Angiotensin 2 Receptor Blocker

Telmisartan and Hydrochlorothiazide

Approved 25 Feb 2014OralTablet

The FDA lists this product in 30 strengths and forms.

Indications

Telmisartan and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION ).

Contraindications

Telmisartan and hydrochlorothiazide tablets, USP are contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, hydrochlorothiazide, or any other component of this product (see ADVERSE REACTIONS ). Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer aliskiren with telmisartan and hydrochlorothiazide tablets in patients with diabetes (see PRECAUTIONS , Drug Interactions ).

Warnings and precautions

Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue telmisartan and hydrochlorothiazide, unless it is considered lifesaving for the mother.

Interactions

Drug Interactions Telmisartan Aliskiren: Do not co-administer aliskiren with telmisartan and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with telmisartan and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min). Digoxin : When telmisartan was co-administered 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. Lithium: 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 telmisartan.

Because lithium should not be used with diuretics, the use of lithium with telmisartan and hydrochlorothiazide is not recommended. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) : In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors. Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C max and AUC of ramipril 2.3 and 2.1 fold, respectively, and C max and AUC of ramiprilat 2.4 and 1.5 fold, respectively.

In contrast, C max and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. 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 : Co-administration 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 telmisartan and hydrochlorothiazide tablets. Non-steroidal anti-inflammatory drugs : In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.

Therefore, when telmisartan and hydrochlorothiazide tablets 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.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Telmisartan

and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see Clinical Considerations). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Studies in rats and rabbits with telmisartan showed fetotoxicity only at maternally toxic doses ( see Data ). When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide tablets as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal adverse reactions Telmisartan Use of drugs that act on the RAS in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

In patients taking telmisartan and hydrochlorothiazide tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue telmisartan and hydrochlorothiazide tablets, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to telmisartan and hydrochlorothiazide tablets for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function [see Use in Specific Populations (8.4)]. Hydrochlorothiazide Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults.

Data Animal Data Telmisartan and Hydrochlorothiazide Tablets A developmental toxicity study was performed in rats with telmisartan/hydrochlorothiazide doses of 3.2/1, 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.

Telmisartan 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 of up to 45 mg/kg/day. In rabbits, embryo lethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg on a mg/m 2 basis).

In rats, maternally toxic (reduced body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (approximately 1.9 times the MRHD on a mg/m 2 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. The no-observed-effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are approximately 0.64 and 3.7 times, respectively, on a mg/m 2 basis, the MRHD of telmisartan (80 mg/day).

Hydrochlorothiazide 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 (about 600 and 400 times the MRHD), provided no evidence of harm to the fetus. Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion.

It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should be avoided.

Adverse reactions

Telmisartan and hydrochlorothiazide tablets 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 telmisartan and hydrochlorothiazide tablets, 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 ≥2% of Telmisartan/Hydrochlorothiazide (HCTZ) Patients* Telm/HCTZ (N=414) (%) Placebo (N=74) (%) Telm (N=209) (%) HCTZ (N=121) (%) Body as a whole Fatigue 3 1 3 3 Influenza-like symptoms 2 1 2 3 Central/peripheral nervous system Dizziness 5 1 4 6 Gastrointestinal system Diarrhea 3 0 5 2 Nausea 2 0 1 2 Respiratory system disorder Sinusitis 4 3 3 6 Upper respiratory tract infection 8 7 7 10 * includes all doses of telmisartan (20 to 160 mg), hydrochlorothiazide (6.25 to 25 mg), and combinations thereof 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 telmisartan and hydrochlorothiazide tablets 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 telmisartan 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 telmisartan 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, increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including telmisartan tablets. Clinical Laboratory Findings In controlled trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan and hydrochlorothiazide 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 telmisartan and hydrochlorothiazide tablets in controlled trials. No patient discontinued treatment with telmisartan and hydrochlorothiazide tablets 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 and Hydrochlorothiazide

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Telmisartan

Adverse reactions

Composition

Strengths and forms

Official product information

At a glance

Guidelines