aliskiren 300 MG Oral Tablet [Tekturna]

INDICATIONS AND USAGE Aliskiren is a renin inhibitor (RI) indicated for the treatment of hypertension in adults and in pediatric patients weighing 50 kg or greater who are at least 6 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) 1.1 Hypertension Aliskiren is indicated for the treatment of hypertension in adults and in pediatric patients weighing 50 kg or greater who are at least 6 years of age and older 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 Aliskiren. 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 1 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 have also 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 (e.g., 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.

DOSAGE AND ADMINISTRATION Starting dose (adults and pediatric patients): 150 mg once daily with a routine pattern with regard to meals. If blood pressure remains uncontrolled titrate up to 300 mg daily. ( 2.1 ) Majority of effect of given dose attained in 2 weeks ( 2.1 ) 2.1 Recommended Dosage In adult patients and in pediatric patients weighing 50 kg or greater who are at least 6 years of age, the recommended starting dose of Aliskiren is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg once daily. 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 dosage is substantially attained (85% to 90%) by 2 weeks. 2.2 Relationship to Meals Patients should establish a routine pattern for taking Aliskiren with regard to meals. High-fat meals decrease absorption substantially [see Clinical Pharmacology ( 12.3 )].

WARNINGS AND PRECAUTIONS Avoid concomitant use with ARBs or ACEIs particularly in patients with renal impairment [creatinine clearance (CrCl) <60 mL/min]. ( 5.2 , 5.4 ) Anaphylactic Reactions and Head and Neck Angioedema. ( 5.3 ) Hypotension: Correct imbalances in volume and/or salt depleted patients. ( 5.4 ) Impaired Renal Function: Monitor serum creatinine periodically. ( 5.5 ) Hyperkalemia: Monitor potassium levels periodically. ( 5.6 ) 5.1 Fetal Toxicity 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 Aliskiren as soon as possible [see Use in Specific Populations ( 8.1 )]. 5.2 Renal Impairment/Hyperkalemia/Hypotension when Aliskiren is Given in Combination with ARBs or ACEIs Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. In general, avoid combined use of Aliskiren with ACE inhibitors or ARBs, particularly in patients with creatinine clearance (CrCl) less than 60 mL/min [see Contraindications ( 4 ), Drug Interactions ( 7 ) and Clinical Studies ( 14.3 )] . 5.3 Anaphylactic Reactions and Head and Neck Angioedema Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACEIs or angiotensin receptor antagonists. Anaphylactic reactions have been reported from postmarketing experience with unknown frequency. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary. Discontinue Aliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Dosage and Administration ( 2.1 ) and Contraindications ( 4 )]. 5.4 Hypotension Symptomatic hypotension may occur after initiation of treatment with Aliskiren in patients with marked volume depletion, patients with salt depletion, or with combined use of Aliskiren and other agents acting on the renin- angiotensin-aldosterone system (RAAS). The volume or salt depletion should be corrected prior to administration of Aliskiren, or the treatment should start under close medical supervision. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.5 Impaired Renal Function Monitor renal function periodically in patients treated with Aliskiren. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAAS. Patients whose renal function may depend in part on the activity of the RAAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or nonsteroidal anti-inflammatory drug (NSAID), including selective Cyclooxygenase- 2 inhibitors (COX-2 inhibitors), therapy may be at particular risk for developing acute renal failure on Aliskiren [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 ), Use in Specific Populations ( 8.6 ), and Clinical Studies ( 14.3 )] . Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function. 5.6 Hyperkalemia Monitor serum potassium periodically in patients receiving Aliskiren. Drugs that affect the RAAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), and Clinical Studies ( 14.3 )] , NSAIDs, or potassium supplements or potassium sparing diuretics. 5.7 Cyclosporine or Itraconazole When Aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of Aliskiren with cyclosporine or itraconazole [see Drug Interactions ( 7 )] .

CONTRAINDICATIONS Do not use Aliskiren with ARBs or ACEIs in patients with diabetes [see Warnings and Precautions ( 5.2 ) and Clinical Studies ( 14.3 )]. Aliskiren is contraindicated in patients with known hypersensitivity to any of the components [see Warnings and Precautions ( 5.3 )]. Aliskiren is contraindicated in pediatric patients less than 2 years of age because of the risk of high aliskiren exposure identified in juvenile animals due to immaturity of transporters and metabolic enzymes [see Use in Specific Populations ( 8.4 )]. Do not use with angiotensin receptor blockers (ARBs) or angiotensin- converting enzyme inhibitors (ACEIs) in patients with diabetes. ( 4 ) Hypersensitivity to any of the components. ( 4 ) Aliskiren is contraindicated in pediatric patients less than 2 years of age. ( 4 )

Mechanism of Action 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 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 ACEIs 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.