CRESAR-H Tablets (Telmisartan + Hydrochlorothiazide)

Table of Content

Black Box Warning: Fetal Toxicity

  • When pregnancy is detected, discontinue Telmisartan/Hydrochlorothiazide as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Composition

CRESAR H

Each tablet contains:

Telmisartan 40 mg and Hydrochlorothiazide 12.5 mg

CRESAR 80 H

Each tablet contains:

Telmisartan 80 mg and Hydrochlorothiazide 12.5 mg            

Dosage Form

Tablet

Description

CRESAR H is a combination of two drugs with antihypertensive properties: a thiazide diuretic, hydrochlorothiazide, and an angiotensin II receptor blocker (ARB), telmisartan.

Pharmacology

Pharmacodynamics

Telmisartan

Telmisartan is a non-peptide ARB . Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS), with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an angiotensin type 2 (AT2) receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3000-fold) for the AT1 receptor than for the AT2 receptor.

Telmisartan does not inhibit the ACE (kininase II) nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity (PRA) and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

In normal volunteers, a dose of telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.

Plasma concentration of angiotensin II and 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).

The antihypertensive effects of telmisartan have been studied in six placebo-controlled clinical trials including a total of 1773 patients with mild to moderate hypertension (diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once-daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.

The onset of antihypertensive activity occurs within 3 hours, with a maximal reduction by approximately 4 weeks. At doses of 20, 40, and 80 mg, the antihypertensive effect of once-daily administration of telmisartan was maintained for the full 24-hour dose interval.

In 30 hypertensive patients with normal renal function treated for 8 weeks with telmisartan 80 mg or telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate (GFR), filtration fraction, renovascular resistance, or creatinine clearance.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium salt and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in PRA, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.

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 of telmisartan are reached in 0.5-1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the area under the plasma concentration time curve of about 6% with the 40 mg tablet and about 20% after a 160 mg dose. Telmisartan /hydrochlorothiazide can be administered with or without food. The absolute bioavailability of telmisartan is dose-dependent. At 40 mg and 160 mg, the bioavailability was 42% and 58%, respectively. The pharmacokinetics of orally administered telmisartan are nonlinear over the dose range of 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 1.5-2.0 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. Following oral administration of telmisartan/hydrochlorothiazide, 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

Telmisartan is highly bound to plasma proteins (more than 99.5%), mainly albumin and alpha1-acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters, indicating additional tissue binding.

Hydrochlorothiazide

Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 l/kg. Hydrochlorothiazide crosses the placenta, but not the blood-brain barrier and is excreted in breast milk.

Metabolism and Elimination

Telmisartan

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 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 (more than 97%) was eliminated unchanged in the 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 more than 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 kidneys. 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.

Special Populations

Pediatric Populations: Telmisartan pharmacokinetics has not been investigated in patients less than 18 years of age.

Geriatric Populations: The 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 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemodialysis. 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: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic impairment can be expected to have reduced clearance and higher blood levels. In patients with hepatic impairment, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%. Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Indication

Hypertension

CRESAR H / CRESAR 80 H (telmisartan and hydrochlorothiazide) tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. This fixed dose combination is not indicated for initial therapy for the treatment of hypertension.

CRESAR H / CRESAR 80 H may be used alone or in combination with other antihypertensive agents.

Dosage and Administration

Initiate a patient whose blood pressure is not adequately controlled with CRESAR 40 on CRESAR H and CRESAR 80 to CRESAR 80 H 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 CRESAR H / CRESAR 80 H 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 CRESAR H / CRESAR 80 H.

CRESAR H / CRESAR 80 H may be administered with other antihypertensive drugs.

Renal Impairment

Safety and effectiveness of CRESAR H / CRESAR 80 H in patients with severe renal impairment (creatinine clearance ≤30 mL/min) have not been established. In patients with severe renal impairment, CRESAR H / CRESAR 80 H tablets are not recommended.

No dose adjustment is required in patients with mild (creatinine clearance 60 to 90 mL/min) or moderate (creatinine clearance 30 to 60 mL/min) renal impairment.

Hepatic Impairment

Initiate patients with biliary obstructive disorders or hepatic insufficiency under close medical supervision using the 40 mg/12.5 mg combination. CRESAR H/ CRESAR 80 H tablets are not recommended for patients with severe hepatic impairment.

