Micardis/Micardis Plus

Micardis/Micardis Plus

telmisartan

telmisartan + hydrochlorothiazide

Manufacturer:

Boehringer Ingelheim

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Telmisartan, or with hydrochlorothiazide.
Description
Each Micardis tablet contains telmisartan 40 or 80 mg.
Each Micardis Plus tablet contains telmisartan (Micardis) 40 or 80 mg and hydrochlorothiazide 12.5 mg or 25 mg.
Telmisartan is [1,1'-biphenyl]-2-carboxylic acid, 4'-[(1,4'dimethyl-2'-propyl[2,6-bi-1H-benzimidazole]-1'-yl)methyl].
Action
Pharmacology: Micardis Plus 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. Micardis Plus once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Micardis/Micardis Plus: Telmisartan: Telmisartan is an orally effective and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II.
Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long lasting. Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. It does not inhibit angiotensin-converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.
In man, an 80-mg dose of Telmisartan almost completely inhibits the angiotensin II-evoked blood pressure increase. The inhibitory effect is maintained over 24 hrs and is still measurable up to 48 hrs.
Treatment of Essential Hypertension: After the 1st dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hrs. The maximum reduction in blood pressure is generally attained 4 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hrs after dosing and includes the last 4 hrs before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently >80% seen after doses of 40 and 80 mg of telmisartan in placebo-controlled clinical studies.
There is an apparent trend to a dose relationship to a time to recovery of baseline SBP. In this respect, data concerning DBP are inconsistent.
In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan has been compared to antihypertensive drugs eg, amlodipine, atenolol, enalapril, hydrochlorothiazide, losartan, lisinopril, ramipril and valsartan.
Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension.
Telmisartan treatment has been shown in clinical trials to be associated with statistically significant reductions in left ventricular mass and left ventricular mass index in patients with hypertension and left ventricular hypertrophy.
Telmisartan treatment has been shown in clinical trials (including comparators eg, losartan, ramipril and valsartan) to be associated with statistically significant reductions in proteinuria (including microalbuminuria and macroalbuminuria) in patients with hypertension and diabetic nephropathy.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those who were given angiotensin-converting enzyme inhibitors in clinical trials directly comparing the 2 antihypertensive treatments.
Prevention of Cardiovascular Morbidity and Mortality: Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25,620 patients ≥55 years with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus accompanied by evidence of end-organ damage (eg, retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), which represents a broad cross-section of cardiovascular high-risk patients.
Patients were randomized to one of the 3 following treatment groups: Telmisartan 80 mg (n=8542), ramipril 10 mg (n=8576) or the combination of telmisartan 80 mg plus ramipril 10 mg (n=8502) and followed for a mean observation time of 4.5 years. The population studied was male 73%, Caucasian 74%, Asian 14% and 43% were ≥65 years. Hypertension was present in nearly 83% of randomized patients: 69% of patients had a history of hypertension at randomization and an additional 14% had actual blood pressure reading >140/90 mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose level. Baseline therapy included acetylsalicylic acid (76%), statins (62%), β-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).
The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for congestive heart failure.
Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been pre-screened for tolerance to treatment with an angiotensin-converting enzyme (ACE) inhibitor. The analysis of adverse events leading to permanent treatment discontinuation of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.
Telmisartan had similar efficacy to ramipril in reducing the primary endpoint. The incidence of the primary endpoint was similar in the telmisartan (16.7%), ramipril (16.5%) and telmisartan plus ramipril combination (16.3%) arms. The hazard ratio for telmisartan versus ramipril was 1.01 [97.5% CI 0.93-1.1, p (non-inferiority)=0.0019]. The treatment effect was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint based on age, gender, race, baseline therapies or underlying disease.
Telmisartan was also found to be similarly effective to ramipril in several prespecified secondary endpoints, including a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, the primary endpoint in the reference study The Heart Outcomes Prevention Evaluation Study (HOPE), which had investigated the effect of ramipril versus placebo. The hazard ratio of telmisartan versus ramipril for this endpoint in ONTARGET was 0.99 [97.5% CI 0.9-1.08, p (non-inferiority)=0.0004].
Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone. In addition, there was a significantly higher incidence of hyperkalemia, renal failure, hypotension and syncope in the combination arm. Therefore, the use of a combination of telmisartan and ramipril is not recommended in this population.
Paediatric Population: The blood pressure lowering effects of 2 doses of telmisartan were assessed in hypertensive patients 6 to <18 years (n=76) after taking telmisartan 1 mg/kg (n=30 treated) or 2 mg/kg (n=31 treated) over a 4-week treatment period. After adjustment for age group effects and baseline SBP values an average placebo-corrected SBP change from baseline (primary objective) of -8.5 mmHg was observed in the telmisartan 2 mg/kg group and a -3.6 mmHg SBP change was found in the telmisartan 1 mg/kg group. The adjusted and placebo-controlled DBP changes from baseline were -4.5 mmHg and -4.8 mmHg in the telmisartan 1 mg/kg and 2 mg/kg groups, respectively. The change was dose dependent. The safety profile appeared generally comparable to that observed in adults.
Micardis Plus: Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect 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 hydrochlorothiazides, onset of diuresis occurs in 2 hrs, and peak effect occurs at about 4 hrs, while the action persists for approximately 6-12 hrs.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
Pharmacokinetics: Concomitant administration of hydrochlorothiazide and Micardis has no effect on the pharmacokinetics of either drug.
Absorption: Following oral administration, peak concentrations of telmisartan are reached in 0.5-1.5 hrs 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 hrs 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 nonlinear over doses from 20-160 mg with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmisartan does not accumulate significantly in plasma on repeated administration.
Micardis Plus: Hydrochlorothiazide: Following oral administration of Micardis Plus, peak concentrations of hydrochlorothiazide are reached in approximately 1-3 hrs after dosing. Based on cumulative renal excretion of hydrochlorothiazide, the absolute bioavailability was about 60%.
Distribution: Telmisartan: Telmisartan is highly bound to plasma proteins (>99.5%) mainly albumin and α1-acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 L indicating additional tissue binding.
Hydrochlorothiazide: Hydrochlorothiazide is 64% protein bound in the plasma and its apparent volume of distribution is 0.8±0.3 L/kg.
Biotransformation and Elimination: Following either IV or oral administration of 14C-labelled telmisartan, most of the administered dose (>97%) was eliminated in feces via biliary excretion. Only minute amounts were found in urine.
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide. No pharmacological activity has been shown for the conjugate. The glucuronide of the parent compound is the only metabolite that has been identified in humans.
After a single dose of 14C-labelled telmisartan, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P-450 isoenzymes are not involved in the metabolism of telmisartan. Total plasma clearance of telmisartan after oral administration is >1500 mL/min. Telmisartan is characterized by biexponential decay pharmacokinetics with a terminal elimination half-life (t½) of >20 hrs. The Cmax and, to a smaller extent, AUC increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan.
After oral (and IV) administration, telmisartan is nearly exclusively excreted with the faeces, exclusively as unchanged compound. Cumulative urinary excretion is <2% of dose.
Total plasma clearance (Cltot) is high (approximately 900 mL/min) compared with hepatic blood flow (about 1500 mL/min).
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hrs. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hrs.
Elderly Patients: Pharmacokinetics of telmisartan do not differ between the elderly and those <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:
Micardis: Lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly-bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination t½ is not changed in patients with renal impairment.
Micardis Plus:
Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild to moderate renal impairment [creatinine clearance (CrCl) 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 CrCl of 90 mL/min, the elimination t½ of hydrochlorothiazide was increased. In functionally anephric patients, the elimination t½ is about 34 hrs.
Patients with Hepatic Impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination t½ is not changed in patients with hepatic impairment.
Paediatric Population: Micardis: The pharmacokinetics of 2 doses of telmisartan were assessed as a secondary objective in hypertensive patients (n=57) aged 6 to <18 years after taking telmisartan 1 mg/kg or 2 mg/kg over a 4-week treatment period. Pharmacokinetic objectives included the determination of the steady state of telmisartan in children and adolescents, and investigation of age-related differences. Although the study was too small for a meaningful assessment of the pharmacokinetics of children <12 years, the results are generally consistent with the findings in adults and confirm the nonlinearity of telmisartan, particularly for Cmax.
