CRESAR AM Tablets (Telmisartan + Amlodipine)

Table of Content

 

 Black Box Warning

 Fetal Toxicity

 

  • When pregnancy is detected, discontinue CRESAR AM/ CRESAR 80 AM as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

 Composition

CRESAR AM

Each uncoated tablet contains telmisartan 40 mg and amlodipine besilate equivalent to amlodipine 5 mg

CRESAR 80 AM

Each uncoated tablet contains telmisartan 80 mg and amlodipine besilate equivalent to amlodipine 5 mg

Dosage Form

Tablet

Description

CRESAR AM/ CRESAR 80 AM is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besilate, and an angiotensin II receptor blocker (ARB), telmisartan.

Pharmacology

Pharmacodynamics

Fixed dose combination of telmisartan and amlodipine has shown to be effective in lowering blood pressure (BP). Both telmisartan and amlodipine lower BP by reducing peripheral resistance but through complementary mechanisms.

Telmisartan

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 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 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (> 3,000 fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the RAS with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not 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 BP.

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 .

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, filtration fraction, renovascular resistance, or creatinine clearance.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in BP.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing BPs. These decreases in BP are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial BP and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or BPs in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in BP with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in BPs (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta-blockers to humans. Similar findings, however, have been observed in normal or well-compensated patients having heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular (AV) conduction in intact animals or humans. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Pharmacokinetics

The pharmacokinetics of amlodipine and telmisartan when combined are similar to the pharmacokinetics of amlodipine and telmisartan when administered separately.

After administering fixed dose combination of telmisartan and amlodipine with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and Cmax for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and Cmax were not altered.

Absorption

Telmisartan

Following oral administration, peak concentrations (Cmax) 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 (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% to 25% of peak plasma concentrations. Telmisartan has an accumulation index in plasma of 1.5 to 2.0 upon repeated once daily dosing.

Amlodipine

Peak plasma concentrations of amlodipine are reached 6 to 12 hours after administration of amlodipine alone. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Distribution

Telmisartan

Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and (alpha)1-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.

Amlodipine

The apparent volume of distribution of amlodipine is 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Metabolism and Excretion

Telmisartan

Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (> 97%) was eliminated unchanged in faeces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).

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.

Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.

Amlodipine

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Special Populations

Renal Impairment

No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Hepatic Impairment

In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%. Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine.

Gender

Plasma concentrations of telmisartan are generally 2-3 times higher in females than in males. In clinical trials, however, no significant increases in BP response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.

Geriatric Patients

The pharmacokinetics of telmisartan does not differ between the elderly and those younger than 65 years. Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. Therefore, start with a low initial dose of amlodipine.

Indication

CRESAR AM/ CRESAR 80 AM is indicated for the treatment of hypertension, alone or with other antihypertensive agents to lower BP. Lowering BP reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (MIs). These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including ARBs and dihydropyridine calcium channel blockers.

CRESAR AM/ CRESAR 80 AM may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their BP goals.

Dosage and Administration

Telmisartan is an effective treatment of hypertension in once daily doses of 20 to 80 mg while amlodipine is effective in doses of 2.5 to 10 mg.

Dosage must be individualized and may be increased after at least 2 weeks. Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks. The recommended dose is one tablet of CRESAR AM once daily. If necessary, the dose may be increased to two tablets of CRESAR AM once daily or one tablet of CRESAR 80 AM daily after at least 2 weeks. The maximum recommended dose of CRESAR AM tablets is two tablets once daily or one tablet of CRESAR 80 AM daily.

CRESAR AM/ CRESAR 80 AM may be taken with or without food.

Add-on Therapy for Patients with Hypertension Not Adequately Controlled on Antihypertensive Monotherapy

CRESAR AM/ CRESAR 80 AM may be used to provide additional BP lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with telmisartan (or another ARB) alone.

Patients treated with 10 mg amlodipine who experience any dose-limiting adverse reactions such as edema, may be switched to CRESAR AM tablets once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response.

Initial Therapy

A patient may be initiated on CRESAR AM if it is unlikely that control of BP would be achieved with a single agent. The usual starting dose of CRESAR AM is 40/5 mg once daily. Patients requiring larger BP reductions may be started on two tablets of CRESAR AM once daily or one tablet of CRESAR 80 AM once daily.