Contraindications 

  • Patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan, hydrochlorothiazide, or any other component of this product.
  • Hypersensitivity to other sulfonamide-derived substances (Since hydrochlorothiazide sulfonamide-derived medicinal product.
  • Patients with anuria
  • Second and third trimesters of pregnancy
  • Cholestasis and biliary obstructive disorders
  • Severe hepatic impairment
  • Severe renal impairment (creatinine clearance <30 ml/min)
  • Refractory hypokalemia, hypercalcemia
  • Do not co-administer aliskiren with CRESAR H/ CRESAR 80 H in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)

Warnings and Precautions

General

Electrolytes Imbalance    

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalemia, hyponatremia and hypochloremic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

Hypokalemia

Although hypokalemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic-induced hypokalemia. The risk of hypokalemia is greater in patients with cirrhosis of liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or Adrenocorticotropic hormone (ACTH).

Hyperkalemia

Conversely, due to the antagonism of the AT1 receptors by the telmisartan component of telmisartan/hydrochlorothiazide, hyperkalemia might occur. Although clinically significant hyperkalemia has not been documented with telmisartan/hydrochlorothiazide, risk factors for the development of hyperkalemia include renal insufficiency and/or heart failure, and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with telmisartan/hydrochlorothiazide.

Hyponatremia and Hypochloremic Alkalosis

There is no evidence that telmisartan/hydrochlorothiazide would reduce or prevent diuretic-induced hyponatremia. Chloride deficit is generally mild and usually does not require treatment.

Hypercalcemia

Thiazides may decrease urinary calcium excretion and cause an 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.

Hypomagnesemia

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

Ethnic Differences

As with all other ARBs, telmisartan is apparently less effective in lowering blood pressure in black patients than in non-blacks, possibly because of higher prevalence of low renin states in the black hypertensive population.

Other

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.

Dual Blockade of the RAS and Changes in Renal Function

Dual blockade of the RAS with ARBs, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and renal impairment. 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 who received the combination of telmisartan and ramipril did not obtain any additional benefit (no additional reduction of risk of cardiovascular death, myocardial infarction, stroke, or hospitalization from heart failure) compared to 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.

In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on telmisartan/hydrochlorothiazide and other agents that affect the RAS (e.g., concomitant use of an ACE inhibitor with an ARB).

Do not co-administer aliskiren with telmisartan/hydrochlorothiazide in patients with diabetes. Avoid concomitant use of aliskiren with telmisartan/hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min/1.73 m2).

Co-administration of telmisartan and ramipril increases the exposure to both ramipril and ramiprilat by a factor of about 2.

Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated RAS, 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/hydrochlorothiazide. Correct volume or salt depletion prior to the administration of telmisartan/hydrochlorothiazide.

Renovascular Hypertension

There is an increased risk of severe 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 RAS.

Intravascular Hypovolemia

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhea or vomiting. Such conditions should be corrected before the administration of telmisartan/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.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics, including hydrochlorothiazide.

Cases of photosensitivity reactions have been reported with thiazide diuretics. If a photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Other Conditions with Stimulation of the RAS

In patients whose vascular tone and renal function depend predominantly on the activity of the RAS (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotemia, oliguria, or rarely acute renal failure.

Primary Aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the RAS. Therefore, the use of telmisartan/hydrochlorothiazide is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Metabolic and Endocrine Effects

Thiazide therapy may impair glucose tolerance, whereas hypoglycemia may occur in diabetic patients under insulin or anti-diabetic 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.

An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in telmisartan/hydrochlorothiazide, minimal or no effects were reported.

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

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.

Drug Interactions

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of thiazide diuretics or ARBs, including telmisartan. Monitor lithium levels in patients receiving telmisartan/hydrochlorothiazide and lithium.

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).

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesaemia favors the onset of digitalis-induced arrhythmia.

Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Monitor digoxin levels in patients taking concomitant telmisartan/hydrochlorothiazide and digoxin.

Medicinal products associated with potassium loss and hypokalemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid and derivatives): If these substances are to be prescribed with the telmisartan/hydrochlorothiazide combination, monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium.

Medicinal products that may increase potassium levels or induce hyperkalemia (e.g. ACE inhibitors, potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, cyclosporine or other medicinal products such as heparin sodium): If these medicinal products are to be prescribed with the telmisartan/hydrochlorothiazide combination, monitoring of potassium plasma levels is advised. Based on the experience with the use of other medicinal products that blunt the RAS, concomitant use of the above medicinal products may lead to increases in serum potassium and is, therefore, not recommended.

Medicinal products affected by serum potassium disturbances: Periodic monitoring of serum potassium and ECG is recommended when telmisartan/hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics) and the following torsades de pointes inducing medicinal products (which include some antiarrhythmics), hypokalemia being a predisposing factor to torsades de pointes.

  • class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide)
  • class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
  • some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
  • others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine IV)

Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustment of the antidiabetic drug may be required when coadministered with hydrochlorothiazide.

