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.

TABLE 1
Adverse Events Occurring in ≥ 2% of Telmisartan/Hydrochlorothiazide (HCTZ) Patients*

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.

Telmisartan

Other adverse experiences that have been reported with telmisartan, without regard to causality, are listed 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).

Hydrochlorothiazide

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed 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

Post-Marketing Experience

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.

Clinical Laboratory Findings

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.

Telmisartan

Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible over- or under-digitalization.

Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR).

Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Hydrochlorothiazide

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 insulin): Dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs: Additive effect or potentiation.

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 the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.

Lithium: Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with MICARDIS HCT.

Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal antiinflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when MICARDIS HCT and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

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