Initial therapy with CRESAR AM/ CRESAR 80 AM is not recommended in patients ≥75 years old or with hepatic impairment.

Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with CRESAR AM/ CRESAR 80 AM tablets.

Replacement Therapy

Patients receiving amlodipine and telmisartan from separate tablets may instead receive CRESAR/ CRESAR 80 AM tablets containing the same component doses once daily. When substituting for individual components, increase the dose of CRESAR AM if BP control has not been satisfactory.

Specific Populations

Renal Impairment: No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Limited experience is available in patients with severe renal impairment or hemodialysis. Caution is advised when using telmisartan/amlodipine in such patients as amlodipine and telmisartan are not dialysable.

Hepatic Impairment: In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients with hepatic impairment. Telmisartan/amlodipine is contraindicated in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment telmisartan/amlodipine should be administered with caution. For telmisartan the posology should not exceed 40 mg once daily.

Pediatric Population: The safety and efficacy of telmisartan/amlodipine in children aged below 18 years have not been established. No data are available.

Geriatric Population (Patients 75 Years of Age and Older): In most patients, initiate amlodipine therapy at 2.5 mg. Titrate slowly in patients 75 years of age and older.

Contraindications 

  • Patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or amlodipine or any other component of this product 
  • Second and third trimesters of pregnancy
  • Biliary obstructive disorders and severe hepatic impairment
  • Shock (including cardiogenic shock)
  • Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis)
  • Hemodynamically unstable heart failure after acute MI
  • Do not co-administer with aliskiren in patients with diabetes

Warnings and Precautions

General

Hypotension

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 initiation of therapy with telmisartan+amlodipine combination. This condition should be corrected prior to administration of CRESAR AM/ CRESAR 80 AM, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, place the patient in the supine position and, if necessary, give 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 BP has stabilized.

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action of amlodipine, acute hypotension is unlikely.

Hyperkalemia

Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.

Hyperkalemia may be fatal in the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the RAS, the benefit risk ratio should be evaluated.

The main risk factors for hyperkalemia to be considered are:

Diabetes mellitus, renal impairment, age (>70 years), combination with one or more other medicinal products that affect the RAS and/or potassium supplements. Medicinal products or therapeutic classes of medicinal products that may provoke hyperkalemia are salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, including selective COX-2 inhibitors, heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.

Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extensive trauma). Serum potassium should be monitored closely in these patients.

Risk of MI or Increased Angina

Worsening angina and acute MI can develop after starting or increasing the dose of telmisartan+amlodipine combination, particularly in patients with severe obstructive coronary artery disease.

Dual Blockade of the RAS

Dual blockade of the RAS with ARBs, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

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 compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone.

In most patients, no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor BP, renal function and electrolytes in patients on CRESAR AM/ CRESAR 80 AM and other agents that affect the RAS.

Do not co-administer aliskiren with CRESAR AM/ CRESAR 80 in patients with diabetes. Avoid concomitant use of aliskiren with CRESAR AM/ CRESAR 80 in patients with renal impairment (GFR <60 mL/min /1.73 m2).

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, hence use of CRESAR AM/ CRESAR 80 AM 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.

Diabetic Patients Treated with Insulin or Antidiabetics

In these patients hypoglycemia may occur under telmisartan treatment. Therefore, in these patients an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required when indicated.

Race

The magnitude of BP lowering in black patients approached that observed in non-black patients but the number of black patients was limited (237 of 1461 patients).

Heart Failure

Closely monitor patients with heart failure.

Amlodipine (5 to 10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute MI, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8 to 12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF. In the PRAISE-2 study, 1654 patients with NYHA class III (80%) or IV (20%) heart failure without evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%) were randomized 1:1 to receive placebo or amlodipine and followed for a mean of 33 months. While there was no statistically significant difference between amlodipine and placebo in the primary endpoint of all- cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine), there were more reports of pulmonary edema in the patients on amlodipine.

Other

As with any antihypertensive medicinal product, excessive reduction of BP in patients with ischemic cardiomyopathy or ischemic cardiovascular disease could result in a MI or stroke.

