Data from FDA - Curated by EPG Health - Last updated 20 December 2016

Indication(s)

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).

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Advisory information

contraindications

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).

Special warnings and precautions

PRECAUTIONS Serum Electrolytes Telmisartan and Hydrochlorothiazide In controlled trials using the telmisartan/hydrochlorothiazide combination treatment, no patient administered 40/12.5 mg, 80/12.5 mg or 80/25 mg had a decrease in potassium ?1.4 mEq/L, and no patient experienced hyperkalemia.

No discontinuations due to hypokalemia occurred during treatment with the telmisartan/hydrochlorothiazide combination.

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 on the kidney.

Hydrochlorothiazide Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia.

Serum and urine electrolyte determinations are particularly important when the patient experiences excessive vomiting or receives parenteral fluids.

Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

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 cause cardiac arrhythmia and may also sensitize or exaggerate 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 specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement 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.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required.

Hyperglycemia may occur with thiazide diuretics.

Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the post sympathectomy patient.

If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion.

Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.

Marked hypercalcemia may be evidence of hidden hyperparathyroidism.

Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Hepatic Function Telmisartan As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance.

Telmisartan and hydrochlorothiazide tablets should therefore be used with caution in these patients.

Impaired Renal Function Telmisartan 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 (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

Similar results may be anticipated in patients treated with telmisartan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed.

There has been no long-term use of telmisartan in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide Thiazides should be used with caution in severe renal disease.

In patients with renal disease, thiazides may precipitate azotemia.

Cumulative effects of the drug may develop in patients with impaired renal function.

Dual Blockade of the Renin-angiotensin-aldosterone

System Telmisartan As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported.

Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.

The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months.

Patients receiving the combination of telmisartan and ramipril did not obtain any additional benefit on the composite endpoint of cardiovascular death, myocardial infarction, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone.

Co-administration of telmisartan and ramipril increases the exposure to both ramipril and ramiprilat by a factor of about 2 (see PRECAUTIONS, Drug Interactions).

Concomitant use of telmisartan and ramipril is not recommended.

Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to telmisartan and hydrochlorothiazide during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving telmisartan and hydrochlorothiazide tablets should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician.

The patients should be told that if syncope occurs, telmisartan and hydrochlorothiazide tablets should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Potassium Supplements: A patient receiving telmisartan and hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes that contain potassium without consulting the prescribing physician.

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 Cmax and AUC of ramipril 2.3 and 2.1 fold, respectively, and Cmax and AUC of ramiprilat 2.4 and 1.5 fold, respectively.

In contrast, Cmax 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility Telmisartan and Hydrochlorothiazide No carcinogenicity, mutagenicity, or fertility studies have been conducted with the combination of telmisartan and hydrochlorothiazide.

Telmisartan There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years.

The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/ m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan.

These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level.

These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/ m2 basis, the MRHD of telmisartan.

This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

Hydrochlorothiazide Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology

Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day).

The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in_vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in_vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.

Positive test results were obtained in the in_vitro CHO Sister Chromatid Exchange (clastogenicity) assay, in the Mouse Lymphoma Cell (mutagenicity) assay, and in the Aspergillus nidulans non-disjunction assay.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.

Nursing Mothers 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.

Pediatric Use Neonates with a history of in utero exposure to telmisartan and hydrochlorothiazide:If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use 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 can not be ruled out.

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.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION The usual starting dose of telmisartan is 40 mg once a day; blood pressure response is dose related over the range of 20 to 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.

Telmisartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

Telmisartan and hydrochlorothiazide tablets may be administered with or without food.

Replacement Therapy The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect Telmisartan and hydrochlorothiazide tablets are 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 telmisartan and hydrochlorothiazide tablets, 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 telmisartan 80 mg/hydrochlorothiazide 12.5 mg or telmisartan 80 mg/hydrochlorothiazide 25 mg tablets once daily.

The clinical response to telmisartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 2 to 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 telmisartan 80 mg/hydrochlorothiazide 12.5 mg tablets once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response.

Patients with Renal Impairment The usual regimens of therapy with telmisartan and hydrochlorothiazide tablets 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 telmisartan and hydrochlorothiazide tablets are not recommended.

Patients with Hepatic Impairment Telmisartan and hydrochlorothiazide tablets are 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).

Pregnancy and lactation
Nursing Mothers 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.

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 Cmax and AUC of ramipril 2.3 and 2.1 fold, respectively, and

Cmax and AUC of ramiprilat 2.4 and 1.5 fold, respectively.

In contrast, Cmax 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.

More information

Category Value
Authorisation number ANDA203010
Agency product number U5SYW473RQ
Orphan designation No
Product NDC 46708-209,46708-210,46708-211
Date Last Revised 14-03-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 477130
Marketing authorisation holder Alembic Pharmaceuticals Limited
Warnings WARNING: FETAL TOXICITY When pregnancy is detected, discontinue telmisartan and hydrochlorothiazide as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see WARNINGS, Fetal Toxicity).