Drug Interactions
Interactions with food have not been established.
Interactions with laboratory tests have not been established.
Hydrochlorothiazide is not metabolized by humans; as such, no pharmacokinetic interaction with agents known to inhibit or induce CYP isozymes or other enzymes systems is expected.
| Hydrochlorothiazide | Effect | Clinical comment |
| Alcohol, barbiturates and narcotics | Potentiation of orthostatic hypotension may occur. | |
| Anti-diabetic drugs (oral agents and insulin) | Potential for hyperglycemia in patients on thiazides | Dosage adjustment of the antidiabetic drug may be required. |
| Cholestyramine and colestipol resins | Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43% respectively. | |
| Corticosteroids, ACTH | Intensified electrolyte depletion, particularly hypokalemia may occur. | |
| Lithium Salts | | Lithium should not generally be administered concurrently with diuretics; if lithium must be administered concurrently with MICARDIS PLUS, serum lithium levels should be carefully monitored. |
| Nonsteroidal Anti-Inflammatory drugs (NSAIDs including ASA and COX-2 inhibitors) | The co-administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. The potential for acute renal insufficiency in patients who are dehydrated may be enhanced. | Patients receiving NSAIDs and MICARDIS PLUS should be adequately hydrated and be monitored for renal function at the beginning of the combined treatment. Monitoring of renal function at the beginning and during the course of the treatment is recommended as well as regular hydration of the patient. Therefore, when MICARDIS PLUS and NSAIDs are used concomitantly, the patient should be observed closely to determine whether the desired effect of the diuretic is obtained. |
| Pressor amines (e.g. norepinephrine) | Decreased response to pressor amines may occur, but the effect is considered not sufficient to preclude their concurrent use. | |
| Skeletal muscle relaxants, nondepolarizing (e.g. tubocurarine) | Possible increased responsiveness to the muscle relaxant | |
| Other antihypertensive drugs | Additive effect or potentiation of antihypertensive effect | |
| β-adrenergic receptor blocking agents propranolol, metoprolol, sotalol, or acebutolol | | No significant pharmacokinetic interactions were noted when these agents were administered concomitantly, separately or in fixed combination. |
| Spironolactone, indomethacin, allopurinol and phenytoin. | | No significant interactions have been noted. |
Interactions with herbal products have not been established.
Interactions with lifestyle have not been established.
Information for the Patient
Micardis Plus
Dosage and Administration
The recommended dose of telmisartan is 80 mg once daily. The antihypertensive effect is present within 2 weeks and maximal reduction is generally attained after four weeks. If additional blood pressure reduction is required, a thiazide diuretic may be added.
No initial dosing adjustment is necessary for elderly patients or for patients with renal impairment but greater sensitivity in some older individuals cannot be ruled out. Markedly reduced telmisartan plasma levels were observed in patients on hemodialysis.
In patients receiving diuretics, telmisartan therapy should be initiated with caution, since these patients may be volume depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of telmisartan to reduce the likelihood of hypotension. (See Warnings and Precautions, Hypotension.) If this is not possible because of the patients’s condition, telmisartan should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.
MICARDIS PLUS (telmisartan/hydrochlorothiazide) is not for initial therapy.
A patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg, may be switched to MICARDIS PLUS, (telmisartan 80 mg/hydrochlorothiazide 12.5 mg) once daily.
A patient whose blood pressure is not adequately controlled with MICARDIS PLUS (telmisartan 80 mg/hydrochlorothiazide 12.5 mg), may be switched to MICARDIS PLUS (telmisartan 80 mg/hydrochlorothiazide 25 mg) once daily.
The usual regimens of therapy with MICARDIS PLUS may be followed as long as the patient's creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides; in this instance, MICARDIS PLUS is not recommended.
MICARDIS PLUS may be administered with or without food, however it should be taken consistently with regard to food intake.
If a dose is missed, patients should not take a double dose; patients should just carry on with the next dose at the usual time.
For patients with hepatic impairment, a starting dose of 40 mg of telmisartan is recommended. MICARDIS PLUS is not recommended for patients with severe hepatic impairment.
MICARDIS PLUS may be substituted in patients who have been stabilized on the individual telmisartan 80 mg and hydrochlorothiazide 12.5 mg components as described below.
