Type A), sorbitol (E420)
What MicardisPlus looks like and contents of the pack
MicardisPlus 40 mg / 12.5 mg tablets are red and white and oval shaped in two layers, embossed with the company logo and the code "H4".
MicardisPlus is available in blister packs, in packs of 14, 28, 56, 84 or 98 tablets or in perforated unit dose blisters with 28 x 1, 30 x 1 or 90 x 1 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MICARDISPLUS 40 MG 12.5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide.
Excipients with known effects:
Each tablet contains 112 mg of lactose monohydrate and 169 mg of sorbitol (E420).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Red and white 5.2 mm oval shaped two-layer tablet, engraved with the company logo and the code "H4".
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of essential hypertension.
MicardisPlus, fixed dose combination (40 mg telmisartan / 12.5 mg hydrochlorothiazide) is indicated in adults in whom adequate blood pressure control is not achieved with telmisartan alone.
04.2 Posology and method of administration
Dosage
MicardisPlus should be used in patients whose blood pressure is not adequately controlled with telmisartan alone. It is recommended to try to find an effective dose of each of the individual components before switching to the fixed dose combination. When clinically appropriate, a direct switch from monotherapy to fixed combination may be considered.
• MicardisPlus 40 mg / 12.5 mg can be administered once daily to patients who do not achieve adequate blood pressure control with Micardis 40 mg.
• MicardisPlus 80 mg / 12.5 mg can be administered once daily to patients who do not achieve adequate blood pressure control with Micardis 80 mg.
Special populations
Patients with renal insufficiency
Periodic monitoring of renal function is recommended (see section 4.4).
Patients with hepatic insufficiency
In patients with mild or moderate hepatic impairment the dose should not be higher than MicardisPlus 40 mg / 12.5 mg once daily. MicardisPlus is not indicated in patients with severe hepatic insufficiency. Thiazide diuretics should be used with caution in patients with impaired hepatic function (see section 4.4).
Elderly patients
There is no need to change the dose.
Pediatric population
The safety and efficacy of MicardisPlus in children and adolescents below 18 years have not been established. There are no data available.
Method of administration
MicardisPlus tablets are for oral, once daily administration and should be taken with liquid, with or without food.
Precautions to be taken before handling or administering the medicinal product
MicardisPlus tablets should be stored in the sealed blister due to their hygroscopic characteristics. They must be removed from the blister just before administration (see section 6.6).
04.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Hypersensitivity to other sulphonamide derived substances (hydrochlorothiazide is a sulphonamide derived substance).
• Second and third trimester of pregnancy (see sections 4.4 and 4.6).
• Cholestasis and biliary obstructions.
• Severe hepatic insufficiency.
• Severe renal insufficiency (creatinine clearance
• Refractory hypokalemia, hypercalcemia.
The concomitant use of MicardisPlus with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).
04.4 Special warnings and appropriate precautions for use
Pregnancy
Angiotensin II receptor antagonist therapy (AIIRA) should not be initiated during pregnancy. An alternative antihypertensive treatment with an established safety profile for use in pregnancy should be used for patients planning pregnancy. unless continued therapy with an AIIRA is considered essential. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Hepatic insufficiency
MicardisPlus should not be given to patients with cholestasis, biliary obstruction or severe hepatic insufficiency (see section 4.3) as telmisartan is eliminated primarily via the biliary route. Reduced hepatic clearance of telmisartan is expected for these patients.
In addition, MicardisPlus should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in fluid or electrolyte balance can cause hepatic coma. There is no clinical experience of using MicardisPlus in patients with hepatic insufficiency. .
Renovascular hypertension
In patients with bilateral renal artery stenosis or renal artery stenosis afferent to a single functioning kidney, treated with a drug that affects the renin-angiotensin-aldosterone system, there is an increased risk of severe hypotension and renal failure.
Renal failure and renal transplant
MicardisPlus should not be used in patients with severe renal impairment (serum creatinine clearance of potassium, creatinine and uric acid. Thiazide-associated diuretics-associated azotaemia may occur in patients with renal insufficiency.
