Telxibloc

White to off white coloured, oblong shaped, biconvex, break line on one side, plain on other side, uncoated tablet.
Each tablet contains: Telmisartan BP 40 mg, Hydrochlorothiazide 12.5 mg.

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics.
Telmisartan/Hydrochlorothiazide is a combination of an Angiotensin II Receptor Antagonist, Telmisartan, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. Telmisartan/Hydrochlorothiazide once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Pharmacology: Pharmacodynamics: Mechanism of action: Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT₁) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT₁ receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT₁ receptor. Telmisartan selectively binds the AT₁ receptor. The binding is long-lasting. Telmisartan does not show affinity for other receptors, including AT₂ and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by Telmisartan. Plasma aldosterone levels are decreased by Telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore, it is not expected to potentiate bradykinin-mediated adverse effects.
An 80 mg dose of Telmisartan administered to healthy volunteers almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides have an effect on the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Presumably through blockade of the renin-angiotensin-aldosterone system, co-administration of Telmisartan tends to reverse the potassium loss associated with these diuretics. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Pharmacokinetics: Concomitant administration of Telmisartan and hydrochlorothiazide does not appear to affect the pharmacokinetics of either substance in healthy subjects.
Absorption: Telmisartan: Following oral administration, peak concentrations of Telmisartan are reached in 0.5-1.5 h after dosing. The absolute bioavailability of Telmisartan at 40 mg and 160 mg was 42% and 58%, respectively. Food slightly reduces the bioavailability of Telmisartan with a reduction in the area under the plasma concentration time curve (AUC) of about 6% with the 40 mg tablet and about 19% after a 160 mg dose. By 3 hours after administration, plasma concentrations are similar whether Telmisartan is taken fasting or with food. The small reduction in AUC is not expected to cause a reduction in the therapeutic efficacy. Telmisartan does not accumulate significantly in plasma on repeated administration.
Hydrochlorothiazide: Following oral administration of the fixed dose combination, peak concentrations of Hydrochlorothiazide are reached in approximately 1.0-3.0 hours after dosing. Based on cumulative renal excretion of Hydrochlorothiazide, the absolute bioavailability was about 60%.
Distribution: Telmisartan is highly bound to plasma proteins (>99.5%) mainly albumin and alpha l-acid glycoprotein. The apparent volume of distribution for Telmisartan is approximately 500 litres indicating additional tissue binding. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.
Biotransformation: Telmisartan is metabolised by conjugation to form a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite that has been identified in humans. After a single dose of ¹⁴C-labelled Telmisartan the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of Telmisartan.
Hydrochlorothiazide is not metabolised in man.
Elimination: Telmisartan: Following either intravenous or oral administration of ¹⁴C-labelled Telmisartan, most of the administered dose (>97%) was eliminated in faeces via biliary excretion. Only minute amounts were found in urine. Total plasma clearance of Telmisartan after oral administration is >1500 mL/min. Terminal elimination half-life was >20 hours.
Hydrochlorothiazide is excreted almost entirely as unchanged substance in urine. About 60% of the oral dose is eliminated within 48 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours.
Linearity/Non-linearity: Telmisartan: The pharmacokinetics of orally administered Telmisartan are non-linear over doses from 20-160 mg with greater than proportional increases of plasma concentrations (C_max and AUC) with increasing doses.
Hydrochlorothiazide exhibits linear pharmacokinetics.
Elderly: Pharmacokinetics of Telmisartan do not differ between the elderly and those younger than 65 years.
Gender: Plasma concentrations of Telmisartan are generally 2-3 times higher in females than in males. In clinical trials however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary. There was a trend towards higher plasma concentrations of hydrochlorothiazide in female than in male subjects. This is not considered to be of clinical relevance.
Renal impairment: Renal excretion does not contribute to the clearance of Telmisartan. Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance of 30-60 mL/min, mean about 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with impaired renal function, the rate of hydrochlorothiazide elimination is reduced. In a typical study in patients with a mean creatinine clearance of 90 mL/min, the elimination half-life of hydrochlorothiazide was increased. In functionally anephric patients, the elimination half-life is about 34 hours.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.

Telmisartan/Hydrochlorothiazide is indicated for the treatment of hypertension. It is also indicated in adults whose blood pressure is not adequately controlled on Telmisartan alone.

The usual initial dosage is one tablet of Telmisartan/Hydrochlorothiazide (Telxibloc) daily. A patient whose blood pressure is not adequately controlled with Telmisartan monotherapy 40 mg may be switched to Telmisartan/Hydrochlorothiazide (Telxibloc). The dose may be increased, if necessary, to two tablets of Telmisartan/Hydrochlorothiazide (Telxibloc) daily. Telmisartan/Hydrochlorothiazide (Telxibloc) may be administered with other antihypertensive agents. It may be administered with or without food. The combination may be substituted for the titrated components.
Patients with Hepatic Impairment: Telmisartan/Hydrochlorothiazide (Telxibloc) is not recommended for patients with severe hepatic impairment. Patients with biliary obstructive disorders or hepatic impairment should have treatment started under close medical supervision.

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. The most likely manifestations of overdosage with hydrochlorothiazide would be electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

Hypersensitivity to any component of this product, anuria and hypersensitivity to other sulfonamide-derived drugs.

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/Hydrochlorothiazide (Telxibloc) tablets. Treatment should be started under close medical supervision. 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.
Fetal/Neonatal Morbidity and Mortality: 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, 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 Telmisartan/Hydrochlorothiazide 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, Telmisartan/Hydrochlorothiazide 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, embryo lethality 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.

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 to 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 an 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/Hydrochlorothiazide (Telxibloc) 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. Concomitant use of Telmisartan and ramipril is not recommended.
Information for Patients: Symptomatic Hypotension: A patient receiving Telmisartan/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/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/Hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes that contain potassium without consulting the prescribing physician.
Safety information on risk of Non-Melanoma Skin Cancer with prolonged use of Hydrochlorothiazide: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry.
Photosensitizing actions of HCTZ could act as a possible mechanism of NMSC.
Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.
Use in Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Pregnancy: 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, Telmisartan/Hydrochlorothiazide tablets should be discontinued as soon as possible.
Lactation: 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.

The combination of Telmisartan and hydrochlorothiazide is generally well tolerated. The most frequent clinical adverse effects in patients treated with this combination are fatigue, dizziness, nausea, back pain, dyspepsia, vomiting, hypokalemia, bronchitis, rash and postural hypotension.

Telmisartan: Digoxin: When Telmisartan was co-administered with Digoxin, medial increases in Digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed.
Monitoring of digoxin levels is recommended when initiating, adjusting, and discontinuing Telmisartan to avoid possible over-or under-digitalization.
Warfarin: Telmisartan administered for 10 days with warfarin slightly decreased the mean warfarin trough plasma concentration without 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 or are 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 (eg, Norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Non-Depolarizing (eg, 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.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In some patients, the administration of a NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Hydrochlorothiazide and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists / Diuretics

C09DA07 - telmisartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.

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