MICARDIS PLUS may be administered with or without food, however it should be taken consistently with regard to food intake.
Adverse Reactions
renal failure, renal dysfunction, interstitial nephritis.
transient blurred vision, xanthopsia.
cerebrovascular disorder, purpura.
Adverse experiences that have been reported with hydrochlorothiazide alone without regard to causality are listed below:
Rare: hepatic function abnormal/liver disorder.
aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.
hypertonia, migraine-aggravated, muscle contraction-involuntary.
Common: edema, palpitation. Uncommon: bradycardia, orthostatic hypotension, hypotension. Rare: tachycardia.
dizziness, vertigo, paraesthesia, restlessness, nervousness.
Common: skin disorders like rash. Uncommon: pruritus. Rare: erythema, drug eruption, angioedema, eczema, toxic skin eruption. Unknown: urticaria.
In placebo-controlled trials, marked increases in serum cholesterol were reported in a total of 6 telmisartan-treated patients (0.4%) and no placebo patients. Two of these patients were followed over time, in both cases cholesterol values reverted to baseline levels.
Serum elevations in cholesterol were reported as adverse events in 11 of 3445 patients (0.3%) in all clinical trials. There were no reported cases of hypercholesterolemia in telmisartan-treated patients in placebo-controlled trials.
bronchospasm, epistaxis, pneumonia, bronchitis.
The incidence of adverse events was not dose-related and did not correlate with the gender, age, or race of patients.
anorexia, appetite increased, flatulence, gastrointestinal disorder nos, gastroenteritis, gastroesophageal reflux, melena, mouth dry, abdominal pain.
muscle spasm, weakness, cramps in legs.
Since the introduction of telmisartan in the market, cases of anxiety, dizziness, vision troubled, vertigo, abdominal distension, abdominal pain, retching, hyperhidrosis, arthralgia, myalgia, muscle spasm, back pain, asthenia, pain in extremity, fatigue, chest pain, blood creatinine increased, erythema, pruritus, syncope/faint, insomnia, depression, stomach discomfort, vomiting, hypotension (including orthostatic hypotension), bradycardia, tachycardia, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, hyperkalemia, dyspnoea, anaemia, eosinophilia, thrombocytopenia and weakness have been reported. The frequency of these effects is unknown. As with other angiotensin II antagonists, rare cases of angioedema, pruritus, rash and urticaria have been reported.
Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
In addition, since the introduction of telmisartan in the market, cases with increased blood creatinine phosphokinase (CPK) have been reported.
In addition, the following adverse events, with no established causality, were reported at an incidence <1% in placebo-controlled clinical trials:
urinary tract infection.
In controlled trials with 1017 patients, 0.3% of patients treated with telmisartan (80 mg) and hydrochlorothiazide (12.5 mg) used in combination discontinued due to hypotension.
Adverse events occurred at approximately the same rates in men and women, older and younger patients and black and non-black patients.
See Warnings and Precautions.
Rare: hypersensitivity. Unknown: anaphylactic reaction.
rash, urticaria, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, photosensitivity reactions, necrotizing angiitis (vasculitis, cutaneous vasculitis), anaphylactic reactions, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus.
Uncommon: upper respiratory tract infections, urinary tract infections. Not known: sepsis including fatal outcome.
The adverse drug events listed below have been accumulated from 27 clinical trials including 5788 hypertensive patients treated with telmisartan. Adverse events have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000).
dysuria, hematuria, micturition disorder, urinary tract infection (including cystitis).
| Laboratory Parameter | % of Patients Treated with Telmisartan/ Hydrochlorothiazide | Clinical Comment |
| Increases in Blood Urea Nitrogen (BUN) (≥11.2 mg/dL) | 2.8% | No patient discontinued treatment due to an increase in BUN. |
Increases in Serum Creatinine
(≥0.5 mg/dL) | 1.4% | No patient discontinued treatment due to an increase in creatinine. |
Decreases in Hemoglobin
(≥2 g/dL) | 1.2% | Changes in hemoglobin were not considered clinically significant and there were no discontinuations due to anemia. |
Decreases in Hematocrit
(≥9%) | 0.6% | Changes in hematocrit were not considered clinically significant and there were no discontinuations due to anemia. |
vision abnormal.