Drug Interactions

Fixed Dose Combination of Telmisartan and Amlodipine Tablets

No interactions between the two components of this fixed dose combinations have been observed in clinical studies.

Interactions common to the combination

No drug interaction studies have been performed.

The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered.

Other antihypertensive medicinal products

The BP lowering effect of telmisartan+amlodipine can be increased by concomitant use of other antihypertensive medicinal products.

Medicinal products with BP lowering potential

Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including this medicinal product, e.g. baclofen, amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated by alcohol.

Corticosteroids (systemic route): Reduction of the antihypertensive effect.

No drug interaction studies have been conducted with telmisartan/amlodipine combination and other drugs, although studies have been conducted with the individual amlodipine and telmisartan components of CRESAR AM/ CRESAR 80 AM tablets, as described below:

Drug Interactions with Amlodipine

Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ARBs including telmisartan. Therefore, monitor serum lithium levels during concomitant use.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (NSAIDs COX-2 Inhibitors): In patients who are elderly, volume-depleted (including diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ARBs, telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically receiving telmisartan and NSAID therapy. The antihypertensive effect of ARBs, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Co-administration of telmisartan and ramipril is not recommended.

Other drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Drug Interactions with Amlodipine

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, NSAIDs, antibiotics, and oral hypoglycemic drugs.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Immunosuppressants: Amlodipine may increase the systemic exposure of ciclosporin or tacrolimus when co-administered. Frequent monitoring of trough blood levels of ciclosporin and tacrolimus and dose adjustment when appropriate is recommended.

The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, magnesium and aluminum hydroxide antacid, sildenafil.

Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, warfarin.

CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A4 inhibitors.

CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, St. John’s Wort) on amlodipine. Patients should be monitored for adequate clinical effect when amlodipine is co-administered with CYP3A4 inducers.

Other drugs: The following have no clinically relevant effects on the pharmacokinetics of amlodipine: cimetidine, grapefruit juice, magnesium and aluminum hydroxide antacid, sildenafil. Amlodipine has no clinically relevant effects on the pharmacokinetics or pharmacodynamics of the following: atorvastatin, digoxin, and warfarin. In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, ACE inhibitors, long acting nitrates, sublingual nitroglycerin, digoxin, warfarin, NSAIDs, antibiotics and oral hypoglycemic drugs.

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. Initiate telmisartan at low doses and titrate slowly in these patients. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hrs in patients with impaired hepatic function. Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency. Since patients with hepatic impairment have decreased clearance of amlodipine, start amlodipine or add amlodipine at 2.5 mg in patients with hepatic impairment. The lowest dose of CRESAR AM is 40/5 mg; therefore, initial therapy with CRESAR AM/ CRESAR 80 AM is not recommended in hepatically impaired patients.

Renal Impairment

As a consequence of inhibiting the RAS, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the RAS system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with ACE inhibitors and ARBs 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 an effect similar to that seen with ACE inhibitors. When telmisartan+amlodipine is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of telmisartan+amlodipine in patients with a recent kidney transplant. Telmisartan and amlodipine are not dialysable.

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 CRESAR AM/ CRESAR 80 AM 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, CRESAR AM/ CRESAR 80 AM should be discontinued unless they are considered life-saving 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+amlodipine combination for hypotension, oliguria, and hyperkalemia.

Lactation

It is not known whether telmisartan or amlodipine is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, 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.

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended to discontinue nursing while amlodipine is administered.

Pediatric Use

Neonates with a History of In Utero Exposure to Telmisartan and Amlodipine Combination

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Safety and effectiveness of telmisartan and amlodipine combination, in paediatric patients have not been established.

Geriatric Use

Of the total number of 3282 hypertensive patients receiving a telmisartan/amlodipine combination in clinical studies, 605 (18%) patients were 65 years of age or older and of these, 88 (3%) patients were 75 years and older. No overall differences in effectiveness and safety were observed in these patient population.

Of the total number of patients receiving telmisartan in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years and older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and 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.