Intravascular hypovolemia
In patients with hypovolaemia and / or sodium depletion caused by high doses of diuretics, salt restricted diets, diarrhea or vomiting, symptomatic hypotension may occur, especially after the first dose. Sodium depletion and / or hypovolaemia must be corrected before starting treatment with MicardisPlus.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Other conditions related to stimulation of the renin-angiotensin-aldosterone system
In patients whose vascular tone and renal function are primarily dependent on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure or with kidney disease, including renal artery stenosis), treatment with medicinal products affecting this system have been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure (see section 4.8).
Primary aldosteronism
Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products which act by inhibiting the renin-angiotensin system. Therefore, the use of MicardisPlus is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, particular caution is advised in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Effects on metabolism and on the endocrine system
Therapy with thiazides may impair glucose tolerance, while hypoglycaemia may occur in diabetic patients receiving insulin or antidiabetic therapy and being treated with telmisartan. Therefore, glucose monitoring should be considered in these patients; dose adjustment of insulin or antidiabetic agents may be required, where indicated. During therapy with thiazides, latent diabetes mellitus may become manifest.
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 or gouty manifestations may occur in some patients treated with thiazides.
Electrolyte imbalance
Periodic monitoring of serum electrolytes should be performed at appropriate intervals, as in all patients undergoing treatment with diuretics.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatremia, and hypochloraemic alkalosis). Signs of fluid or electrolyte imbalance are dry mouth, thirst, fatigue, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
- Hypokalemia
Although hypokalaemia may develop with the use of thiazide diuretics, concomitant therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients with profuse diuresis, in patients with inadequate oral intake of electrolytes and in patients on concomitant treatment with corticosteroids or adrenocorticotropic hormone (ACTH) (see section 4.5). .
- Hyperkalemia
Conversely, due to the antagonism of the angiotensin II (AT1) receptors by the telmisartan contained in MicardisPlus, hyperkalaemia may occur. Although clinically significant hyperkalaemia associated with the use of MicardisPlus has not been documented, risk factors for the development of hyperkalaemia include renal failure and / or heart failure and diabetes mellitus. Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes should be administered with caution concomitantly with MicardisPlus (see section 4.5).
- Hyponatremia and hypochloraemic alkalosis
There is no evidence that MicardisPlus reduces or prevents diuretic-induced hyponatraemia.
Chloride deficiency is usually mild and usually does not require treatment.
- Hypercalcemia
Thiazide diuretics can reduce urinary excretion of calcium and cause, in the absence of known disturbances of calcium metabolism, an intermittent and mild increase in serum calcium. Marked hypercalcaemia may be indicative of latent hyperparathyroidism. Administration of thiazide diuretics should be discontinued before performing parathyroid function tests.
- Hypomagnesemia
Thiazide diuretics have been shown to increase urinary excretion of magnesium resulting 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 and / or galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ethnic differences
Like all other angiotensin II receptor antagonists, telmisartan is apparently less effective in lowering blood pressure in black patients than in white patients, possibly due to a higher prevalence of low renin levels in the hypertensive population. of color.
Other
As with any antihypertensive agent, an excessive decrease in blood pressure in patients with ischemic heart disease or ischemic cardiovascular disease could cause myocardial infarction or stroke.
General
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a previous history of allergy or bronchial asthma, but are more likely to occur in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics, including hydrochlorothiazide.
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs during treatment, it is recommended that treatment be discontinued. If re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to sunlight or artificial UVA rays.
Acute myopia and angle-closure glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute narrow-angle glaucoma. Symptoms include the acute onset of decreased visual acuity or eye pain and typically occur within hours to weeks after you start taking the medicine. Untreated acute angle-closure glaucoma can lead to permanent loss of vision.Primary treatment is to "discontinue" hydrochlorothiazide as quickly as possible. Immediate medical or surgical treatment may need to be considered if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
04.5 Interactions with other medicinal products and other forms of interaction
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during co-administration of lithium with ACE inhibitors (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 such co-administration is really necessary, careful monitoring is recommended. of serum lithium levels during concomitant use of the two medicinal products.
Medicines associated with potassium loss and hypokalaemia (e.g. other non-potassium-sparing diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives)
If these substances are to be prescribed with the combination hydrochlorothiazide-telmisartan, it is recommended that plasma potassium levels be monitored. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium (see section 4.4).