Angioedema has been reported rarely in patients treated with telmisartan.
Uncommon: blood creatinine increased. Unknown: haemoglobin decreased. Rare: blood uric acid increased, hepatic enzymes increased, blood creatinine phosphokinase increased, haemoglobin decreased.
hypotension, hypotension-postural, leg edema.
Very common: headache. Common: dizziness, insomnia. Uncommon: vertigo.
Additional adverse reactions reported in clinical trials with telmisartan plus hydrochlorothiazide are listed below according to system organ class:
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
arthritis, arthritis aggravated, arthrosis, bursitis, fascitis plantar, tendon pain.
Uncommon: renal impairment including acute renal failure.
hypokalemia, loss of diabetic control, hyperuricemia.
metabolic: hyperglycaemia, glucosuria, hyperuricaemia.
Common: anxiety, nervousness. Uncommon: depression.
diabetes mellitus, hypokalemia.
electrolyte imbalances (including hyponatraemia and hypokalaemia), increases in triglycerides, hypercholesterolemia.
Common: arthralgia, muscle spasms (cramps in legs) or pain in extremity (leg pain), myalgia, arthritis, arthrosis. Uncommon: tendon pain (tendonitis like symptoms), back pain.
abscess, infection, bacterial, moniliasis genital, otitis media.
Clinically significant changes in hemoglobin and hematocrit (<10 g/dL and <30%, respectively) were rarely observed with telmisartan treatment and did not differ from rates in placebo-treated patients. No patients discontinued therapy due to anemia.
respiratory distress including pneumonia and pulmonary edema.
Uncommon: syncope (faint).
jaundice (hepatocellular cholestatic jaundice).
pancreatitis, sialadenitis, gastric irritation, anorexia, nausea, vomiting, diarrhea, constipation.
Common: upper respiratory tract infections including pharyngitis and sinusitis, bronchitis, coughing, dyspnea, rhinitis.
| Laboratory Parameter | % of Placebo Patients | % of Patients Treated with Telmisartan | Clinical Comment |
| Increases in ALT >3 times the upper limit of normal | 1.7% | 0.5% | No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. |
| Increases in AST >3 times the upper limit of normal | 0.8% | 0.1% | No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. |
| Increases in Blood Urea Nitrogen (BUN) ≥11.2 mg/dL | 0.3% | 1.5% | These increases occurred primarily with telmisartan in combination with hydrochlorothiazide. One telmisartan treated patient discontinued therapy due to increases in blood urea nitrogen and creatinine. |
Increases in Creatinine
≥0.5 mg/dL | 0.3% | 0.6% | These increases occurred primarily with telmisartan in combination with hydrochlorothiazide. One telmisartan treated patient discontinued therapy due to increases in blood urea nitrogen and creatinine. |
| Increases in Serum Potassium ≥1.4 mEq/L | 0.6% | 0.3% | Clinically significant changes in potassium (that exceeded 3 mEq/L) were found in 0.6% of telmisartan-treated patients, with 0.5% of these reported at baseline. The corresponding rates for placebo-treated patients were 0.6% and 0.8%. |
| Decreases in Serum Potassium ≥1.4 mEq/L | 0.3% | 0.1% | Clinically significant changes in potassium (that exceeded 3 mEq/L) were found in 0.6% of telmisartan-treated patients, with 0.5% of these reported at baseline. The corresponding rates for placebo-treated patients were 0.6% and 0.8%. |
| Increases in Serum Uric Acid ≥2.7 mg/dL | 0.0% | 1.7% | Clinically significant hyperuricemia (>10 mEq/L) was observed in 2.3% of patients with telmisartan, with 0.4% reported in patients at baseline. Increases in serum uric acid were primarily observed in patients who received telmisartan in combination with hydrochlorothiazide. No patient was discontinued from treatment due to hyperuricemia. |
Common: chest pain, influenza-like symptoms, symptoms of infection (e.g. urinary tract infection including cystitis), fatigue, conjunctivitis. Uncommon: hyperhidrosis, asthenia (weakness).