Clinical studies of amlodipine besilate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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 disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required. Since patients age 75 and older have decreased clearance of amlodipine, start amlodipine or add amlodipine 2.5 mg to telmisartan. The lowest dose of telmisartan/amlodipine is 40/5 mg; therefore, initial therapy with telmisartan/amlodipine tablets is not recommended in patients > 75 years of age.

Undesirable Effects

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reactions 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.

Fixed Dose Combination of Telmisartan and Amlodipine

The concomitant use of telmisartan and amlodipine has been evaluated for safety in more than 3700 patients with hypertension; approximately 1900 of these patients were exposed for at least 6 months and over 160 of these patients were exposed for at least one year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

In the placebo-controlled factorial design study, the population treated with a telmisartan and amlodipine combination had a mean age of 53 years and included approximately 50% males, 79% were Caucasian, 17% Blacks, and 4% Asians. Patients received doses ranging from 20/2.5 mg to 80/10 mg orally, once daily.

The frequency of adverse reactions was not related to gender, age, or race.

The adverse reactions that occurred in the placebo-controlled factorial design trial in ≥2% of patients treated with fixed dose combination of telmisartan and amlodipine and at a higher incidence in patients treated with fixed dose combination of telmisartan and amlodipine (n=789) than placebo-treated patients (n=46) were peripheral edema (4.8% vs 0%), dizziness (3.0% vs 2.2%), and back pain (2.2% vs 0%). Edema (other than peripheral edema), hypotension, and syncope were reported in <2% of patients treated with fixed dose combination of telmisartan and amlodipine tablets.

In the placebo-controlled factorial design trial, discontinuation due to adverse events occurred in 2.2% of all treatment cells of patients in the telmisartan/amlodipine treated patients and in 4.3% in the placebo-treated group. The most common reasons for discontinuation of therapy with fixed dose combination of telmisartan and amlodipine tablets were peripheral edema, dizziness, and hypotension (each ≤0.5%).

Peripheral edema is a known, dose-dependent adverse reaction of amlodipine, but not of telmisartan. In the factorial design study, the incidence of peripheral edema during the 8 week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg (Table).

Table: Incidence of peripheral edema during the 8 week treatment period

 

Telmisartan

Placebo

40 mg

80 mg

Amlodipine

Placebo

0%

0.8%

0.7%

5 mg

0.7%

1.4%

2.1%

10 mg

17.8%

6.2%

11.3%

Other adverse events: cystitis, depression, anxiety, insomnia, dizziness, somnolence, migraine, headache, paresthesia, syncope, peripheral neuropathy, hypoesthesia, dysgeusia, vertigo, bradycardia, palpitations, hypotension, orthostatic hypotension, flushing, cough, interstitial lung disease, abdominal pain, diarrhea, nausea, tremor, vomiting, gingival hypertrophy, dyspepsia, dry mouth, pruritus, eczema, erythema, rash, arthralgia, muscle spasms (cramps in legs), myalgia, back pain, pain in extremity (leg pain), nocturia, erectile dysfunction, peripheral edema, asthenia, chest pain, fatigue, edema, malaise, hepatic enzyme increased, blood uric acid increased.

Telmisartan

Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20 to 160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo.

Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than patients treated with placebo irrespective of their causal association, are as presented in table below.

Table: Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and placebo

Adverse Events

Telmisartan (n = 1455)

%

Placebo (n = 380)

%

Upper respiratory tract infection

7

6

Back Pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with telmisartan and 6.1% of 380 placebo patients in placebo-controlled clinical trials.

The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.

The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).

In addition to those listed above, adverse events that occurred in > 0.3% of 3500 patients treated with telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to telmisartan:

