Product Index

For the use of Registered Medical Practitioner or Hospital or Laboratory Only.

Black Box Warning

Fetal Toxicity When pregnancy is detected, discontinue AMLOPRES TL as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

Qualitative and Quantitative Composition

Each uncoated bilayered tablet contains:

Amlodipine Besilate IP

equivalent to Amlodipine                 5 mg

Telmisartan IP                               80 mg

Excipients                                          q.s.

Colour: Lake of Ponceau 4R (In Amlodipine Besilate Layer)

Dosage Form(S) and Strength(S)

Uncoated bilayered tablets, Telmisartan 80 mg and Amlodipine 5 mg.

Clinical Particulars

Therapeutic Indication

AMLOPRES TL is indicated for the treatment of essential hypertension in adults.

Posology and Method of Administration

General Considerations

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 maximum recommended dose of AMLOPRES TL, tablets is 80/10 mg once daily.   

The adverse reactions of telmisartan are uncommon and independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.

AMLOPRES TL may be taken with or without food.

Replacement Therapy

Patients receiving amlodipine and telmisartan from separate tablets may instead receive AMLOPRES TL tablets containing the same component doses once daily. When substituting for individual components, increase the dose of AMLOPRES TL if blood pressure control has not been satisfactory.

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

AMLOPRES TL may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with telmisartan (or another angiotensin receptor blocker) alone.

Patients treated with 10 mg amlodipine who experience any dose-limiting adverse reactions such as edema, may be switched to AMLOPRES TL40/5 mg tablets once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response.

Initial Therapy

A patient may be initiated on amlodipine + telmisartan combination if it is unlikely that control of blood pressure would be achieved with a single agent. The usual starting dose is AMLOPRES TL 40/5 mg once daily. Patients requiring larger blood pressure reductions may be started on AMLOPRES TL 80/5 mg once daily.

Initial therapy with AMLOPRES TL is not recommended in patients ≥75 years old or with hepatic impairment.

Correct imbalances of intravascular volume- or salt-depletion, before initiating therapy with AMLOPRES TL tablets.

Method of Administration

For oral administration only.

AMLOPRES TL should be swallowed with a glass of water, with or without food. Patients should try to take their daily dose at about the same time each day. Tablets should be kept in the sealed blister due to the hygroscopic property of the tablets. Tablets should be taken out of the blister shortly before administration.

Contraindications

• Telmisartan+amlodipine is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or amlodipine or any other component of this product.

Hypersensitivity to any of the active substance or to any of the excipients.

Telmisartan is contraindicated in patients with:

Second and third trimester of pregnancy.

Biliary obstructive disorders.

Severe hepatic impairment.

The concomitant use of telmisartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2).

Amlodipine is contraindicated in patients with:

Shock (including cardiogenic shock).

Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).

Unstable angina (excluding Prinzmetal's angina).

Severe hypotension, haemodynamically unstable heart failure after acute myocardial infarction.

Special Warnings and Precautions for use

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

Telmisartan

In patients with an activated RAS, such as volume- and/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. This condition should be corrected prior to administration of telmisartan+amlodipine, 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 blood pressure has stabilized.

Amlodipine

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

Hyperkalemia

Telmisartan

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.

Amlodipine

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Renovascular Hypertension:

Telmisartan

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 renin-angiotensin aldosterone system.

Intravascular Hypovolaemia

Telmisartan

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

Dual Blockade of the Renin-angiotensin-aldosterone System (RAAS):

Telmisartan

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure).

Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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 blood pressure, renal function and electrolytes in patients on telmisartan+ amlodipine and other agents that affect the RAS.

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

Primary Aldosteronism

Telmisartan

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic Cardiomyopathy

Telmisartan

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

Telmisartan

In these patients hypoglycaemia 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.

Hyperkalaemia

Telmisartan + Amlodipine

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia. 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, hyperkalaemia may be fatal. 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.

Risk of Myocardial Infarction or Increased Angina

Amlodipine

Amlodipine Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of telmisartan+amlodipine, particularly in patients with severe obstructive coronary artery disease. There are no data to support the use of telmisartan/amlodipine in unstable angina pectoris and during or within one month of a myocardial infarction.

Heart Failure

Amlodipine

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 myocardial infarction, 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.

Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t_1/2) is 56 hours in patients with impaired hepatic function. 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 amlodipine is 40/5 mg; therefore, initial therapy with amlodipine tablets is not recommended in hepatically impaired patients.

Patients with heart failure should be treated with caution.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Other

Telmisartan + Amlodipine

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

Drugs Interactions

Drug Interactions with Telmisartan and Amlodipine Tablets

The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered. No drug interaction studies have been conducted with amlodipine+telmisartan tablets and other drugs, although studies have been conducted with the individual amlodipine and telmisartan, as described below:

Drug Interactions with Telmisartan

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.

Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state C_max and AUC of ramipril 2.3- and 2.1-fold, respectively, and C_max and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, C_max 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.

Non-Steroidal Anti-Inflammatory Agents 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. 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.

Other Drugs: Co-administration 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 cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate.

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.

In Vitro Data: In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Co-administration of Amlodipine with cimetidine did not alter the

pharmacokinetics of Amlodipine.

Grapefruit Juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Magnesium and Aluminum Hydroxide Antacid: Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of Amlodipine had no significant effect on the pharmacokinetics of Amlodipine.

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlodipine. When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Co-administration of multiple 10 mg doses of Amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Co-administration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (Alcohol): Single and multiple 10 mg doses of Amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Co-administration of Amlodipine with warfarin did not change the warfarin prothrombin response time.

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 co-administered 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.

Use in Special Population

Patients with Renal Impairment

Telmisartan

When Telmisartan is used in patients with impaired renal function, periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Telmisartan in patients with recent kidney transplantation.

No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration. 

As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with telmisartan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.

Amlodipine

Amlodipine may be used in such patients at normal doses.

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable. There are no data to support the use of amlodipine alone, during or within one month of a myocardial infarction.

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Patient with Hepatic Impairment

Monitor carefully and up-titrate 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 2.5 mg to telmisartan. The lowest dose of AMLOPRES TL is 40/5 mg; therefore, initial therapy with AMLOPRES TL tablets is not recommended in hepatically impaired patients.

Telmisartan

Telmisartan is not to be given to patients with cholestasis, biliary obstructive disorders or severe hepatic impairment since telmisartan is mostly eliminated with the bile. These patients can be expected to have reduced hepatic clearance for telmisartan.

Telmisartan should be used only with caution in patients with mild to moderate 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.

In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%

Amlodipine

 As with all calcium antagonists, amlodipine's half life is prolonged and AUC values are higher in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when

increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

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.

Pregnant Women

Teratogenic effects; Pregnancy categories C (first trimester) and D (second and third trimesters).

Pregnancy Category D.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue telmisartan+amlodipine as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue telmisartan+amlodipine, 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+amlodipine for hypotension, oliguria, and hyperkalemia.

Telmisartan

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue telmisartan as soon as possible

Lactating Women

Telmisartan

It is not known whether telmisartan 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, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Amlodipine

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 Patients

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

If oliguria or hypotension occurs, direct attention toward support 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 +amlodipine in pediatric patients have not been established.

Geriatric Patients

Of the total number of 3282 hypertensive patients receiving a telmisartan and 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 efficacy or safety of telmisartan+amlodipine were observed in this patient population.

Telmisartan

The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years

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.

Amlodipine

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

Clinical studies of amlodipine besylate 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 AMLOPRES TL is 40/5 mg; therefore, initial therapy with AMLOPRES TL tablets is not recommended in patients 75 years of age and older.

Race

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

Gender

Plasma concentrations of telmisartan are generally 2 to 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.

Effects on Ability to Drive and Use Machines

This medicinal product has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience adverse reactions such as syncope, somnolence, dizziness, or vertigo during treatment. Therefore, caution should be recommended when driving a car or using machines. If patients experience these adverse reactions, they should avoid potentially hazardous tasks such as driving or using machines

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 (Table 1). The incidence was notably lower when telmisartan was used in combination with amlodipine 10 mg.

		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%

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, an overall incidence of adverse events was similar to the patients treated with placebo.

Adverse events occurring at an incidence of ≥1% in patients treated with telmisartan and at a greater rate than in patients treated with placebo irrespective of their causal association are as listed in Table 2.

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,
• Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, peripheral 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,
• Metabolic: gout, hypercholesterolemia, diabetes mellitus,
• Musculoskeletal: arthritis, arthralgia, leg cramps,
• Psychiatric: anxiety, depression, nervousness
• Resistance Mechanism: infection, fungal infection, abscess, otitis media
• Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis
• Skin: dermatitis, rash, eczema, pruritus,
• Urinary: micturition frequency, cystitis
• Vascular: cerebrovascular disorder
• Special Senses: abnormal vision (vision disturbance), conjunctivitis, tinnitus, ear ache

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

Gingival Hypertrophy and Alopecia as an adverse drug reaction has been reported with amlodipine.

The most commonly reported adverse reactions during amlodipine treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue. The following adverse reactions have been observed and reported during treatment with amlodipine with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness:

Blood and lymphatic system disorders: Very rare: Leukocytopenia, hrombocytopenia.