Toxicology:
In nonclinical 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. There were no toxicological findings observed of relevance to human therapeutic use.
Toxicological findings also well known from nonclinical studies with angiotensin-converting enzyme (ACE) 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.
There is no clear evidence of a teratogenic or embryotoxic potential for either telmisartan or hydrochlorothiazide administered as single entities or in combination. At toxic dose levels, however, nonclinical studies indicated some hazardous potential of telmisartan to fetal development (increased number of late resorptions in rabbits) and to the postnatal development of the offspring (lower body weight, delayed eye opening, andhigher mortality).
Indications/Uses
Treatment of essential hypertension.
Prevention of cardiovascular morbidity and mortality in patients ≥55 years at high risk of cardiovascular disease.
As fixed-dose combination, Micardis Plus is indicated in patients whose blood pressure is not adequately controlled on Micardis or hydrochlorothiazide alone.
Dosage/Direction for Use
Micardis: Adults: Treatment of Essential Hypertension: Recommended Dose: 40 mg once daily.
In cases where the target blood pressure is not achieved, telmisartan dose can be increased to a maximum of 80 mg once daily. Alternatively, telmisartan may be used in combination with thiazide-type diuretics eg, hydrochlorothiazide which has been shown to have an additive blood pressure-lowering effect with Micardis. When considering raising the dose, it must be borne in mind that the maximum antihypertensive effect is generally attained 4-8 weeks after the start of treatment. In patients with severe hypertension treatment with telmisartan at doses up to 160 mg alone and in combination with hydrochlorothiazide 12.5-25 mg daily was well tolerated and effective.
Prevention of Cardiovascular Morbidity and Mortality: The recommended dose is 80 mg once daily. It is not known whether doses lower than telmisartan 80 mg are effective in preventing cardiovascular morbidity and mortality. When initiating telmisartan therapy for the prevention of cardiovascular morbidity and mortality, monitoring of blood pressure is recommended, and if appropriate adjustment of medications that lower blood pressure may be necessary.
Elderly: No dosing adjustment is necessary.
Renal Impairment: No dosage adjustment is required for patients with renal impairment, including patients on hemodialysis. Telmisartan is not removed from blood by hemofiltration.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, the dosage should not exceed 40 mg once daily.
Micardis Plus: Adults: Micardis Plus should be taken once daily. The dose of telmisartan could be up-titrated before switching to Micardis Plus. Direct change from monotherapy to the fixed combinations may be considered.
Micardis Plus 40/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by telmisartan 40 mg or hydrochlorothiazide.
Micardis Plus 80/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by Micardis 80 mg or by Micardis Plus 40/12.5 mg.
The maximum antihypertensive effect is generally attained with Micardis Plus 4-8 weeks after the start of treatment.
When necessary, Micardis Plus may be administered with another antihypertensive drug.
In patients with severe hypertension, treatment with telmisartan at doses up to 160 mg alone and in combination with hydrochlorothiazide 12.5-25 mg daily was well tolerated and effective.
Elderly: No dosage adjustment is necessary.
Renal Impairment: Due to the hydrochlorothiazide component, Micardis Plus should not be used in patients with severe renal dysfunction (CrCl <30 mL/min). Loop diuretics are preferred to thiazides in this population. Experience in patients with mild to moderate renal impairment is modest but has not suggested adverse renal effects and dose adjustment is not considered necessary. Periodic monitoring of renal function is advised.
Hepatic Impairment: In patients with mild to moderate hepatic impairment, the dosage should not exceed Micardis Plus 40/12.5 mg once daily. Micardis Plus is not indicated in patients with severe hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.
Administration: Micardis/Micardis Plus may be taken with or without food.
Overdosage
Symptoms: Limited information is available with regard to overdose in humans.
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia also occured. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
Treatment: No specific information is available on the treatment of overdose with Micardis Plus. The patient should be closely monitored and the treatment should be symptomatic and supportive depending on the time since ingestion and the severity of symptoms. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patients should be placed in a supine position, with salt and volume replacement given quickly. Telmisartan is not removed by hemodialysis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Contraindications
Hypersensitivity to telmisartan and/or hydrochlorothiazide or to any of the excipients of Micardis/Micardis Plus. For Micardis Plus, hypersensitivity to other sulphonamide-derived substances (hydrochlorothiazide is a sulphonamide-derived substance).
