Aliskiren

Aliskiren is an antihypertensive agent belonging to the Direct Renin Inhibitor

Aliskiren is approved for the treatment of Hypertension.

Aliskiren is poorly absorbed from GI tract, and absorption is reduced with bioavailability of approx 2.5%. It gets distributed extensively into extravascular space with plasma protein binding of approx 50% with minimal metabolism via CYP3A4 isoenzyme.

The common side effects associated with Aliskiren include headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain, etc. It gets excreted mainly in the form of faeces (via the bile) and urine (approx 25% of absorbed dose) as unchanged drug with an elimination half-life of Approx 24-40 hr.

Aliskiren is available in the dosage forms such as tablets and Capsules.

Aliskiren is available in China, India, Italy, Russia, Spain.

Aliskiren, belonging to Direct Renin Inhibitor, acts as a Antihypertensive agent. Aliskiren works by blocking an enzyme in the body that is necessary to produce a substance that causes blood vessels to tighten. As a result, blood vessels relaxes and this reduces the blood pressure.

Aliskiren acts as a renin inhibitor, which blocks the conversion of angiotensinogen to angiotensin I. This effect subsequently reduces the formation of angiotensin II. Angiotensin II acts on the AT1 receptor, which is responsible for vasoconstriction, aldosterone secretion, and catecholamine release.

The onset of action of Aliskiren occurs within 2 hours..

The Duration of Action for Aliskiren is 48 hours.

The Tmax was found within 1-3 hour and Cmax in blood reached upto 481±497 ng/ml.

Aliskiren is available in the form of tablets and capsules.

Aliskiren tablets and capsules should be taken orally by mouth with or without water.

Aliskiren is approved for the treatment of essential or primary Hypertension.

Aliskiren is active in the renin-angiotensin-aldosterone system (RAAS). Renin secretion occurs by specialized cells found in the juxta glomerular apparatus within the kidney based on changes in blood volume and renal perfusion as sensed by the macula densa in the distal tubule of the nephron. Renin is responsible for converting angiotensinogen to angiotensin I. Angiotensin I is then converted to angiotensin II by the angiotensin-converting enzyme (ACE), which is present in the capillaries of the lungs as well as endothelial cells present in the kidneys.

Aliskiren is approved for use in the following clinical indications

Hypertension

• Aliskiren is indicated for the treatment of hypertension, to reduce blood pressure. Lowering blood pressure decreases the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infractions. 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 the 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.
• 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 mm Hg 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.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Aliskiren is available in the form of tablets and capsules.

Aliskiren should be used for the treatment of essential or primary Hypertension.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per patient requirements.

Aliskiren may be contraindicated in the following

• Aliskiren is contraindicated in patients with a known hypersensitivity to any component, in pediatric patients less than two years, and in patients with diabetes mellitus who are taking an ACE inhibitor or an angiotensin receptor blocker.

• Patients should not use aliskiren in pregnancy or if they are taking an ARB or ACEI. Caution is necessary for patients who have volume depletion.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy decreases 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.

• Renal Impairment/Hyperkalemia/Hypotension when Aliskiren is given in combination with ARBs or ACEI

Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEI because of the gain risk of renal impairment, hyperkalemia, and hypotension Avoid use of Aliskiren with ARBs or ACEI in patients with moderate renal impairment (GFR < 60 ml/min.)

• Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has 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 the patients with and without the history of angioedema with ACE inhibitors or angiotensin receptor antagonists. If angioedema involves 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 effect, even without respiratory distress, require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of the subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) and measure to ensure the patent airway may be necessary. Discontinue Aliskiren immediately in patients who develop angioedema, and do not readminister.

• Hypotension

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Aliskiren This condition 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.

• 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 renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAIDs) therapy may be at particular risk for developing acute renal failure on Aliskiren .Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.

• Hyperkalemia

Monitor serum potassium periodically in patients receiving Aliskiren Drugs that affect the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEI.

• 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

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

It is not known whether aliskiren is excreted in human breast milk. Aliskiren was secreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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 Aliskiren 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 Aliskiren, 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 Aliskiren for hypotension, oliguria, and hyperkalemia.

GENERALLY AVOID:

Coadministration with orange, apple, or grapefruit juice may significantly decrease the oral bioavailability and renin-inhibiting effect of aliskiren. The exact mechanism of the interaction is unknown, but may include inhibition of OATP2B1-mediated influx of aliskiren in the small intestine, formation of insoluble complexes between fruit juice constituents and aliskiren, and/or increased ionization of aliskiren due to decreased intestinal pH. In 12 healthy volunteers, 200 mL of either orange juice or apple juice administered three times daily for 5 days in combination with a single 150 mg oral dose of aliskiren on day 3 decreased the mean aliskiren peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 80% and 60%, respectively, compared to water. Plasma renin activity was 87% and 67% higher at 24 hr post dose when aliskiren was administered with orange juice and apple juice, respectively, compared to water.

The adverse reactions related to molecule Aliskiren can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripherial ischemia, dry mouth,asthenia and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Aliskiren is briefly summarized here.

· Cyclosporine

Avoid co-administration of cyclosporine with aliskiren.

· Itraconazole

· Avoid co-administration of itraconazole with aliskiren.

· Non-Steroidal Anti-Inflammatory Agents (NSAIDs) 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 agents that affect the renin-angiotensin-aldosterone system, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy.

The antihypertensive effect of aliskiren may be attenuated by NSAIDs.

Dual Blockade of the renin-angiotensin-aldosterone system

• The concomitant use of aliskiren with other agents acting on the renin-angiotensin-aldosterone system such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the renin-angiotensin-aldosterone system.

• The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated and should be avoided in patients with moderate renal impairment.

Furosemide

• Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren.

Pediatric Use

• Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established.
• Neonates with a history of in utero exposure to Aliskiren
• If oliguria or hypotension occurs, direct attention toward support of 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.

Geriatic Use

• Of the total number of patients receiving aliskiren in clinical studies, 1,275 (19%) were 65 years or older and 231 (3.4%) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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.

Pharmacodynamics:

In placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 50- 80%. This reduction in PRA was not dose-related and did not correlate with the blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

Pharmacokinetics :

• Absorption

Aliskiren is poorly absorbed (bioavailability about 2.5%) with an approximate accumulation half life of 24 hours. Steady state blood levels are reached in about 7-8 days.

• Distribution

Following oral administration, peak plasma concentrations of aliskiren are reached within 1 – 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals.

• Metabolism and Elimination

About one fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP 3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP 3A4. Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of the transporter.

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