Immune system disorders: Very rare: Allergic reactions.

Metabolism and nutrition disorders: Very rare: hyperglycaemia.

Nervous system disorders: Common: Somnolence, dizziness, headache (especially at the beginning of the treatment). Uncommon: Tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia. Very rare: Hypertonia, peripheral neuropathy.

Ear and labyrinth disorders: Common: Visual disturbance (including diplopia). Uncommon: Tinnitus.

Vascular disorders: Common: flushing. Uncommon: hypotension. Very rare: vasculitis.

Hepatobiliary disorders: Very rare: Hepatitis, jaundice, hepatic enzyme increased.

Investigations: Uncommon: Weight increased, weight decreased.

Exceptional cases of extrapyramidal syndrome have been reported.

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 amlodipine-treated 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 which occurred in a dose-related manner are presented in Table 3.

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 are presented in Table 4.

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,
• 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,
• 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
• Skin and Appendages: angiedema, erythema multiforme, , pruritus**, rash**, rash erythematous, rash maculopapular,
• Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
• Urinary System: micturition frequency, micturition disorder, nocturia,
• Autonomic Nervous System: dry mouth, sweating increased.
• Metabolic and Nutritional: hyperglycemia, thirst.
• Hemopoietic: leukopenia, purpura, thrombocytopenia.

**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 myocardial infarction 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, myocardial infarction, blood pressure 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 angiotensin II receptor blockers, 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.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, 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 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose   

Telmisartan

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage with telmisartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.  If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

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/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine 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, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Pharmacological Properties

Mechanism of Action

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 angiotensin type 1 receptor (AT₁) 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 receptor (AT₂) 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 blood pressure.

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 blood pressure.

Pharmacodynamic Properties

Fixed dose combination of telmisartan and amlodipine tablets have been shown to be effective in lowering blood pressure.

Both telmisartan and amlodipine lower blood pressure by reducing peripheral resistance but through complementary mechanisms.

Telmisartan

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, high-density lipoprotein , low-density lipoprotein , glucose, or uric acid).

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

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure 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 blood pressure 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 blood pressures 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 blood pressure with amlodipine is also correlated with the height of pre-treatment 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 blood pressures (+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 man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal- or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular (AV) conduction in intact animals or man. 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.

Pharmacokinetic Properties

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 80 mg and amlodipine 10 mg tablet with a high-fat meal, the total area under the plasma concentration-time curve (AUC) and peak concentration (C_max) for telmisartan decreased by about 24% and 60%, respectively. For amlodipine, AUC and C_max were not altered.

Absorption

Telmisartan

Following oral administration, C_max of telmisartan are reached in 0.5 to 1 hour after dosing. Food slightly reduces the bioavailability of telmisartan, with a reduction in the 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 to 160 mg, with greater than proportional increases of plasma concentrations (C_max 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 80%. 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 litres 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 Elimination

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.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Telmisartan

No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day . In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m² basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m² basis, the maximum recommended human dose of telmisartan (80 mg/day).

Amlodipine  

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m² basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Telmisartan

There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m² basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).

Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.

No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m² basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).

Amlodipine

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).

Description

AMLOPRES TL is a combination of two drugs with antihypertensive properties: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker (ARB), telmisartan.

AMLOPRES TL tablets contain telmisartan, a non-peptide angiotensin II receptor (type AT1) antagonist. Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Telmisartan is chemically described as 4'--1'-yl)methyl]--2-carboxylic acid. Its empirical formula is C₃₃H₃₀N₄O₂ and its structural formula is:

 

AMLOPRES TL tablets contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2--4-(2chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its empirical formula is C₂₀H₂₅ClN₂O₅•C₆H₆O₃S and its structural formula is:

 

Pharmaceutical Particulars

Incompatibility

Not applicable.

Shelf-Life

Telmisartan: 40 and 80 mg tablets – 4 years

Amlodipine: 3 years

As per Carton

Packaging Information

AMLOPRES TL: Alu-Alu Strip of 15 tablets 

Storage and Handling Information

Store protected from light and moisture, at a temperature not exceeding 30°C.

Keep out of reach of children.

Patient Counselling Information

What is AMLOPRES TL?

AMLOPRES TL is a prescription medicine that contains telmisartan and amlodipine. AMLOPRES TL tablets may be used to treat high blood pressure (hypertension):

• when one of these medicines (or a similar one) is not enough to lower your high blood pressure
• as the first medicine to lower your high blood pressure if your doctor decides you are likely to need more than one medicine

It is not known if AMLOPRES TL is safe and effective in children.

Who should not take AMLOPRES TL?