Medicines that can increase potassium levels or induce hyperkalaemia (eg. ACE inhibitors, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, cyclosporine or other medications such as sodium heparin)
If these medicinal products are to be prescribed with the hydrochlorothiazide-telmisartan combination, it is recommended that plasma potassium levels be monitored. Based on the experience gained with the use of other medicinal products that inhibit the renin-angiotensin system, concomitant use of these medicinal products may induce an increase in serum potassium and is therefore not recommended (see section 4.4).
Medicinal products affected by changes in serum potassium
Periodic monitoring of serum potassium and ECG is recommended when MicardisPlus is administered with these medicinal products affected by serum potassium abnormalities (eg digitalis glycosides, antiarrhythmics) and the following torsade de pointes inducing medicinal products (which include some antiarrhythmics), hypokalemia being a predisposing factor to torsades de pointes.
- class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
- class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
- some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, thiapride, pimozide, haloperidol, droperidol)
- others (e.g. bepridil, cisapride, difemanil, erythromycin IV, alofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Digitalis glycosides
Thiazide-induced hypokalaemia or hypomagnesaemia favors the onset of digitalis-induced cardiac arrhythmia (see section 4.4).
Digoxin
When telmisartan was co-administered with digoxin, mean increases in peak plasma concentration (49%) and trough concentration (20%) of digoxin were observed. If telmisartan treatment is initiated, modified and discontinued, digoxin levels should be monitored to keep them within the therapeutic range.
Other antihypertensive agents
Telmisartan may enhance the hypotensive effect of other antihypertensive agents.
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).
Antidiabetic medicines (oral agents and insulin)
Dosage adjustment of antidiabetic medicinal products may be required (see section 4.4).
Metformin
Metformin should be used with caution: risk of lactic acidosis induced by a possible functional renal failure related to hydrochlorothiazide.
Colestyramine and colestipol resins
The absorption of hydrochlorothiazide is reduced in the presence of anionic exchange resins.
Non-steroidal anti-inflammatory drugs
NSAIDs (eg acetylsalicylic acid in anti-inflammatory dosages, 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 impaired renal function (such as dehydrated patients or elderly patients with impaired renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may lead to further deterioration of renal function, including possible acute renal failure which is usually reversible. Therefore, co-administration should be undertaken with caution, especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy and thereafter periodically.
In one study, co-administration of telmisartan and ramipril resulted in an up to 2.5-fold increase in ramipril and ramiprilat AUC0-24 and Cmax. The clinical relevance of this observation is unknown.
Pressor amines (e.g. norepinephrine)
The effect of pressor amines can be reduced.
Nondepolarizing muscle relaxants (e.g. tubocurarine)
The effect of non-depolarising muscle relaxants can be enhanced by hydrochlorothiazide.
Medicines used in the treatment of gout (such as probenecid, sulfinpyrazone, and allopurinol)
Dosage adjustment of uricosuric medicinal products may be required as hydrochlorothiazide may increase the serum uric acid level. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant administration of thiazide may increase the incidence of hypersensitivity reactions all "allopurinol.
Calcium salts
Thiazide diuretics may cause an increase in serum calcium levels by reducing its excretion. If calcium supplementation is to be prescribed, serum calcium levels should be monitored and its dosage adjusted accordingly.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and stomach emptying rate.
Amantadina
Thiazides may increase the risk of side effects caused by amantadine.
Cytotoxic agents (e.g. cyclophosphamide, methotrexate)
Thiazides can reduce the renal excretion of cytotoxic drugs and enhance their myelosuppressive effect.
Based on their pharmacological characteristics the following medicinal products can be expected to potentiate the hypotensive effects of all antihypertensive agents including telmisartan: baclofen, amifostine.
In addition, orthostatic hypotension can be aggravated by alcohol, barbiturates, narcotics, or antidepressants.
04.6 Pregnancy and lactation
Pregnancy
The use of angiotensin II receptor antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).
There are insufficient data on the use of MicardisPlus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Epidemiological evidence on 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. Although no controlled epidemiological data on risk with angiotensin II receptor antagonists (AIIRAs) are available, a similar risk may also exist for this class of medicinal products. An alternative antihypertensive treatment should be used for patients planning pregnancy. with a proven safety profile for use in pregnancy unless continued therapy with an AIIRA is considered essential. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to AIIRAs during the second and third trimesters is known to induce fetal toxicity (reduced renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women. (See paragraph 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken AIIRAs should be closely monitored for hypotension (see sections 4.3 and 4.4).
