Micardis^® HCT
(telmisartan and hydrochlorothiazide)
Tablets, 40mg/12.5 mg
80 mg/12.5 mg and 80 mg/25 mg

Prescribing Information

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® HCT (telmisartan/hydrochlorothiazide) tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

MICARDIS® HCT (telmisartan/hydrochlorothiazide) is a combination of telmisartan, an orally active angiotensin II antagonist acting on the AT₁ receptor subtype, and hydrochlorothiazide, a diuretic.

Telmisartan, a nonpeptide molecule, is chemically described as 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C₃₃H₃₀N₄O₂, its molecular weight is 514.63, and its structural formula is:

Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.

Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder with a molecular weight of 297.74. It is slightly soluble in water, and freely soluble in sodium hydroxide solution. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂, and its structural formula is:

MICARDIS HCT tablets are formulated for oral administration in three combinations of 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25 mg telmisartan and hydrochlorothiazide, respectively. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch glycolate. As coloring agents, the 40 mg/12.5 mg and 80 mg/12.5 mg tablets contain iron oxide red, and the 80 mg/25 mg tablets contain iron oxide yellow. MICARDIS HCT tablets are hygroscopic and require protection from moisture.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT₂ receptor found in many tissues, but AT₂ is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT₁ receptor than for the AT₂ receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is not fully understood.

MICARDIS HCT (telmisartan/hydrochlorothiazide) is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

MICARDIS HCT (telmisartan/hydrochlorothiazide) is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS HCT (telmisartan/hydrochlorothiazide) tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS HCT tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, MICARDIS HCT tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist 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 or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

A developmental toxicity study was performed in rats with telmisartan/hydrochlorothiazide doses of 3.2/1.0, 15/4.7, 50/15.6, and 0/15.6 mg/kg/day. Although the two higher dose combinations appeared to be more toxic (significant decrease in body weight gain) to the dams than either drug alone, there did not appear to be an increase in toxicity to the developing embryos.

No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m² basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m² basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m² basis, the maximum recommended human dose of telmisartan (80 mg/day).

Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Initiation of antihypertensive therapy in patients whose renin-angiotensin system are activated such as patients who are intravascular volume- or sodium-depleted, e.g., in patients treated vigorously with diuretics, should only be approached cautiously. These conditions should be corrected prior to administration of MICARDIS HCT. Treatment should be started under close medical supervision (see DOSAGE AND ADMINISTRATION). If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment which usually can be continued without difficulty once the blood pressure has stabilized.

Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

In the controlled clinical trials (n=1017), approximately 20% of patients treated with telmisartan/hydrochlorothiazide were 65 years of age or older, and 5% were 75 years of age or older. No overall differences in effectiveness and safety of telmisartan/hydrochlorothiazide were observed in these patients compared to younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

MICARDIS HCT (telmisartan/hydrochlorothiazide) has been evaluated for safety in over 1700 patients, including 716 treated for over six months and 420 for over one year. In clinical trials with MICARDIS HCT, no unexpected adverse events have been observed. Adverse experiences have been limited to those that have been previously reported with telmisartan and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo. Most adverse experiences were mild in intensity and transient in nature and did not require discontinuation of therapy.

Adverse events occurring at an incidence of 2% or more in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.

The following adverse events were reported at a rate less than 2% in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo: back pain, dyspepsia, vomiting, tachycardia, hypokalemia, bronchitis, pharyngitis, rash, hypotension postural, abdominal pain.

Finally, the following adverse events were reported at a rate of 2% or greater in patients treated with telmisartan/hydrochlorothiazide, but were as, or more common in the placebo group: pain, headache, cough, urinary tract infection.

Adverse events occurred at approximately the same rates in men and women, older and younger patients, and black and non-black patients.

In controlled trials (n=1017), 0.3% of patients treated with MICARDIS HCT 40/12.5 mg, 80/12.5 mg or 80/25 mg discontinued due to orthostatic hypotension, and the incidence of dizziness was 4%, 7%, and 1% respectively.

Other adverse experiences that have been reported with telmisartan, without regard to causality, are uled below:

Autonomic Nervous System: impotence, increased sweating, flushing

Body as a Whole: allergy, fever, leg pain, malaise, chest pain

Cardiovascular: palpitation, dependent edema, angina pectoris, leg edema, abnormal ECG, hypertension, peripheral edema

CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia

Gastrointestinal: flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders

Metabolic: gout, hypercholesterolemia, diabetes mellitus

Musculoskeletal: arthritis, arthralgia, leg cramps, myalgia

Psychiatric: anxiety, depression, nervousness

Resistance Mechanism: infection, fungal infection, abscess, otitis media

Respiratory: asthma, rhinitis, dyspnea, epistaxis

Skin: dermatitis, eczema, pruritus

Urinary: micturition frequency, cystitis

Vascular: cerebrovascular disorder

Special Senses: abnormal vision, conjunctivitis, tinnitus, earache

A single case of angioedema was reported (among a total of 3781 patients treated with telmisartan).

