Telarb Plus

Telmisartan: Chemical Name: as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid.
Molecular weight: 514.63.
Molecular formula: C₃₃H₃₀N₄O₂.
Hydrochlorothiazide: Chemical Name: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7sulfonamide 1,1-dioxide.
Molecular weight: 297.74.
Molecular formula: C₇H₈ClN₃O₄S₂.
Telarb Plus 40 mg/12.5 mg: Biconvex, two layered oblong shaped uncoated tablet. White to off white, plain on one side and red layered debossed "058" on other side.
Each uncoated bilayer tablet contains: Telmisartan BP 40 mg, Hydrochlorothiazide 12.5 mg.
Telarb Plus 80 mg/12.5 mg: Biconvex, two layered oblong shaped, uncoated tablets. White to off white, plain on one side and red layered debossed "059" on the other side.
Each uncoated bilayer tablet contains: Telmisartan BP 80 mg, Hydrochlorothiazide 12.5 mg.
Telarb Plus 80 mg/25 mg: Biconvex, two layered oblong shaped, uncoated tablets. White to off white, plain on one side and yellow layered debossed "060" on the other side.
Each uncoated bilayer tablet contains: Telmisartan BP 80 mg, Hydrochlorothiazide 25 mg.

Pharmacological category: Angiotensin II Receptor Blocker (ARB) + Diuretic.
Pharmacology: Mechanism of action: TELARB PLUS 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. TELARB PLUS once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.
Telmisartan: 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: 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 HCTZ, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Pharmacodynamics: Telmisartan: In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by approximately 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).
Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics: Absorption: Telmisartan: Following oral administration, peak concentrations (Cmax) of telmisartan, are reached in 0.5-1.5 hour after dosing. 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 20% after a 160 mg dose. The absolute bioavailability of telmisartan is dose dependent. At 40 and 160 mg the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range 20-160 mg, with greater than proportional increases of plasma concentrations (Cmax and AUC) with increasing doses. Telmisartan shows bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours. Trough plasma concentrations of telmisartan with once daily dosing are about 10-25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.
Hydrochlorothiazide: When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Distribution: Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1-glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution of telmisartan is approximately 500 liters, indicating additional tissue binding.
Metabolism and Elimination: Telmisartan: Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively). Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Toxicology: Preclinical safety data: In preclinical safety studies performed with co-administration of telmisartan and hydrochlorothiazide in normotensive rats and dogs, doses producing exposure comparable to that in the clinical therapeutic range caused no additional findings not already observed with administration of either substance alone. The toxicological findings observed appear to have no relevance to human therapeutic use.
Toxicological findings also well known from preclinical studies with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists were: a reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit), changes of renal haemodynamics (increased blood urea nitrogen and creatinine), increased plasma renin activity, hypertrophy/hyperplasia of the juxtaglomerular cells and gastric mucosal injury. Gastric lesions could be prevented/ameliorated by oral saline supplementation and group housing of animals. In dogs renal tubular dilation and atrophy were observed. These findings are considered to be due to the pharmacological activity of telmisartan.
No clear evidence of a teratogenic effect was observed, however at toxic dose levels of telmisartan an effect on the postnatal development of the offsprings such as lower body weight and delayed eye opening was observed.
Telmisartan showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice. Studies with HCTZ have shown equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the extensive human experience with HCTZ has failed to show an association between its use and an increase in neoplasms.

Telmisartan and Hydrochlorothiazide is indicated for the treatment of hypertension. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
Telmisartan and hydrochlorothiazide may be used alone or in combination with other antihypertensive agents.

Dosing information: Initiate a patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg on Telmisartan and Hydrochlorothiazide, 80 mg/12.5 mg once daily. Dose can be titrated up to 160 mg/25 mg after 2 to 4 weeks, if necessary.
Initiate a patient whose blood pressure is not adequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen on telmisartan and hydrochlorothiazide tablets 80 mg/12.5 mg once daily. Dose can be titrated up to 160 mg/25 mg after 2 to 4 weeks, if necessary.
Patients titrated to the individual components (telmisartan and hydrochlorothiazide) may instead receive the corresponding dose of telmisartan and hydrochlorothiazide tablets.
Telmisartan and hydrochlorothiazide tablets may be administered with other antihypertensive drugs.
Dose Adjustment for Hepatic Impairment: Initiate patients with biliary obstructive disorders or hepatic insufficiency under close medical supervision using the 40 mg/12.5 mg combination. Telmisartan and hydrochlorothiazide tablets are not recommended for patients with severe hepatic impairment.
Important Administration Instructions: Telmisartan and hydrochlorothiazide tablets should not be removed from blisters until immediately before administration.

Telmisartan: 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. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.
Hydrochlorothiazide: The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Hypersensitivity to any component of this product; In patients with anuria; For co-administration with aliskiren in patients with diabetes.

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with telmisartan and hydrochlorothiazide. Correct volume or salt depletion prior to administration of telmisartan and hydrochlorothiazide.
Impaired Renal Function: Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on telmisartan and hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on telmisartan and hydrochlorothiazide.
Electrolytes and Metabolic Disorders: Drugs, including telmisartan, that inhibit the renin-angiotensin system can cause hyperkalemia, particularly in patients with renal insufficiency, diabetes, or combination use with other angiotensin receptor blockers or ACE inhibitors and the concomitant use of other drugs that raise serum potassium levels.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Because telmisartan decreases uric acid, telmisartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Hydrochlorothiazide: 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.
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 acute 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.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Postsympathectomy Patients: The antihypertensive effects of hydrochlorothiazide may be enhanced in the postsympathectomy patient.
Non-melanoma skin cancer: An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking Hydrochlorothiazide 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 hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC.
Effects on ability to drive and use machines: No effects have been observed.

Pregnancy: 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.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the rennin-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. Closely observe infants with histories of in utero exposure to Micardis HCT for hypotension, oliguria, and hyperkalemia.
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.

Hypotension; Renal Impairment; Electrolytes and Metabolic Disorders; Other adverse reactions observed for telmisartan/hydrochlorothiazide were: pain (including back and abdominal), dyspepsia, erythema, vomiting, bronchitis and pharyngitis.
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.
Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia.
Telmisartan: Other adverse experiences that have been reported with telmisartan, without regard to causality, are listed as follows: 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, paresthesia, involuntary muscle contractions, hypoaesthesia.
Gastrointestinal: flatulence, constipation, gastritis, dry mouth, hemorrhoids, gastroesophageal reflux, toothache.
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.
Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.
Hydrochlorothiazide: Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed as follows: 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.

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with telmisartan and hydrochlorothiazide. Correct volume or salt depletion prior to administration of telmisartan and hydrochlorothiazide.
Impaired Renal Function: Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on telmisartan and hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on telmisartan and hydrochlorothiazide.
Electrolytes and Metabolic Disorders: Drugs, including telmisartan, that inhibit the renin-angiotensin system can cause hyperkalemia, particularly in patients with renal insufficiency, diabetes, or combination use with other angiotensin receptor blockers or ACE inhibitors and the concomitant use of other drugs that raise serum potassium levels.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Because telmisartan decreases uric acid, telmisartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Hydrochlorothiazide: 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.
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 acute 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.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Postsympathectomy Patients: The antihypertensive effects of hydrochlorothiazide may be enhanced in the postsympathectomy patient.

Store at temperature 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.

Rx