Experience with hydrochlorothiazide in pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Considering the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters can compromise feto-placental perfusion and cause fetal and neonatal effects such as jaundice, disturbances in electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, with no beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment can be used.
Feeding time
As no data are available regarding the use of MicardisPlus during lactation, MicardisPlus is not recommended and alternative treatments with a proven safety profile for use during lactation are preferred, especially when breastfeeding newborns and preterm babies.
Hydrochlorothiazide is excreted in human breast milk in small quantities. Thiazides in high doses, causing intense diuresis, can inhibit milk production. The use of MicardisPlus during breastfeeding is not recommended. If MicardisPlus is used during breastfeeding. breastfeeding, doses should be kept as low as possible.
Fertility
In preclinical studies, no effect of telmisartan and hydrochlorothiazide on male and female fertility was observed.
04.7 Effects on ability to drive and use machines
When driving vehicles or operating machines, it should be taken into account that somnolence and dizziness may occasionally occur with antihypertensive therapy, such as MicardisPlus.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reaction is dizziness. Severe angioedema (≥1 / 10,000,
The overall incidence of adverse reactions reported with MicardisPlus was comparable to that reported with telmisartan alone in randomized controlled trials involving 1,471 patients randomized to receive telmisartan and hydrochlorothiazide or telmisartan alone. A relationship between the reactions has not been established. adverse events and dose and gender, age or race of patients.
Summary table of adverse reactions
Adverse reactions reported in all clinical studies and occurring more frequently (p ≤ 0.05) with telmisartan and hydrochlorothiazide than with placebo are listed below according to system organ class. Known adverse reactions for any of the individual components, which were not observed in clinical studies, may occur during treatment with MicardisPlus.
Adverse reactions have been ranked by frequency using the following convention:
very common (≥1 / 10); common (≥1 / 100,
Within each frequency group, adverse reactions are listed in order of decreasing severity.
1: Based on post marketing experience
2: For further description, see subsection "Description of selected adverse reactions'
Learn more about the individual components
Adverse reactions previously reported for any of the individual components may be potential adverse reactions associated with MicardisPlus, even if not observed in clinical studies with this product.
Telmisartan:
Adverse reactions occurred with similar frequency in telmisartan-treated and placebo-treated patients.
The overall incidence of adverse reactions reported with telmisartan (41.4%) was usually comparable to that reported with placebo (43.9%) in controlled studies. The following adverse reactions were collected from all clinical studies in patients treated with telmisartan for hypertension or in patients of at least 50 years of age at high risk of cardiovascular events.
sup3 ;: For further description, see subsection "Description of selected adverse reactions'
Hydrochlorothiazide:
Hydrochlorothiazide may cause or exacerbate hypovolaemia which could lead to electrolyte imbalance (see section 4.4).
Adverse reactions of not known frequency reported with the use of hydrochlorothiazide alone include:
Description of selected adverse reactions
Impaired liver function / liver disorder
Most post-marketing cases of impaired liver function / liver disorder with telmisartan have occurred in Japanese patients. Japanese patients are more likely to experience these adverse reactions.
Sepsis
An "increased incidence of sepsis with telmisartan compared to placebo" was observed in the PRoFESS study. The event may be a random result or may be related to a currently unknown mechanism (see section 5.1).
Interstitial lung disease
Cases of interstitial lung disease have been reported post-marketing in temporal association with the intake of telmisartan. However, a causal relationship has not been established.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
There is limited information available regarding telmisartan overdose in humans. The amount of hydrochlorothiazide that is removed by hemodialysis has not been established.
Symptoms
The most prominent manifestations related to telmisartan overdose were hypotension and tachycardia; Bradycardia, dizziness, vomiting, increased serum creatinine and acute renal failure have also been reported. Overdose of hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia and hypochloremia) and hypovolaemia caused by excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia can induce muscle spasm and / or accentuate cardiac arrhythmias. the concomitant use of digitalis glycosides or some antiarrhythmic drugs.