Metformin: Metformin should be used with precaution; risk of lactic acidosis induced by a possible functional renal failure linked to hydrochlorothiazide.

Cholestyramine and Colestipol Resins: Absorption of telmisartan/hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.

Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Monitor digoxin levels in patients taking concomitant telmisartan/hydrochlorothiazide and digoxin.

Digitalis Glycosides: Thiazide-induced hypokalemia or hypomagnesaemia favors the onset of digitalis induced arrhythmia.

Other Antihypertensive Agents: Telmisartan may increase the hypotensive effect of other antihypertensive agents.

Clinical trial data has shown that dual blockade of the RAS through the combined use of ACE inhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single RAS acting agent.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 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 ARBs, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. The antihypertensive effect of ARBs may be attenuated by NSAIDs. Therefore, monitor renal function and blood pressure periodically in patients receiving telmisartan/hydrochlorothiazide and NSAIDs.

Administration of NSAIDs including selective COX-2 inhibitors, can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. Therefore, when telmisartan/hydrochlorothiazide tablets and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Also, renal function should be monitored periodically in patients receiving telmisartan/hydrochlorothiazide tablets and NSAID therapy.

Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter. In one study the coadministration of telmisartan and ramipril led to an increase of up to 2.5 fold in the AUC0-24 and Cmax of ramipril and ramiprilat. The clinical relevance of this observation is not known.

Medicinal Products Used in the Treatment for Gout (e.g. Probenecid, Sulfinpyrazone and Allopurinol): Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.

Calcium Salts: Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Beta-blockers and Diazoxide: The hyperglycemic 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.

Amantadine: Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic Agents (e.g. Cyclophosphamide, Methotrexate): Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including telmisartan: Baclofen, amifostine.

Furthermore, orthostatic hypotension may be aggravated by alcohol, barbiturates, narcotics or antidepressants.

Renal Impairment

Changes in renal function including acute renal failure can be caused by drugs that inhibit the RAS and by diuretics. Patients whose renal function may depend in part on the activity of the RAS (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/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/hydrochlorothiazide. Experience with telmisartan/hydrochlorothiazide is modest in the patients with mild to moderate renal impairment, therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. Telmisartan/hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).

Hepatic Impairment

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 tablets should therefore be used with caution in these patients.

Pregnancy

Pregnancy Category D

Use of drugs that act on the RAS 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/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 RAS 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 RAS 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/hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to telmisartan/hydrochlorothiazide for hypotension, oliguria, and hyperkalemia.

When pregnancy is diagnosed, treatment with ARBs should be stopped immediately, and if appropriate, alternative therapy should be started.

Exposure to ARB therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). Should exposure to ARB have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

There is limited experience with hydrochlorothiazides 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 foeto and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

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, decide 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 Combination

If oliguria or hypotension occurs, attention should be directed towards 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 cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

Undesirable Effects

The following are the adverse reactions:

  • Hypotension
  • Renal Impairment
  • Electrolytes and Metabolic Disorders

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Telmisartan/hydrochlorothiazide has been evaluated for safety in more than 1700 patients, including 716 treated for hypertension for longer than 6 months and 420 for more than 1 year. Adverse reactions have been limited to those that have been previously reported with telmisartan and/or hydrochlorothiazide.

Adverse reactions occurring at an incidence of ≥2% in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo, are presented in Table 1.

Table 1: Adverse reactions occurring at an incidence of ≥2% in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo*

Adverse Events

Telm/HCTZ

(N=414)

(%)

Placebo

(N=74)

(%)

Telm

(N = 209)

(%)

HCTZ

(N=121)

(%)

Body as a whole

 

3

 

1

 

3

 

3

Fatigue

Influenza-like symptoms

 

2

 

1

 

2

 

3

Central/peripheral nervous system

 

 

5

 

 

1

 

 

4

 

 

6

Dizziness

Gastrointestinal system

 

 

3

 

 

0

 

 

5

 

 

2

Diarrhea

Nausea

2

0

1

2

Respiratory system disorder

 

 

 

4

 

 

 

3

 

 

 

3

 

 

 

6

Sinusitis

Upper respiratory tract infection

8

7

7

10

*includes all doses of telmisartan (20-160 mg), hydrochlorothiazide (6.25-25 mg) and combinations thereof

Other adverse reactions observed for telmisartan/hydrochlorothiazide were: pain (including back and abdominal), dyspepsia, erythema, vomiting, bronchitis, and pharyngitis.

Adverse reactions occurred at approximately the same rates in men and women, older and younger patients, and black and non-black patients.