Occasional elevations of liver enzymes and/or serum bilirubin have occurred. No telmisartan/hydrochlorothiazide treated patients discontinued therapy due to abnormal liver function.
Indications and Clinical Use
Safety and efficacy of MICARDIS PLUS have not been established in children and in adolescents up to 18 years.
No dosage adjustment is necessary. It should be recognized, however, that greater sensitivity in some older individuals can not be ruled out.
Overdosage
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Based on limited data, the most prominent manifestations of overdose are hypotension, dizziness and tachycardia; bradycardia also occurred in this setting as a result of parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.
Dosage Forms, Composition and Packaging
Each bilayered, oblong-shaped, uncoated tablet, the telmisartan layer being white and the hydrochlorothiazide layer being red, marked BOEHRINGER INGELHEIM logo and “H8” on the white layer, contains: telmisartan 80 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: iron oxide red, lactose monohydrate, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, povidone, sodium hydroxide, sodium starch glycolate and sorbitol. Individually blister-sealed cartons of 28 (4 cards of 7 tablets each).
Each bilayered, oblong-shaped, uncoated tablet, the telmisartan layer being white and the hydrochlorothiazide layer being yellow, marked BOEHRINGER INGELHEIM logo and “H9” on the white layer, contains: telmisartan 80 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: iron oxide yellow, lactose monohydrate, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, povidone, sodium hydroxide, sodium starch glycolate and sorbitol. Individually blister-sealed cartons of 28 (4 cards of 7 tablets each).
Warnings and Precautions
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
During thiazide diuretic therapy, periodic determinations of serum electrolytes to detect possible electrolyte imbalances should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, particularly hyponatremia, hypokalemia and hypochloremic alkalosis. Serum and urine electrolyte determinations are particularly important when the patient experiences excessive vomiting or receives parenteral fluids.
Hypokalemia may develop especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may induce cardiac arrhythmia and may also sensitize or exacerbate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require special treatment except under extraordinary circumstances (as in liver or renal disease), chloride replacement therapy may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Calcium excretion is decreased by thiazide diuretics which may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may also be evidence of hyperparathyroidism. In the event of significant hypercalcemia, MICARDIS PLUS should be discontinued followed by assessment of parathyroid function.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia.
Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients receiving thiazide therapy.
Insulin requirements in diabetic patients may be altered and latent diabetes mellitus may become manifest during thiazide diuretic therapy.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy.
Thiazide may decrease serum PBI levels without signs of thyroid disturbance.
In controlled trials using telmisartan (80 mg) and hydrochlorothiazide (12.5 mg) in combination, there were no reports of hyperkalemia. Hypokalemia was reported in 1.4% of patients treated with the combination. No discontinuations due to hypokalemia occurred during treatment. The absence of significant changes in serum potassium levels may be due to the opposing mechanisms of action of telmisartan and hydrochlorothiazide on potassium excretion by the kidney.
The use of a dual renin-angiotensin-aldosterone system (RAAS) blockade may lead to increased occurrence of hyperkalemia when given as add-on therapy in patients with controlled blood pressure.
In patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting, symptomatic hypotension may occur after initiation of therapy with telmisartan. Such conditions, especially volume and/or sodium depletion, should be corrected prior to administration of telmisartan. In these patients, because of the potential fall in blood pressure, therapy with telmisartan should be initiated under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
The use of a dual renin-angiotensin-aldosterone system (RAAS) blockade may lead to increased occurrence of hypotension when given as add-on therapy in patients with controlled blood pressure.
As the predominant route of elimination of telmisartan is through biliary excretion, patients with cholestasis, biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance leading to increased systemic exposure. MICARDIS PLUS should therefore be used with caution in these patients. Dosage reduction should be considered which would necessitate usage of the individual tablet formulations.
MICARDIS PLUS is not recommended for patients with severe hepatic impairment. Thiazides 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 (see Dosage and Administration, Patients with Hepatic Impairment).
Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, MICARDIS PLUS should be discontinued as soon as possible.
The use of angiotensin receptor (AT1) blockers (ARBs) is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARB, similar risks may exist for this class of drugs. 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 antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Infants with a history of in utero exposure to ARBs should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as a means of reversing hypotension and/or substituting for disordered renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Thiazides cross the placenta and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary risks, including fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
It is not known if telmisartan can be removed from the body by hemodialysis.