Treatment
Telmisartan is not removed by hemodialysis. The patient should be closely monitored and treatment should be symptomatic and supportive. Treatment depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and / or gastric lavage. Activated charcoal can be useful in the treatment of overdose. Serum electrolyte and creatinine levels should be checked frequently. In the event of hypotension, the patient should be placed in the supine position and salts and fluids should be rapidly replenished.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: angiotensin II 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 active substances exerts an additive antihypertensive effect, reducing blood pressure to a greater extent than does each of the two active ingredients used alone. MicardisPlus, given once daily at the therapeutic dosage, produces an effective and gradual reduction in blood pressure.
Telmisartan is an orally effective angiotensin II subtype 1 (AT1) specific receptor antagonist. Telmisartan displaces angiotensin II with a "high affinity" from its binding site to the subtype AT1 receptor, responsible for the known effects of " angiotensin II. Telmisartan does not exhibit any partial agonist activity for the AT1 receptor. Telmisartan selectively binds to the AT1 receptor. This bond is long-lasting. Telmisartan does not show affinity for other receptors, including AT2 and other less characterized AT receptors. The functional role of these receptors is not known, nor the effect of their possible overstimulation by angiotensin II, whose levels are increased. from telmisartan. Telmisartan causes a decrease in plasma aldosterone levels. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit the angiotensin converting enzyme (kininase II), which also degrades Therefore, potentiation of bradykinin-mediated adverse events is not expected.
An 80 mg dose of telmisartan administered to healthy volunteers results in "almost complete inhibition of the" angiotensin II induced "blood pressure increase. The inhibitory effect lasts for 24 hours and is still measurable for up to 48 hours.
The antihypertensive activity begins to manifest itself within 3 hours of the administration of the first dose of telmisartan. The maximum reduction in blood pressure is generally achieved 4-8 weeks after the start of treatment and is maintained during long-term therapy. The antihypertensive effect continues consistently for 24 hours after administration and includes the last 4 hours before the next administration, as demonstrated by continuous 24 hour blood pressure measurements. This is confirmed by measurements taken at the time of maximum effect and immediately before. the next dose (trough-to-peak ratio was consistently above 80% after doses of 40 or 80 mg telmisartan in placebo-controlled clinical trials).
In hypertensive patients, telmisartan reduces both systolic and diastolic blood pressure without affecting heart rate. The antihypertensive efficacy of telmisartan is comparable to that of medicinal products representative of other classes of antihypertensive agents (as demonstrated in clinical studies comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide and lisinopril).
After abrupt discontinuation of telmisartan treatment, blood pressure gradually returns to pre-treatment values over a period of several days, without an apparent rebound effect.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those treated with ACE inhibitors in clinical trials that directly compared the two medicines.
Cardiovascular prevention
ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25,620 patients aged at least 55 years with a history of coronary heart disease, stroke , TIA, peripheral arterial disease, or type 2 diabetes mellitus associated with "evidence of target organ damage (eg, retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), representing a population at risk for cardiovascular events.
Patients were randomized to one of the following three treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576) or the combination of telmisartan 80 mg and ramipril 10 mg (n = 8502) and followed for an average observation period of 4.5 years.
Telmisartan has shown similar efficacy to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. The hazard ratio for telmisartan versus ramipril was 1.01 (97.5% CI 0.93 - 1.10, p (non-inferiority) = 0.0019 with a margin of 1.13). The incidence of mortality for all causes it was 11.6% and 11.8% in patients treated with telmisartan and ramipril, respectively.
Telmisartan was found to be as effective as ramipril in the pre-specified secondary endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke [0.99 (97.5% CI 0.90 - 1.08), p (non-inferiority) = 0.0004], primary endpoint in the reference study HOPE (The Heart Outcomes Prevention Evaluation Study), which evaluated the effect of ramipril versus placebo.