Second and 3rd trimesters of pregnancy and lactation (see Use in pregnancy & lactation as follows). Cholestasis and biliary obstructive disorders. Severe hepatic impairment. For Micardis Plus, severe renal impairment (CrCl <30 mL/min). Refractory hypokalemia, hypercalcemia. Patients with diabetes mellitus or renal impairment [glomerular filtration rate (GFR) <60 mL/min/1.73 m2].
In case of rare hereditary conditions that may be incompatible with an excipient of Micardis/Micardis Plus, the use of Micardis/Micardis Plus is contraindicated.
Use in pregnancy & lactation: 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.
Telmisartan: The use of angiotensin II receptor antagonists is not recommended during the 1st trimester of pregnancy and should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of angiotensin II receptor antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy.
Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.
Angiotensin II receptor antagonists exposure during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
Should exposure to angiotensin II receptor antagonists have occurred from the 2nd 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.
Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the 1st trimester. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 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 could be used.
Micardis/Micardis Plus is contraindicated during lactation. It is not known whether telmisartan is excreted in human milk. Nonclinical studies have shown excretion of telmisartan in breast milk. Thiazides appear in human milk and may inhibit lactation.
Warnings
Micardis/Micardis Plus is contraindicated during pregnancy (see also Contraindications).
Patient should consult the physician if depression or nausea/vomiting occur.
Patient should discontinue the drug and immediately consult a physician if the following symptoms are observed: Swelling of face, lips, tongue and larynx; dyspnoea.
Micardis/Micardis Plus may cause renal failure hence should be used with special precaution. It may lead to an increase in serum potassium and should therefore not be used in patients administered with potassium supplements or potassium-sparing diuretics.
Special Precautions
Hepatic Impairment: Micardis Plus should not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.
Micardis Plus 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 Micardis Plus 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 Transplant: When telmisartan is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended.
Micardis Plus should not be used in patients with severe renal impairment (CrCl <30 mL/min) (see Contraindications).
There is no experience regarding the administration of Micardis/Micardis Plus in patients with severe renal impairment or with a recent kidney transplant. Experience with Micardis Plus 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 Volume Depletion: Symptomatic hypotension, especially after the 1st 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 Micardis/Micardis Plus.
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 (eg, patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria or rarely, acute renal failure.
Dual Blockade of the Renin-Angiotensin-Aldosterone System: As a consequence of inhibiting the renin-angiotensin-aldosterone system 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 [eg, adding an angiotensin-converting enzyme (ACE) inhibitor or the direct renin-inhibitor aliskiren to an angiotensin II receptor antagonist] should therefore, be limited to individually defined cases with close monitoring of renal function (see Contraindications).
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 Micardis/Micardis Plus 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 manifest during thiazide therapy.
Increase in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, at the 12.5-mg dose contained in Micardis Plus, 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 (hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances eg, nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest 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 adenocorticotropic hormone (ACTH). Conversely, due to the antagonism of the angiotensin II (AT1) receptors by the telmisartan component of Micardis Plus, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not been documented with Micardis Plus, 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 Micardis Plus.
There is no evidence that Micardis Plus would reduce or prevent diuretic-induced hyponatremia. Chloride deficit is generally mild and usually does not require treatment.
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.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Hyperkalemia: During treatment with medicinal products that affect the renin-angiotensin-aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Monitoring of serum potassium in patients at risk is recommended.
Based on experience with the use of medicinal products that affect the renin-angiotensin system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase the potassium level (heparin, etc.) may lead to an increase in serum potassium and should therefore be co-administered cautiously with Micardis.
Sorbitol: The maximum recommended daily dose of Micardis Plus contains 169 mg sorbitol in the dose strength 40/12.5 mg and 338 mg sorbitol in the dose strength 80/12.5 mg. Patients with the rare hereditary condition of fructose intolerance should not take Micardis/Micardis Plus.
