Sintel A

Uses

This combination is used for the treatment of essential hypertension in adults.

Replacement Therapy: Patients receiving telmisaitan and amlodipine from separate tablets may instead receive Telmisartan & Amlodipine containing the same component doses.

Add-On Therapy: Telmisartan & Amlodipine is used for patients whose blood pressure is not adequately controlled on telmisaitan or amlodipine monotherapy.

Initial Therapy: Telmisartan & Amlodipine may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. Base the choice of Telmisartan & Amlodipine tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Telmisartan & Amlodipine tablets.

Patients with moderate or severe hypeitension are at relatively high-risk for cardiovascular events (eg, stroke, heait attacks and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant. Consider the patient’s baseline blood pressure, the target goals and the incremental likelihood of achieving goals with a combination compared to monotherapy when deciding whether to use Telmisartan & Amlodipine tablets as initial therapy. Individual blood pressure goals may vary based upon the patient’s risk.

Sintel A is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Events, Chronic Stable Angina Pectoris, Coronary Artery Disease (CAD), High Blood Pressure (Hypertension), Homozygous Familial Hypercholesterolemia, Hypertension,Essential, Mixed Dyslipidemias, Primary Hypercholesterolemia, Vasospastic AnginaCardiovascular Events, Diabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension)

How Sintel A works

Mechanism of action on blood pressure

Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells . Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure .

Mechanism of action in angina

The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold:

Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements .

Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking .

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT₁-receptor by binding reversibly and selectively to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Telmisartan does not inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Studies also suggest that telmisartan is a partial agonist of PPARγ, which is an established target for antidiabetic drugs. This suggests that telmisartan can improve carbohydrate and lipid metabolism, as well as control insulin resistance without causing the side effects that are associated with full PPARγ activators.

Dosage

Sintel A dosage

Each tablet contains Telmisartan 40 mg & Amlodipine 5 mg

Adults: One tablet should be taken once daily. Maximum Recommendation Dose: two tablets/day.

Replacement Therapy: Patients receiving telmisartan and amlodipine from separate tab can instead receive. Telmisartan & Amlodipine containing the same component doses in 1 tablet once daily eg, to enhance convenience or compliance.

Add-On Therapy:Telmisartan & Amlodipine may be administered in patients whose blood pressure is not adequately controlled with amlodipine or telmisartan alone. Patients treated with amlodipine 10 mg who experience any dose-limiting adverse reactions eg, oedema, may be switched to Telmisartan & Amlodipine 40/5 mg once daily, reducing the dose of amlodipine without reducing the overall ected antihypertensive response.Individual dose titration with the components (ie, am odipine and telmisaitan) is recommended before changing to the fixed-dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered.

Initial Therapy:A patient may be initiated on Telmisartan & Amlodipine if it is unlikely that control of blood pressure would be achieved with a single agent.

Usual Starting Dose: 40/5 mg once daily. Initial therapy with Telmisartan & Amlodipine is not recommended in patients 75 years or with hepatic impairment. Correct imbalances on intravascular volume- or salt-depletion, before initiating therapy with Telmisartan & Amlodipine tablet. Telmisartan & Amlodipine may be taken with or without food.

Children and Adolescents: Telmisartan & Amlodipine is not recommended for use in patients below 18 years due to a lack of data on safety and efficacy.

Elderly:No dose adjustment is necessary for elderly patients. Limited information is available in the very elderly patients.

Telmisartan tablets may be administered with other antihypertensive agents with or without food.

Side Effects

The most common adverse reactions include Dizziness, peripheral oedema. Somnolence, migraine, headache, paraesthesia, vertigo, bradycardia, palpitations, hypotension, orthostatic hypotension, flushing, cough, abdominal pain, diarrhoea, nausea, pruritus, arthralgia, muscle spasms, myalgia, erectile dysfunction, asthenia, chest pain, fatigue, oedema, increased hepatic enzyme.