TRANSCEND randomized ACE-I intolerant patients with similar inclusion criteria as ONTARGET to receive either telmisartan 80 mg (n = 2954) or placebo (n = 2972), both given on top of standard therapy. The mean duration of follow up was 4 years and 8 months. There was no statistically significant difference in the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure) [15.7% in the telmisartan group and 17.0% in the placebo group with a hazard ratio of 0.92 (95% CI 0.81 - 1.05, p = 0.22)]. There was a benefit of telmisartan over placebo in the pre-specified secondary composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke [0.87 (95% CI 0.76-1.00, p = 0.048) There was no evidence of benefit on cardiovascular mortality (hazard ratio 1.03, 95% CI 0.85 - 1.24).
Cough and angioedema were reported less frequently in patients treated with telmisartan than in patients treated with ramipril, while hypotension was reported more frequently with telmisartan.
The combination of telmisartan and ramipril did not add any benefit over ramipril or telmisartan alone. CV mortality and all cause mortality were numerically higher with the combination. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination arm. Therefore, the use of a combination of telmisartan and ramipril is not recommended in this patient population.
In the study "Prevention Regimen For Effectively avoiding Second Strokes" (PRoFESS) in patients aged at least 50 who had recently had a stroke, an "increased incidence of sepsis was observed with telmisartan compared to placebo, 0.70% versus 0.49% [RR 1.43 (95% confidence interval 1.00 - 2.06)]; the incidence of fatal cases of sepsis was increased for patients treated with telmisartan (0.33%) compared to patients treated with placebo (0.16%) [RR 2.07 (95% confidence interval 1.14 - 3.76)]. The increased incidence of sepsis observed in association with the use of telmisartan may be a random result or related to a currently unknown mechanism.
Two large randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA Nephron-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an antagonist of the angiotensin II receptor.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. For more detailed information see above under "Cardiovascular Prevention".
VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy. These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.
ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.
Hydrochlorothiazide is a thiazide diuretic. The mechanism by which thiazide diuretics exert their antihypertensive effect is not fully understood. Thiazide diuretics affect the reabsorption of electrolytes at the level of the mechanisms of the renal tubules, directly increasing the excretion of sodium and chlorine in equal quantities. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases the secretion of aldosterone, with consequent increase in urinary potassium and loss of bicarbonate, and reduces serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of telmisartan tends to balance the potassium loss associated with these diuretics. The diuretic effect of hydrochlorothiazide occurs within 2 hours, reaches its maximum in about 4 hours, while the action persists for about 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effects of the fixed combination telmisartan / hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.
05.2 Pharmacokinetic properties
Concomitant administration of hydrochlorothiazide and telmisartan has no effect on the pharmacokinetics of either substance in healthy subjects.
Absorption
Telmisartan: Maximum telmisartan concentrations are reached in 0.5-1.5 hours after oral administration. The absolute bioavailability of telmisartan doses of 40 mg and 160 mg is 42% and 58%, respectively. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration / time curve (AUC) ranging from 6% with a 40 mg dose to approximately 19% with a 160 mg dose. 3 hours post dosing, plasma concentrations are similar whether telmisartan is taken fasting or with a meal. The slight decrease in AUC is not expected to cause a reduction in therapeutic efficacy. The pharmacokinetics of orally administered telmisartan are not linear for doses ranging from 20 to 160 mg with increases in plasma concentrations (Cmax and AUC) greater than proportionality to increasing dose. Telmisartan in repeated doses does not accumulate significantly in plasma.
Hydrochlorothiazide: After oral administration of MicardisPlus maximum concentrations of hydrochlorothiazide are reached in approximately 1.0-3.0 hours. Based on the cumulative renal excretion of hydrochlorothiazide the absolute bioavailability is approximately 60%.
Distribution
Telmisartan is highly bound to plasma proteins (> 99.5%), particularly albumin and alpha-1 acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 l indicative of further tissue binding.
Hydrochlorothiazide is 68% bound to plasma proteins and its apparent volume of distribution is 0.83-1.14 l / kg.
Biotransformation
Telmisartan is metabolised by conjugation to form a pharmacologically inactive acylglucuronide. The parent compound glucuronide is the only metabolite that has been identified in humans. After a single dose of 14C-labeled telmisartan the glucuronide accounts for approximately 11% of the measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Hydrochlorothiazide is not metabolised in humans.
Elimination
Telmisartan: Following both intravenous and oral administration of 14C-labeled telmisartan the majority of the administered dose (> 97%) was eliminated in the faeces via biliary excretion. Only small amounts were found in the urine. Total plasma clearance of telmisartan following oral administration is> 1,500 mL / min. The terminal elimination half-life was> 20 hours.