You should not take AMLOPRES TL tablets if you are allergic (hypersensitive) to the active ingredients (telmisartan or amlodipine) or any of the other ingredients listed at the end of this leaflet.

For patients with diabetes, if you are taking Amlopres TL you should not take aliskiren

What should I tell my doctor before taking AMLOPRES TL tablets?

Before you take AMLOPRES TL tablets, tell your doctor if you:

• have liver problems
• have kidney problems
• have heart problems
• have any other medical conditions
• are pregnant or are planning to become pregnant. See “What is the most important  information I should know about AMLOPRES TL tablets?”
• are breast-feeding or plan to breast-feed. It is not known if AMLOPRES TL passes into your breast milk. You and your doctor should decide if you will take AMLOPRES TL tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take AMLOPRES TL tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

For patients with diabetes, if you are taking AMLOPRES TL you should not take aliskiren

AMLOPRES TL may affect the way other medicines work, and other medicines may affect how AMLOPRES TL works. Especially tell your doctor if you take:

• aliskiren

• digoxin
• lithium
• medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors
• ramipril or other medicines that may be used to treat high blood pressure or a heart problem
• simvastatin
• water pills (diuretics)

Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.

How should I take AMLOPRES TL tablets?

• Take AMLOPRES TL tablets exactly as your doctor tells you to take it.
• Your doctor will tell you how much AMLOPRES TL to take and when to take it. Your doctor may change your dose if needed.
• Take AMLOPRES TL one time each day at the same time.
• Take AMLOPRES TL tablets with or without food.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
• If you take too much AMLOPRES TL, call your doctor or go to the nearest hospital emergency room right away.

What are possible side effects of AMLOPRES TL tablets?

AMLOPRES TL tablets may cause serious side effects, including:

• Injury or death to your unborn baby. See “What is the most important information I should know about AMLOPRES TL tablets?”
• Low blood pressure (hypotension) is most likely to happen if you also:
  
  •  take water pills (diuretics)
  • are on a low-salt diet
  • get dialysis treatments
  • have heart problems
  • get sick with vomiting or diarrhea

If you feel faint or dizzy, lie down and call your doctor right away.

• Kidney problems. Kidney problems may get worse if you already have kidney disease. You may have changes in your kidney test results, and you may need a lower dose of AMLOPRES TL tablets. Call your doctor if you get:

• swelling in your feet, ankles, or hands
• unexplained weight gain

Call your doctor right away if you get any of the symptoms listed above.

• Heart problems or heart attack. Heart problems may get worse in people that already have heart disease. This may happen when you start AMLOPRES TL tablets or when there is an increase in your dose of AMLOPRES TL. Get emergency help if you get worse chest pain or chest pain that does not go away.
• High potassium in the blood (hyperkalemia). Your doctor may check your potassium levels as needed.
• Muscle rigidity, tremor and/or abnormal muscle movement.

Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:

• swelling of face, tongue, throat
• difficulty breathing
• skin rash

The most common side effects of AMLOPRES TL tablets include:

• swelling in your hands, ankles, or feet
• feeling like your heart is pounding or racing
• flushing or sudden redness of the face and neck
• dizziness
• back pain
• feeling tired or sleepy
• abdominal pain, nausea, or diarrhea
• low blood pressure or a sudden drop in blood pressure with fainting

These are not all the possible side effects of AMLOPRES TL tablets. Tell your doctor if you have any side.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, 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 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product

How should I store AMLOPRES TL tablets?

• Store AMLOPRES TL tablets between 59° to 86°F (15° to 30°C).
• Do not remove AMLOPRES TL tablets from blisters until right before you take them.
• Keep AMLOPRES TL tablets out of the light and away from moisture.

Keep AMLOPRES TL tablets and all medicines out of the reach of children. General information about AMLOPRES TL tablets

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use AMLOPRES TL tablets for a condition for which it was not prescribed. Do not give AMLOPRES TL tablets to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in AMLOPRES TL tablets?

Active ingredients: telmisartan and amlodipine besylate

Inactive ingredients: sodium hydroxide, povidone, meglumine, sorbitol, magnesium stearate, microcrystalline cellulose, pregelatinized starch, corn starch, colloidal silicon dioxide, ferric oxide black, ferric oxide yellow and FD&C blue #1.

Details of Manufacturer

Manufactured by:

Akums Drugs & Pharmaceuticals Ltd.

At: Plot No. 26A, 27-30, Sector-8A, I.I.E., SIDCUL, Ranipur, Haridwar-249 403, Uttarakhand.

Marketed By:

Cipla Ltd.

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam marg Lower Parel, Mumbai – 400 013, India

Details of Permission or Licence Number with Date

4/UA/LL/2014, dated: 22.12.2021

Date of Revision

26/Jun/2022