Toxicity

Acute oral toxicity (LD50): 37 mg/kg (mouse) .

Overdose

An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported .

Carcinogenesis, mutagenesis, impairment of fertility

Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose .

Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects .

There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose) .

Use in pregnancy

The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug . Use amlodipine only if the potential benefit justifies the potential risk .

Use in nursing

Discontinue when administering amlodipine .

Intravenous LD₅₀ in rats is 150-200 mg/kg in males and 200 to 250 mg/kg in females. Acute oral toxicity is low: no deaths and no changes occurred in rats or dogs at 2000 mg/kg, the highest dose tested. Limited data are available with regard to overdosage in humans. The most likely manifestations of overdosage with telmisartan would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

Precaution

Hepatic & renal impairment, renovascular HTN, intravascular hypovolaemia, severe CHE renal artery stenosis, primary aldosteronism, aortic or mitral valve stenosis, obstructive hypertrophic cardiomyopathy, NYHA III & IV heart failure of non-ischaemic aetiology, hyperkalaemia. Fructose intolerance. May impair ability to drive or operate machinery. Children & adolescent 18 years.

Impairment of Fertility: No data from controlled clinical studies with the fixed dose combination or with the individual components are available.

Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted. In preclinical studies, no effects of telmisartan on male and female fertility were observed. Similarly, no effects on male and female fertility were reported for amlodipine.

Interaction

No interactions between the 2 components of this fixed-dose combinations have been observed in clinical studies. Interactions Common to the Combination: No drug interaction studies have been performed with Telmisartan & Amlodipine and other medicinal products.

Volume of Distribution

21 L/kg , .

• 500 L

Elimination Route

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food .

Absolute bioavailability depends on dosage. Food slightly decreases the bioavailability (a decrease of about 6% is seen when the 40-mg dose is administered with food).

Half Life

The terminal elimination half-life of about 30–50 hours .

Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment .

Bi-exponential decay kinetics with a terminal elimination half-life of approximately 24 hours.

Clearance

Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers , .

Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required .

• >800 mL/min

Elimination Route

Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing . Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure , .

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

Pregnancy & Breastfeeding use

Pregnancy: Category D. There is positive evidence of human foetal risk, but the benehts from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Use in lactation: It is not known whether telmisartan and/or amlodipine are excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk. Because of the potential adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy, taking into account the importance of this therapy for the mother

Contraindication

Hypersensitivity to telmisartan, amlodipine, dihydropyridine derivatives or to any of the excipients of Telmisartan & Amlodipine. Biliary obstructive disorders, severe hepatic impairment & hypotension, cardiogenic shock, left ventricle outflow tract obstuction, haemodynamically unstable heart failure after acute MI.

Special Warning

Children with hypertension from 6 years to 17 years of age: 2.5 mg once daily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients.

Children under 6 years old: The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Elderly: Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.

Renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

Hepatic impairment: Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautions and should start at the lower end of the dosing range. The pharmacokinetics of Amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose (2.5 mg once daily) and titrated slowly in patients with severe hepatic impairment.

Renal Impairment: Severe impairment or on haemodialysis: Initially, 20 mg once daily.

Hepatic Impairment: Mild to moderate: Max: 40 mg once daily. Severe: Contraindicated.

Acute Overdose

There is no well documented experience with Amlodipine overdosage. In case of clinically significant hypotension due to Amlodipine over dosage, calls for active cardiovascular support including monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. Since Amlodipine is highly protein-bound, dialysis is unlikely to be of benefit.

Symptoms: Hypotension, bradycardia, tachycardia, dizziness, acute renal failure and elevated serum creatinine.

Management: Supportive and symptomatic treatment. Induction of emesis and/or gastric lavage. Activated charcoal may be useful. Salt and volume replacement should be given immediately if hypotension occurs and place patient in supine position.

Storage Condition

Store in a cool and dry place, protected from light. Keep out of children’s reach.

Innovators Monograph

You find simplified version here Sintel A