Telmisartan and Hydrochlorothiazide
Generic: TELMISARTAN AND HYDROCHLOROTHIAZIDE
Basic Information
Manufacturer
Alembic Pharmaceuticals Limited
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
5b476740-e3f0-4f68-b07c-cd9eb2fa27ca
Indications & Usage
INDICATIONS & USAGE 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 ).
This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION ).
Warnings
WARNINGS 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.
Fetal testing may be appropriate, based on the week of pregnancy.
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 for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS , Pediatric Use ).
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/m 2 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/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, 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/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their 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.
Hypotension in Volume-Depleted Patients 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 telmisartan and hydrochlorothiazide tablets.
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.
Hydrochlorothiazide Hepatic Impairment : Thiazide diuretics 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.
Hypersensitivity Reaction : 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.
Systemic Lupus Erythematosus : Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium Interaction : Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Hydrochlorothiazide , Lithium ).
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 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.
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.
Fetal testing may be appropriate, based on the week of pregnancy.
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 for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS , Pediatric Use ).
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/m 2 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/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, 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/m 2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
Studies in which hydrochlorothiazide was administered to pregnant mice and rats during their 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.
Hypotension in Volume-Depleted Patients 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 telmisartan and hydrochlorothiazide tablets.
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.
Hydrochlorothiazide Hepatic Impairment : Thiazide diuretics 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.
Hypersensitivity Reaction : 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.
Systemic Lupus Erythematosus : Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium Interaction : Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Hydrochlorothiazide , Lithium ).
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 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.
Adverse Reactions
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 .
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 .