Diabetes Mellitus: In diabetic patients with an additional cardiovascular risk ie, patients with diabetes mellitus and coexistent coronary artery disease, the risk of fatal myocardial infarction and unexpected cardiovascular death may be increased when treated with blood pressure lowering agents eg, angiotensin receptor blockers (ARBs) or ACE inhibitors. In patients with diabetes mellitus, coronary artery disease may be asymptomatic and therefore undiagnosed. Patients with diabetes mellitus should undergo appropriate diagnostic evaluation eg, exercise stress testing, to detect and to treat coronary artery disease accordingly before initiating treatment with Micardis/Micardis Plus.
Lactose: The maximum recommended daily dose Micardis Plus contains lactose monohydrate 112 mg in the dose strengths 40/12.5 mg and 80/12.5 mg. Patients with the rare hereditary conditions of galactose intolerance eg, galactosaemia should not take Micardis Plus.
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Others: As observed for ACE inhibitors, Micardis and the other angiotensin antagonists are apparently less effective in lowering blood pressure in Black people than in non-Blacks, possibly because of higher prevalence of low renin states in the Black hypertensive population.
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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effect on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery, it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy.
Impairment of Fertility: No studies on fertility in humans have been performed. In nonclinical studies, an effect of telmisartan and hydrochlorothiazide on male and female fertility was not observed.
Use in children: There are no data on the safety and efficacy of Micardis in children.
Safety and efficacy of Micardis Plus have not been established in children and in adolescents up to 18 years.
Use In Pregnancy & Lactation
Micardis/Micardis Plus is contraindicated during pregnancy.
Use in pregnancy & lactation: 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.
Telmisartan: The use of angiotensin II receptor antagonists is not recommended during the 1st trimester of pregnancy and should not be initiated during pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of angiotensin II receptor antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy.
Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.
Angiotensin II receptor antagonists exposure during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.
Should exposure to angiotensin II receptor antagonists have occurred from the 2nd 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.
Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the 1st trimester. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a 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 could be used.
Micardis/Micardis Plus is contraindicated during lactation. It is not known whether telmisartan is excreted in human milk. Nonclinical studies have shown excretion of telmisartan in breast milk. Thiazides appear in human milk and may inhibit lactation.
Adverse Reactions
Micardis: The overall incidence of adverse events reported with telmisartan (41.4%) was usually comparable to placebo (43.9%) in controlled trials in patients treated for hypertension. The incidence of adverse events was not dose-related and showed no correlation with gender, age or race of the patients.
The safety profile of Micardis in patients treated for prevention of cardiovascular morbidity and mortality was consistent with that obtained in hypertensive patients.
The adverse drug reactions listed as follows have been accumulated from controlled clinical trials in hypertensive patients treated with telmisartan and from post-marketing reports. The listing also takes into account serious adverse events leading to discontinuation reported in 3 clinical long-term studies including 21642 patients treated with telmisartan for prevention of cardiovascular morbidity and mortality for up to 6 years.
Infections and Infestations: Urinary tract infections (including cystitis), upper respiratory tract infections, sepsis including fatal outcome.
Blood and Lymphatic System Disorders: Anaemia, eosinophilia, thrombocytopenia.
Immune System Disorders: Anaphylactic reaction, hypersensitivity.
Metabolism and Nutrition Disorders: Hyperkalaemia, hypoglycaemia (in diabetic patients).
Psychiatric Disorders:
Insomnia, depression, anxiety.
Nervous System Disorders: Syncope (faint).
Eye Disorders: Visual disturbance.
Ear and Labyrinth Disorders: Vertigo.
Cardiac Disorders: Bradycardia, tachycardia.
Vascular Disorders: Hypotension, orthostatic hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea.
Gastrointestinal Disorders: Abdominal pain, diarrhea, dyspepsia, flatulence, vomiting, dry mouth, stomach upset.
Hepatobilary Disorders: Abnormal hepatic function/liver disorder*.
*Most cases of abnormal hepatic function/liver disorder from post-marketing experience with telmisartan occured in patients in Japan, who are more likely to experience these adverse reactions.
Skin and Subcutaneous Tissue Disorders:
Pruritus, hyperhidrosis, rash, angioedema (with fatal outcome), eczema, erythema, urticaria, drug and toxic skin eruption.
Musculoskeletal, Connective Tissue and Bone Disorders: Back pain, muscle spasms (cramps in legs), myalgia, arthralgia, pain in extremity (leg pain), tendon pain (tendinitis like symptoms).