There has been no clinical experience with MICARDIS PLUS (telmisartan/hydrochlorothiazide) in pregnancy.
Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals (such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure). Dual blockade of the renin-angiotensin-aldosterone system (e.g. concomitant use of an angiotensin II receptor antagonist and an ACE-inhibitor) has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. Upon treatment with such combination, renal function should be closely monitored.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. Appropriate assessment of renal function should be conducted prior to use of MICARDIS PLUS.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. Although there has been no long-term experience with telmisartan in this patient population, an effect similar to that observed with ACE inhibitors should be anticipated.
Due to the hydrochlorothiazide component, MICARDIS PLUS is not recommended in patients with severe renal impairment (creatinine clearance ≤30 mL/min).
Thiazide diuretics should be used with caution in patients with renal impairment.
There is no experience regarding the administration of MICARDIS PLUS in patients with a recent kidney transplant.
There is a concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction.
In clinical trials (n=1725) of patients treated with the combination of telmisartan and hydrochlorothiazide, 348 (20.2%) were 65 to 74 years of age and 78 (4.5%) were 75 years of age or older. No overall differences in the safety or efficacy profiles were observed in elderly patients compared with younger patients. It should be recognized however, that greater sensitivity of some older individuals cannot be ruled out.
Hypersensitivity reactions to the hydrochlorothiazide component of MICARDIS PLUS may occur in patients with or without a history of allergy or bronchial asthma.
Azotemia may be precipitated or increased by the hydrochlorothiazide component of MICARDIS PLUS. Cumulative effects of the drug may develop in patients with impaired renal function since the primary route of excretion is through the urine.
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, the diuretic should be discontinued.
For specific monitoring and laboratory tests, see Warnings and Precautions (Cardiovascular, Endocrine and Metabolism, Hepatic/Biliary/Pancreatic and Renal) and Drug Interactions.
Safety and effectiveness of MICARDIS PLUS in pediatric patients have not been established.
MICARDIS PLUS is contraindicated during lactation since it is not known whether telmisartan is excreted in human milk but significant levels have been found in the milk of lactating rats. Animal studies have shown excretion of telmisartan in breast milk. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Thiazide diuretics are excreted in human milk at low levels.
Storage and Stability
MICARDIS PLUS tablets are packaged in blisters and should be stored at room temperature (15-30°C). MICARDIS PLUS tablets are hygroscopic and require protection from moisture. Tablets should not be removed from blisters until immediately prior to administration.
Action and Clinical Pharmacology
Hydrochlorothiazide is 40% protein bound in the plasma and its apparent volume of distribution is 2 to 5 L/kg.
Following oral administration, peak concentrations of hydrochlorothiazide were reached approximately 2.0 hours after dosing. Based on cumulative renal excretion of hydrochlorothiazide the absolute bioavailability was about 60% to 70%.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. The plasma-half life has been observed to vary between 5.6 and 14.8 hours when the plasma levels can be followed for up to 24 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placenta but not the blood-brain barrier and is excreted in breast milk.
Plasma concentrations of telmisartan are generally 2-3 times higher in females than in males administered the same oral dose. 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 on the basis of gender.
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acylglucuronide; this is the only metabolite that has been detected in human plasma and urine. Following both oral dosing and intravenous administration of radiolabelled telmisartan, the parent compound represented approximately 85%, and the glucuronide approximately 11% of total radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
No studies were conducted to evaluate the influence of genetic polymorphisms on the pharmacokinetics or pharmacodynamics of telmisartan.
Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.
The pharmacokinetics of telmisartan does not differ between elderly patients and those younger than 65 years of age.
In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% (see Warnings and Precautions and Dosage and Administration). Reduction of the dose of telmisartan should be considered which would necessitate usage of the individual tablet formulations.
MICARDIS PLUS (telmisartan/hydrochlorothiazide) is a combination of telmisartan, a selective angiotensin II antagonist and hydrochlorothiazide, a thiazide diuretic.
