Telmisartan, hydrochlorothiazide.
Each film-coated tablet contains: Telmisartan 40.0 mg, Hydrochlorothiazide 12.5 mg.
Pharmacology: Pharmacodynamics: Telmisartan is an orally effective and specific angiotensin II receptor subtype 1 (AT1) antagonist. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting. 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.
Hydrochlorothiazide is a thiazide diuretic. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonates 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.
Pharmacokinetics: 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 40mg and 160mg 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 40mg tablet and about 19% after a 160mg dose.
Hydrochlorothiazide: Following oral administration 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 1-acid glycoprotein. The apparent volume of distribution for telmisartan is approximately 500 liters 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 metabolized 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.
Hydrochlorothiazide is not metabolized in man.
Elimination: Telmisartan: Following either intravenous or oral administration of C-labelled telmisartan most if 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 > 1500ml/min. Telmisartan 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 250-300ml/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours.
Treatment of essential hypertension.
Telmisartan and Hydrochlorothiazide fixed dose combination is indicated in adults whose blood pressure is not adequately controlled on telmisartan alone.
Recommended dose: Telmisartan and Hydrochlorothiazide tablet should be taken in patients whose blood pressure is not adequately controlled by telmisartan alone. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
Telmisartan and Hydrochlorothiazide 40mg/12.5mg tablets may be administered once daily in patients whose blood pressure is not adequately controlled by Telmisartan 40mg.
Mode of Administration: Telmisartan and Hydrochlorothiazide tablets are for once-daily oral administration and should be taken with liquid, with or without food.
Symptoms: The most prominent manifestations of Telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, vomiting, increase in serum creatinine, and acute renal failure have also been reported. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and/or accentuate arrhythmia associated with the concomitant use of digitalis glycoside or certain anti-arrhythmic medicinal products.
Treatment: Telmisartan is not removed by haemodialysis. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatine should be monitored frequently. If hypotension occurs, the patient should place in a supine position, with salt and volume replacements given quickly.
Hypersensitivity to any of the active substances or to any of the excipients in formulation.
Hypersensitivity to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).
Second and third trimester of pregnancy.
Cholestasis and biliary obstructive disorders.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance <30ml/min).
Refractory hypokalaemia, hypercalcaemia.
The concomitant use of telmisartan with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.74m2).
Hepatic Impairment: Telmisartan and Hydrochlorothiazide should not be given to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.
Renovascular hypertension: There is an increased risk of sever hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
The use of telmisartan in combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m2).
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance whereas hypoglycaemic may occur in diabetic patients under insulin or antidiabetic therapy and telmisartan treatment.
Therefore, in these patients, blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required, when indicated. Latent diabetes mellitus may become manifest during thiazide therapy.
Pregnancy: There is no adequate data from the use of Telmisartan and Hydrochlorothiazide tablets in pregnant women. Studies in animals have shown reproductive toxicity. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE Inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and if appropriate alternative therapy should be stared.
Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women in rare situations where no other treatment could be used.
Breast-feeding: Because no information is available regarding the use of Telmisartan and hydrochlorothiazide tablet during breast-feeding. Telmisartan and hydrochlorothiazide tablet is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Telmisartan and Hydrochlorothiazide tablet during breastfeeding is not recommended. If Telmisartan and Hydrochlorothiazide tablet is used during breastfeeding, doses should be kept as low as possible.
The most commonly reported adverse reactions is dizziness. Serious angioedema may occur rarely.
(>1/10,000 to <1/1,000): Hepatic function abnormal/liver disorder.
Most cases of hepatic function abnormal/liver disorder from post-marketing experience with telmisartan occurred in Japanese patients. Japanese patients are more likely to experience these adverse reactions.
Sepsis: In the profess trial, an increased incidence of sepsis was observed with telmisartan compared with placebo. The event may be a chance finding or related to a mechanism currently not known.
Interstitial lung disease: Cases of interstitial lung disease have been reported from post-marketing experience in temporal association with the intake of telmisartan. However, a causal relationship has not been established.
Dual blockade of the renin-aldosterone system (RAAS): The combination of telmisartan with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m2) and is not recommended in other patients.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Rare cases have also been reported with angiotensin II receptor antagonists. Co-administration of lithium and Telmisartan and Hydrochlorothiazide tablets is not recommended. If this combination proves essential, careful monitoring of serum lithium level is recommended during concomitant use.
Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia favours the onset of digitalis-induced arrhythmia.
Non-steroidal anti-inflammatory medicinal products: NSAIDs (i.e., acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics and the anti-hypertensive effects of angiotensin II receptor antagonists.
Beta-blockers and diazoxide: The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g., atropine, biperiden) may increase the bioavailability of thiazide- type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.
Store at temperatures not exceeding 30°C. Protect from light and moisture.
Shelf-Life: 24 months.
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