Telmisartan

Other adverse experiences that have been reported with telmisartan 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, tachycardia, leg edema, abnormal electrocardiogram (ECG), hypertension, peripheral edema, arrhythmias
  • Central nervous system (CNS): insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia, sleep disorders
  • Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, nonspecific gastrointestinal disorders, dyspepsia, abdominal pain, diarrhea
  • Hepato-biliary: elevations of liver enzymes or serum bilirubin, abnormal hepatic function/ liver disorder
  • Metabolic: gout, hypercholesterolemia, diabetes mellitus, hyperuricemia, blood creatinine increased, blood creatinine phosphokinase (CPK) increased, hypokalemia, hyponatremia
  • Musculoskeletal: arthritis, arthralgia, leg cramps, myalgia, back pain, muscle cramps, pain in limb
  • Psychiatric: anxiety, depression, nervousness
  • Resistance Mechanism: infection, fungal infection, abscess, otitis media
  • Respiratory: asthma, rhinitis, dyspnea, epistaxis, Respiratory distress (including pneumonitis and pulmonary edema), bronchitis, pharyngitis, sinusitis, Influenza-like illness
  • Skin: dermatitis, eczema, pruritus, angioedema (also with fatal outcome), erythema, hyperhidrosis, urticaria, exacerbation or activation of systemic lupus erythematosus, rash
  • Urinary: micturition frequency, cystitis
  • Vascular: cerebrovascular disorder, hypotension, orthostatic hypotension
  • Special Senses: abnormal vision, vision blurred, conjunctivitis, tinnitus, earache.

Hydrochlorothiazide

Other adverse experiences that have been reported with hydrochlorothiazide are listed below:

  • Body as a Whole: weakness
  • Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
  • Hematologic: aplastic anemia, agranulocytosis, leucopenia, 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, anorexia, electrolyte imbalance, hypercholesterolemia, hypovolemia, decreased appetite
  • Musculoskeletal: muscle spasm
  • Nervous System/Psychiatric: restlessness, light-headedness, erectile dysfunction
  • Renal: interstitial nephritis
  • Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, lupus-like syndrome, skin vasculitis
  • Special Senses: transient blurred vision, xanthopsia, acute myopia, acute angle-closure glaucoma, vertigo

Clinical Laboratory Findings

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of telmisartan/hydrochlorothiazide. 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.

  • Blood and Lymphatic System Disorders: anemia, thrombocytopenia, eosinophilia, decreased hemoglobin, aplastic anemia, hemolytic anemia, bone marrow failure, leukopenia, neutropenia,
  • Cardiac Disorders: atrial fibrillation, congestive heart failure, myocardial infarction, tachycardia, bradycardia
  • Ear and Labyrinth Disorders: vertigo
  • General Disorders and Administration Site Conditions: asthenia, edema, pyrexia
  • Hepato-biliary: Abnormal hepatic function / liver disorder, jaundice hepatocellular, jaundice cholestatic
  • Immune System Disorders: anaphylactic reaction, hypersensitivity
  • Infections and Infestations: urinary tract infection including cystitis, sepsis including fatal outcome, stomach discomfort, sialadenitis, pancreatitis
  • Investigations: increased CPK, triglycerides increased
  • Metabolism and Nutrition Disorders: hypoglycemia (in diabetic patients), hyperkalemia, Diabetes mellitus inadequate control, anorexia, appetite decreased, electrolyte imbalance
  • Musculoskeletal and Connective Tissue Disorders: tendon pain (including tendonitis, tenosynovitis), rhabdomyolysis, arthrosis, weakness
  • Nervous System Disorders: syncope, somnolence, restlessness, light-headedness
  • Renal and Urinary Disorders: renal failure, renal impairment including acute renal failure, nephritis interstitial, renal dysfunction, glycosuria
  • Reproductive System and Breast Disorders: erectile dysfunction
  • Respiratory, Thoracic and Mediastinal Disorders: upper respiratory tract disorders, cough, interstitial lung disease
  • Skin and Subcutaneous Tissue Disorders: drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), angioedema (with fatal outcome), eczema, lupus-like syndrome, photosensitivity reactions, skin vasculitis, toxic epidermal necrolysis
  • Vascular Disorder: orthostatic hypotension, vasculitis necrotizing

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024. 

By reporting side-effects, you can help provide more information on the safety of this product.

Overdosage

Telmisartan

Limited data are available related to over-dosage in humans. The most likely manifestations of over-dosage would be hypotension 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.

Incompatibility

Not applicable

Shelf-Life

Two years

Storage & Handling Instruction

Store in a cool dry place

Packaging Information

CRESAR H: Aluminium Strip of 10 tablets

CRESAR 80 H: Aluminium Strip of 10 tablets

Last Updated: April 2017

Last Reviewed: April 2017