TEKAMLO- aliskiren hemifumarate and amlodipine besylate tablet, film coated
Novartis Pharmaceuticals Corporation
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue Tekamlo as soon as possible. (5.1)
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)
1 INDICATIONS AND USAGE
Tekamlo is indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine. There are no controlled trials demonstrating risk reduction with Tekamlo.
DOSAGE AND ADMINISTRATION
2.1 General Considerations
The recommended initial once-daily dose of Tekamlo is 150 mg/5 mg. Titrate as needed to a maximum of 300 mg/10 mg.
The blood pressure lowering effects are largely attained within 1 to 2 weeks. If blood pressure remains uncontrolled after 2 to 4 weeks of therapy, titrate the dose to a maximum of Tekamlo 300 mg/10 mg once daily.
DESCRIPTION
Tekamlo is a single tablet for oral administration of aliskiren hemifumarate (an orally active, nonpeptide, potent direct renin inhibitor) and amlodipine besylate (a dihydropyridine calcium channel blocker).
Aliskirenhemifumarate
Aliskiren hemifumarate is chemically described as (2S ,4S ,5S ,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate.
Molecular formula: C30 H53 N3 O6 � 0.5 C4 H4 O4
Aliskiren hemifumarate is a white to slightly yellowish powder with a molecular weight of 609.8 (free base- 551.8). It is highly soluble in water, and freely soluble in methanol, ethanol and isopropanol.
Amlodipine besylate
Amlodipine besylate, USP is chemically described as 3-Ethyl 5-methyl (�)-2-[(2-aminoethoxy)methyl]-4-(o -chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate.
CLINICAL PHARMACOLOGY
Figure 5: The impact of co-administered drugs on the pharmacokinetics of aliskiren.Figure 6: The impact of aliskiren on the pharmacokinetics of co-administered drugs.
12.1 Mechanism of Action
Aliskiren
Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known.
Amlodipine besylate
Amlodipine is a dihydropyridine calcium 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.