Renal and Urinary Disorders: Renal impairment including acute renal failure (see Precautions).
General Disorders and Administration Site Conditions: Chest pain, asthenia (weakness), influenza-like-illness.
Investigations: Increased blood creatinine, uric acid, hepatic enzymes, blood creatine phosphokinase (CPK), decreased hemoglobin.
Micardis Plus: The overall incidence of adverse events reported with Micardis Plus was comparable to those reported with telmisartan alone in randomized controlled trials involving 1471 patients receiving telmisartan plus hydrochlorothiazide (835) or telmisartan (636) alone. There was no dose-relationship to undesirable effects and there was no correlation with gender, age or race of the patients.
Adverse reactions reported in clinical trials with telmisartan plus hydrochlorothiazide are shown as follows according to system organ class. Adverse reactions not observed in clinical trials with telmisartan plus hydrochlorothiazide but expected during treatment with Micardis Plus based on the experience with telmisartan or hydrochlorothiazide alone have been included and are detailed in separate sections as follows.
Infections and Infestations: Bronchitis, pharyngitis, sinusitis.
Immune System Disorders: Exacerbation or activation of systemic lupus erythematosus*.
*Based on post-marketing experience.
Metabolism and Nutrition Disorders: Hypokalaemia, hyponatraemia, hyperuricaemia.
Psychiatric Disorders: Anxiety, depression.
Nervous System Disorders: Dizziness, syncope/faint, paraesthesia, sleep disturbances, insomnia.
Eye Disorders: Abnormal vision, transient blurred vision.
Ear and Labyrinth Disorders: Vertigo.
Cardiac Disorders: Cardiac arrhythmias, tachycardia.
Vascular Disorders: Hypotension (including orthostatic hypotension).
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea, respiratory distress (including pneumonitis and pulmonary oedema).
Gastrointestinal Disorders: Diarrhoea, dry mouth, flatulence, abdominal pain, constipation, dyspepsia, vomiting, gastritis.
Hepatobiliary Disorders: Abnormal hepatic function/liver disorder*.
*Most cases of abnormal hepatic function/liver disorder from post-marketing experience with telmisartan occurred in patients in Japan, who are more likely to experience these adverse reactions.
Skin and Subcutaneous Tissue Disorders: Angioedema (with fatal outcome), erythema, pruritus, rash, increased sweating, urticaria.
Musculoskeletal, Connective Tissue and Bone Disorders: Back pain, muscle spasm, myalgia, arthralgia, leg pain, cramps in legs.
Reproductive System and Breast Disorders: Impotence.
General Disorders and Administration Site Conditions: Chest pain, influenza-like symptoms, pain.
Investigations: Increase in uric acid, creatinine, liver enzymes, blood creatine phosphokinase.
Telmisartan: Additional side effects reported in clinical trials with telmisartan monotherapy in the indication hypertension or in patients ≥50 years at high risk of cardiovascular events were as follows: Infections and Infestations: Upper respiratory tract infections, urinary tract infections (including cystitis), sepsis including fatal outcome.
Blood and Lymphatic System Disorders: Anaemia, thrombocytopenia, eosinophilia.
Immune System Disorders: Anaphylactic reaction, hypersensitivity.
Metabolism and Nutrition Disorders: Hyperkalaemia, hypoglycaemia (in diabetic patients).
Cardiac Disorders: Bradycardia.
Gastrointestinal Disorders: Stomach upset.
Skin and Subcutaneous Tissue Disorders: Eczema, drug eruption, toxic skin eruption.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthrosis, tendon pain (tendinitis like symptoms).
Renal and Urinary Disorders: Renal impairment including acute renal failure (see Warnings and Precautions).
General Disorders and Administration Site Conditions: Asthenia (weakness).
Investigations: Decrease in haemoglobin.
Hydrochlorothiazide: Additional side effects reported with hydrochlorothiazide monotherapy were as follows: Infections and Infestations: Sialadenitis.
Blood and Lymphatic System Disorders: Thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression, leukopenia, neutropenia/agranulocytosis.
Immune System Disorders: Anaphylactic reactions, allergy.