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are uled below:

Body as a whole: weakness

Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation

Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia

Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions

Metabolic: hyperglycemia, glycosuria, hyperuricemia

Musculoskeletal: muscle spasm

Nervous System/Psychiatric: restlessness

Renal: renal failure, renal dysfunction, interstitial nephritis

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

Special Senses: transient blurred vision, xanthopsia

The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK.

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.

In controlled trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS HCT tablets.

Hemoglobin and Hematocrit: Decreases in hemoglobin (≥ 2 g/dL) and hematocrit (≥ 9%) were observed in 1.2% and 0.6% of telmisartan/hydrochlorothiazide patients, respectively, in controlled trials. Changes in hemoglobin and hematocrit were not considered clinically significant and there were no discontinuations due to anemia.

Creatinine, Blood Urea Nitrogen (BUN): Increases in BUN (≥ 11.2 mg/dL) and serum creatinine (≥ 0.5 mg/dL) were observed in 2.8% and 1.4%, respectively, of patients with essential hypertension treated with MICARDIS HCT in controlled trials. No patient discontinued treatment with MICARDIS HCT due to an increase in BUN or creatinine.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. No telmisartan/hydrochlorothiazide treated patients discontinued therapy due to abnormal hepatic function.

Serum Electrolytes: See PRECAUTIONS.

Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

The most common signs and symptoms observed in patients 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. The oral LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

The usual starting dose of telmisartan is 40 mg once a day; blood pressure response is dose related over the range of 20-80 mg. Patients with depletion of intravascular volume should have the condition corrected or telmisartan tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS).

Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The side effects (see WARNINGS) of telmisartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of telmisartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

MICARDIS HCT (telmisartan/hydrochlorothiazide) tablets may be administered with other antihypertensive agents.

MICARDIS HCT tablets may be administered with or without food.

The combination may be substituted for the titrated components.

MICARDIS HCT is available as tablets containing either telmisartan 40 mg and hydrochlorothiazide 12.5 mg, or telmisartan 80 mg and hydrochlorothiazide 12.5 mg or 25 mg. A patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg (see above) may be switched to MICARDIS HCT, telmisartan 80 mg/hydrochlorothiazide 12.5 mg once daily, and finally titrated up to 160/25 mg, if necessary.

A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide may be switched to MICARDIS HCT (telmisartan 80 mg/hydrochlorothiazide 12.5 mg or telmisartan 80 mg/hydrochlorothiazide 25 mg) once daily. The clinical response to MICARDIS HCT should be subsequently evaluated and if blood pressure remains uncontrolled after 2-4 weeks of therapy, the dose may be titrated up to 160/25 mg, if necessary. Those patients controlled by 25 mg hydrochlorothiazide but who experience hypokalemia with this regimen, may be switched to MICARDIS HCT (telmisartan 80 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response.

The usual regimens of therapy with MICARDIS HCT 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, so MICARDIS HCT is not recommended.

MICARDIS HCT is not recommended for patients with severe hepatic impairment. Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision using the 40/12.5 mg combination (see PRECAUTIONS).

MICARDIS HCT (telmisartan/hydrochlorothiazide) is available in three strengths as biconvex two-layered, oblong-shaped, uncoated tablets in three combinations of 40 mg/12.5 mg, 80 mg/12.5 mg and 80 mg/25 mg telmisartan and hydrochlorothiazide, respectively. The hydrochlorothiazide layer is red in the 40 mg/12.5 mg and 80 mg/12.5 mg tablets, and yellow in the 80 mg/25 mg tablets, and all are unmarked. The telmisartan layer for all three strengths is white, but may contain red specks in the 40 mg/12.5 mg and 80 mg/12.5 mg tablets and yellow specks in the 80 mg/25 mg tablets. The telmisartan layer is marked with the BOEHRINGER INGELHEIM logo and H4 for the 40 mg/12.5 mg dose strength, H8 for the 80 mg/12.5 mg dose strength and H9 for the 80 mg/25 mg dose strength.

Tablets are provided as follows:

MICARDIS HCT tablets 40 mg/12.5 mg are individually buler-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0043-37).

MICARDIS HCT tablets 80 mg/12.5 mg are individually buler-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0044-37).

MICARDIS HCT tablets 80 mg/25 mg are individually buler-sealed in cartons of 30 tablets as 3 x 10 cards (NDC 0597-0042-37).

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Tablets should not be removed from bulers until immediately before administration.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH,
Ingelheim, Germany

©Copyright 2006, Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED

Micardis HCT Tablets are covered by U.S. Patent 5,591,762

Revised: June 2, 2006

IT1105A
340139/US/4
340139/04
10004142/US/2
10004142/02