Single Dose Pharmacokinetics in Normotensive Subjects (10 Male and 10 Female Caucasian Subjects, 18 to 45 Years of Age). Given are Arithmetic Means (%CV)
| Drug | Therapy | Cmax
(ng/mL) | t½
(h) | AUC0-∞
(ng· h/mL) | Clearance
(CL/f)
(mL/min) | Volume of Distribution
(Vz/f)
(L) |
| Telmisartan: monotherapy | A | 246
(%CV 69.4) | 22.2
(%CV 30) | 1439
(%CV 94) | 1650
(%CV 62) | 2908
(%CV 60) |
| Telmisartan: combination therapy | B | 266
(%CV 103) | 24.4
(%CV 33) | 1467
(%CV 94) | 1565
(%CV 63) | 3091
(%CV 63) |
| Hydrochlorothiazide: combination therapy | A | 75.3
(%CV 26) | 11.4
(%CV 43) | 580.4
(%CV 27) | 380
(%CV 23) | 363.8
(%CV 43) |
| Hydrochlorothiazide: monotherapy | B | 75.7
(%CV 22) | 11.5
(%CV 36) | 563.9
(%CV 20) | 384
(%CV 20) | 380.4
(%CV 40) |
In a placebo-controlled clinical study, the combination of telmisartan and hydrochlorothiazide resulted in decreases in trough systolic blood pressure (SBP) and diastolic blood pressure (DBP) which were greater than the decreases induced by either agent administered as monotherapy.
In a controlled clinical trial directly comparing MICARDIS PLUS with telmisartan (80 mg) monotherapy, trough SBP and DBP reductions observed with MICARDIS PLUS were significantly greater than with telmisartan alone.
Similarly, in other controlled studies with patients who did not achieve or maintain adequate response with telmisartan monotherapy, the addition of 12.5 mg hydrochlorothiazide to titrated doses of telmisartan further reduced systolic and diastolic pressure.
The antihypertensive effect of telmisartan/hydrochlorothiazide (80 mg/12.5 mg) was independent of age or gender. The overall response to the combination was similar for black and non-black patients.
There was essentially no change in heart rate in patients treated with the combination of telmisartan and hydrochlorothiazide in the placebo-controlled trial.
Renal excretion of telmisartan is negligible. In patients with mild to moderate renal impairment, (creatinine clearance of 30-80 mL/min), no dosage adjustment is necessary (see Warnings and Precautions, Renal Impairment and Dosage and Administration, Patients with Renal Impairment). Telmisartan is not removed by hemodialysis.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. Appropriate assessment of renal function should be conducted prior to use of MICARDIS PLUS.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. Although there has been no long-term experience with telmisartan in this patient population, an effect similar to that observed with ACE inhibitors should be anticipated.
Due to the hydrochlorothiazide component, MICARDIS PLUS is not recommended in patients with severe renal impairment (creatinine clearance ≤30 mL/min).
Thiazide diuretics should be used with caution in patients with renal impairment.
There is no experience regarding the administration of MICARDIS PLUS in patients with a recent kidney transplant.
No initial dosing adjustment for telmisartan is necessary for elderly patients or for patients with renal impairment but greater sensitivity in some older individuals cannot be ruled out. Markedly reduced telmisartan plasma levels were observed in patients on hemodialysis.
The usual regimens of therapy with MICARDIS PLUS may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides; in this instance MICARDIS PLUS is not recommended.
Azotemia may be precipitated or increased by the hydrochlorothiazide component of MICARDIS PLUS. Cumulative effects of the drug may develop in patients with impaired renal function since the primary route of excretion is through the urine.
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, the diuretic should be discontinued.
Contraindications
Patients with rare hereditary problems of fructose intolerance should not take this medicine. A recommended daily dose of MICARDIS PLUS tablets contains 338 mg sorbitol. MICARDIS PLUS is therefore unsuitable for patients with rare hereditary fructose intolerance.
Patients with rare hereditary problems of galactose intolerance, the Lapp Lactase deficiency or glucose-galactose malabsorption should not take this medication. The maximum recommended daily dose of MICARDIS PLUS contains 112 mg of lactose monohydrate in the dose strength of 80/12.5 mg or 99 mg of lactose monohydrate in the dose strength of 80/25 mg. Patients with rare hereditary conditions of galactose intolerance, e.g. galactosaemia, should not take this medicine.