  • Autonomic Nervous System: impotence, increased sweating, flushing
  • Body as a Whole: allergy, fever, leg pain, malaise
  • Blood and Lymphatic System Disorders: anemia, thrombocytopenia, eosinophilia, blood creatinine increased, hyperuricemia, blood creatine phosphokinase increased, haemoglobin decreased
  • Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal electrocardiogram (ECG)
  • Central Nervous System (CNS): insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia
  • Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, nonspecific gastrointestinal disorders, stomach discomfort
  • Metabolic: gout, hypercholesterolemia, diabetes mellitus, hyperkalemia, hypoglycaemia (in diabetic patients)
  • Musculoskeletal: arthritis, arthralgia, leg cramps, tendon pain (tendinitis like symptoms)
  • Psychiatric: anxiety, depression, nervousness
  • Resistance Mechanism: infection, fungal infection, abscess, otitis media
  • Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis, cough, interstitial lung disease, dyspnoea, upper respiratory tract infection including pharyngitis and sinusitis
  • Skin: dermatitis, angioedema (with fatal outcome), drug eruption, toxic skin eruption, urticaria, rash, eczema, pruritus, hypersensitivity, anaphalactic reaction, hyperhidrosis
  • Hepato-biliary disorders: hepatic function abnormal, liver disorder
  • Urinary: micturition frequency, urinary tract infection including cystitis
  • Renal: renal impairment including acute renal failure
  • Vascular: cerebrovascular disorder
  • Infections: sepsis including fatal outcome, influenza-like illness
  • Special Senses: abnormal vision, conjunctivitis, tinnitus, earache, visual disturbances

During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).

Clinical Laboratory Findings

In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan tablets.

  • Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy because of anemia.
  • Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy because of increases in creatinine and blood urea nitrogen.
  • Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy because of abnormal hepatic function.

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n=1730) at doses up to 10 mg to placebo (n=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo-treated patients (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose-related manner are as presented in Table.

Table: Incidence (%) of side effects

Adverse Events

Amlodipine 2.5 mg

(n = 275)

%

Amlodipine

5 mg

(n = 296)

%

Amlodipine 10 mg

(n = 268)

%

Placebo

(n = 520)

%

Edema

1.8

3.0

10.8

0.6

Dizziness

1.1

3.4

3.4

1.5

Flushing

0.7

1.4

2.6

0.0

Palpitation

0.7

1.4

4.5

0.6

Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials as mentioned in Table.

Table: Adverse experiences with an incidence greater than 1.0% in placebo-controlled clinical trials

Adverse Events

Amlodipine (n = 1730)

(%)

Placebo ( n = 1250)

(%)

Headache

7.3

7.8

Fatigue

4.5

2.8

Nausea

2.9

1.9

Abdominal Pain

1.6

0.3

Somnolence

1.4

0.6

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

  • Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis, MI
  • Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo
  • Gastrointestinal: anorexia, constipation, dyspepsia**, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia, change in bowel habit
  • General: allergic reaction, asthenia**, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease, gynecomastia
  • Musculoskeletal System: arthralgia, arthrosis, muscle cramps**, myalgia.
  • Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization, mood change
  • Respiratory System: dyspnea**, epistaxis, rhinitis
  • Skin and Appendages: angioedema, erythema multiforme, pruritus**, rash**, rash erythematous, rash maculopapular, alopecia, purpura, skin discoloration, hyperhidrosis, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity
  • Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
  • Urinary System: micturition frequency, micturition disorder, nocturia, pollakiuria
  • Autonomic Nervous System: dry mouth, sweating increased.
  • Metabolic and Nutritional: hyperglycemia, thirst.
  • Hemopoietic: leukopenia, purpura, thrombocytopenia.
  • Hepato-biliary disorders: hepatitis, jaundice, hepatic enzyme elevations (mostly consistent with cholestasis)

**These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as MI and angina.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of telmisartan or amlodipine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to telmisartan or amlodipine.

Telmisartan

The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, MI, BP increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased creatine phosphokinase, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (e.g. toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).

Rare cases of rhabdomyolysis have been reported in patients receiving ARBs, including telmisartan.

 Amlodipine

Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

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 with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan tablets would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Amlodipine

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Treatment

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 of both telmisartan and amlodipine.

Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position with elevation of extremities, with salt and volume replacement given quickly. Supportive treatment should be instituted. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Telmisartan and amlodipine are not removed by hemodialysis.

Incompatibility

Not applicable

Shelf-Life

Two years

Storage & Handling Instruction

Store in a cool dry place

Packaging Information

CRESAR AM: Aluminium Strip of l0 tablets 

CRESAR 80 AM: Aluminium Strip of 10 tablets

Last updated: March 2017

Last reviewed: March 2017