Tekturna® (aliskiren) tablets

Molecular formula: C30H53N3O6 • 0.5 C4H4O4

Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-octanol, and highly soluble in water.

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.

All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.

Hypertension
Tekturna is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes. There are no controlled trials demonstrating risk reduction with Tekturna.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Tekturna may be used alone or in combination with other antihypertensive agents. Use with maximal doses of ACE inhibitors has not been adequately studied.

• Avoid neonatal/fetal exposure 
• Head and neck angioedema. Discontinue use of Tekturna and monitor until signs and symptoms resolve
• Hypotension in volume and/or salt depleted patients: Correct imbalances before initiating therapy with Tekturna 
• Patients with severe renal dysfunction: Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances 
• Hyperkalemia: Caution should be exercised when co-administered with ACEI, potassium-sparing diuretics, potassium supplements or other potassium containing salt substitutes

Hypertension
The usual recommended starting dose of Tekturna is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. Doses above 300 mg did not give an increased blood pressure response but resulted in an increased rate of diarrhea. The antihypertensive effect of a given dose is substantially attained (85-90%) by 2 weeks.

Use with Other Antihypertensives
Tekturna may be administered with other antihypertensive agents. Most exposure to date is with diuretics, an angiotensin receptor blocker (valsartan) or a calcium channel blocker (amlodipine). Aliskiren used together with these drugs has a greater effect at their maximum recommended doses than either drug alone. It is not known whether additive effects are present when Tekturna is used with angiotensin-converting enzyme inhibitors (ACEI) or beta blockers (BB).

Relationship to Meals
Patients should establish a routine pattern for taking Tekturna with regard to meals. High fat meals decrease absorption substantially.

Dosing in Special Populations
No adjustment of the starting dose is required in elderly patients, patients with mild-to-severe renal impairment or mild-to-severe hepatic insufficiency. However, clinical experience in patients with severe renal impairment is limited.

150 mg light pink biconvex round tablet, imprinted NVR/IL (Side 1/Side 2)
300 mg light red biconvex ovaloid round tablet, imprinted NVR/IU (Side 1/Side 2)

HOW SUPPLIED/STORAGE AND HANDLING

Tekturna is supplied as a light-pink, biconvex round tablet containing 150 mg of aliskiren, and as a light-red biconvex ovaloid tablet containing 300 mg of aliskiren. Tablets are imprinted with NVR on one side and IL, IU, on the other side of the 150, and 300 mg tablets, respectively.

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense in original container.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
© Novartis
T2011-116/T2009-52
October 2011/November 2009