Hydrochlorothiazide is excreted almost completely unchanged in the urine. Approximately 60% of the oral dose is eliminated within 48 hours. Renal clearance is approximately 250-300 ml / min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours. .
Special populations
Senior citizens
The pharmacokinetics of telmisartan do not differ in elderly patients compared to those aged less than 65 years.
Sex
Plasma concentrations of telmisartan are generally 2 to 3 times higher in women than in men. However, no significant increases in treatment response or the incidence of orthostatic hypotension were found in women in clinical trials. No dosage adjustment was necessary.Plasma concentrations of hydrochlorothiazide tend to be higher in women than in men. This is not considered to be of clinical importance.
Kidney dysfunction
Renal excretion does not contribute to the clearance of telmisartan. No dosage adjustment is necessary in patients with impaired renal function, based on limited experience in patients with mild to moderate renal dysfunction (creatinine clearance of 30-60 ml / min , average about 50 ml / min). Telmisartan is not cleared from the blood by hemodialysis. The elimination rate of hydrochlorothiazide is reduced in patients with impaired renal function. In a 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 approximately 34 hours.
Liver dysfunctions
An increase in absolute bioavailability up to almost 100% was observed in pharmacokinetic studies in patients with hepatic insufficiency. The elimination half-life does not vary in patients with hepatic dysfunction.
05.3 Preclinical safety data
In preclinical safety studies conducted with the co-administration of telmisartan and hydrochlorothiazide in normotensive rats and dogs, doses such as to determine an exposure comparable to that of the range of doses to be used in clinical therapy did not reveal further data that had not already been observed with the administration of single medicinal products. No significant toxicological findings have been found for therapeutic use in humans.
Toxicological data also known in preclinical studies conducted with ACE inhibitors and angiotensin II antagonists were: a reduction in erythrocyte parameters (erythrocytes, hemoglobin, hematocrit), changes in renal haemodynamics (increased azotemia and creatininemia), increased activity renin, hypertrophy / hyperplasia of renal juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented / improved by administering oral saline supplements and grouping multiple animals per cage. Renal tubule dilation and atrophy have been observed in the dog. that these results are due to the pharmacological activity of telmisartan.
No clear evidence of a teratogenic effect was observed, however effects on the postnatal development of the offspring such as lower body weight and delayed eye opening were observed at toxic doses of telmisartan.
With telmisartan there was no evidence of mutagenesis, nor of clastogenic activity relevant in in vitro studies, nor of carcinogenicity in rats and mice. Studies conducted with hydrochlorothiazide have shown equivocal evidence of genotoxic or carcinogenic effects in some experimental models. However, the extensive experience in humans on the use of hydrochlorothiazide has not shown the existence of a correlation between its use and the increase in neoplasms.
For the foetotoxic potential of the combination telmisartan / hydrochlorothiazide, see section 4.6.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Magnesium stearate
Cornstarch
Meglumine
Microcrystalline cellulose
Povidone (K25)
Red iron oxide (E172)
Sodium hydroxide
Sodium carboxymethyl starch (type A)
Sorbitol (E420).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicinal product does not require any special storage temperatures. Store in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / aluminum blisters (PA / Al / PVC / Al or PA / PA / Al / PVC / Al). One blister contains 7 or 10 tablets.
Packaging:
- Blister packs with 14, 28, 56, 84 or 98 tablets or
- Divisible unit dose blister with 28 x 1, 30 x 1 or 90 x 1 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
MicardisPlus must be kept in the sealed blister due to the hygroscopic characteristics of the tablets. The tablets should be removed from the blister just before administration.
Occasionally it has been observed that the outer layer of the blister may separate from the inner layer between the blisters. If this occurs, no precautions need to be taken.
07.0 MARKETING AUTHORIZATION HOLDER
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/02/213 / 001-005
035608013
035608025
035608037
035608049
035608052
EU / 1/02/213/011
EU / 1/02/213 / 013-014
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: April 19, 2002
Date of most recent renewal: April 19, 2007
10.0 DATE OF REVISION OF THE TEXT
September 2014