Endocrine Disorders: Loss of diabetic control.
Metabolism and Nutrition Disorders: Cause or exacerbate volume depletion, electrolyte imbalance, anorexia, loss of appetite, hyperglycaemia, hypercholesterolaemia.
Psychiatric Disorders: Restlessness.
Nervous System Disorders: Lightheadedness.
Eye Disorders: Xanthopsia, acute myopia, acute angle-closure glaucoma.
Vascular Disorders: Necrotizing angiitis (vasculitis).
Gastrointestinal Disorders: Stomach upset, pancreatitis.
Hepatobiliary Disorders: Jaundice (hepatocellular or cholestatic jaundice).
Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, cutaneous vasculitis, photosensitivity reactions.
Musculoskeletal, Connective Tissue and Bone Disorders: Weakness.
Renal and Urinary Disorders: Interstitial nephritis, renal dysfunction, glycosuria.
General Disorders and Administration Site Conditions: Fever.
Investigations: Increase in triglycerides.
Drug Interactions
Micardis: Telmisartan may increase the hypotensive effect of other antihypertensive agents. Other interactions of clinical significance have not been identified.
Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol and amlodipine. For digoxin, a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.
In one study, the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin-converting enzyme inhibitors.
Cases have also been reported with angiotensin II receptor antagonists including Micardis. Therefore, serum lithium level monitoring is advisable during concomitant use.
Treatment with NSAIDs (ie, acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and nonselective NSAIDs) is associated with the potential for acute renal insufficiency in patients who are dehydrated.
Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and Micardis should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.
A reduced effect of antihypertensive drugs like telmisartan by inhibition of vasodilating prostaglandins has been reported during combined treatment with NSAIDs.
Micardis Plus: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Cases have also been reported with angiotensin II receptor antagonists, including telmisartan. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with Micardis Plus.
Lithium and Micardis Plus should only be co-administered under medical supervision and serum lithium level monitoring is advisable during concomitant use.
The potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of Micardis. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia (eg, other kaliuretic diuretics, laxatives, corticosteroids, adrenocorticotropic hormone, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives).
If these drugs are to be prescribed with Micardis Plus, monitoring of potassium plasma levels is advised.
Conversely, based on the experience with the use of other drugs that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes-containing potassium or other drugs that may increase serum potassium levels (eg, heparin sodium) may lead to increase in serum potassium.
If these drugs are to be prescribed with Micardis Plus, monitoring of potassium plasma levels is advised.
Periodic monitoring of serum potassium is recommended when Micardis Plus is administered with drugs affected by serum potassium disturbances eg, digitalis glycosides, antiarrhythmic agents and drugs known to induce Torsades de pointes.
Treatment with NSAIDs including acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and nonselective NSAIDs is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin-angiotensin-system like telmisartan may have synergistic effects. Patients receiving NSAIDs and Micardis Plus should be adequately hydrated and be monitored for renal function at the beginning of combined treatment.
The co-administration of NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.
Telmisartan may increase the hypotensive effect of other antihypertensive agents. Other interactions of clinical significance have not been identified. Co-administration of telmisartan did not result in a clinically significant interaction with digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin, a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.
In 1 study, the co-administration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.
When administered concurrently, the following drugs may interact with thiazide diuretics:Alcohol, Barbiturates or Narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulins): Dosage adjustment of the antidiabetic drug may be required.
Metformin: There is a risk of lactic acidosis when co-administered with hydrochlorothiazide.
Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Digitalis Glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia favour the onset of digitalis-induced cardiac arrhythmias.
Pressor Amines (eg, Noradrenaline): The effect of pressor amines may be decreased.
Nondepolarizing Skeletal Muscle Relaxants (eg, Tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Treatment for Gout: Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. 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.
Other Interactions: The hyperglycaemic effect of β-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (eg, atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach-emptying rate.
Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic drugs (eg, cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Storage
Do not store above 30°C. Protect from moisture.
ATC Classification
C09DA07 - telmisartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
C09CA07 - telmisartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Presentation/Packing
Micardis: Tab 40 mg x 30's. 80 mg x 30's.
Micardis Plus: Tab 40/12.5 mg x 30's. 80/12.5 mg x 30's.
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