Aliskiren

551.76

551.76

1308068-626-2

502FWN4Q32

C65222

C09XA02|C09XA52|C09XA53|C09XA54|C - Cardiovascular system

146

3.5

Solid

1.067±0.06 g/cm3(Predicted)

98-99 °C

748.4±60.0 °C(Predicted)

406.4±32.9 °C

1.514

Highly soluble in water (as hemifumarate salt)

1.9X10-20 mm Hg at 25 deg C (est)

9.49None

Henry's Law constant = 9.09X10-24 atm-cu m/mol at 25 °C (est)

9.49|pKa = 9.49

Hydroxyl radical reaction rate constant = 1.69X10-10 cu cm/molec-sec at 25 °C (est)|White to slightly yellowish crystalline powder; MW: 609.8; soluble in phosphate buffer, n-octanol and highly soluble in water /Aliskiren hemifumarate/|MW: 1219.59 /Aliskiren hemifumarate/

P261, P272, P273, P280, P302+P352, P321, P333+P313, P363, P391, P501

H317

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including aliskiren hemifumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Aliskiren hemifumarate/

|Warning|H317 (78.57%): May cause an allergic skin reaction [Warning Sensitization, Skin]|P261, P272, P273, P280, P302+P352, P321, P333+P313, P363, P391, and P501|Aggregated GHS information provided by 42 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H302 (16.67%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 12 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral LD50 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose.

Serum aminotransferase elevations during aliskiren therapy are uncommon and rates of such elevations have not been reported in the large clinical trials that demonstrated its efficacy in hypertension. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of aliskiren and several instances of marked serum enzyme elevations during therapy with few symptoms and without jaundice have been reported. In most instances, the pattern of enzyme elevation was distinctly hepatocellular and recovery was prompt once aliskiren was stopped. There have also been reports to the sponsor of severe hepatic reactions including hepatic failure and more recently a published case report of acute liver injury attributed to this agent. The latency to onset has ranged from 1 to 6 months and the pattern of injuryis typically cholestatic or mixed. Most cases have been mild to moderate in severity and marked by rapid recovery once aliskiren is stopped.

Furosemide: When aliskiren was coadministered with furosemide, the AUC and Cmax of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.|Verapamil: Coadministration of 240 mg of verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in Cmax and AUC of aliskiren. However, no dosage adjustment is necessary.|Cyclosporine: Coadministration of 200 mg and 600 mg cyclosporine with 75 mg aliskiren resulted in an approximately 2.5-fold increase in Cmax and 5-fold increase in AUC of aliskiren. Concomitant use of aliskiren with cyclosporine is not recommended.|Ketoconazole: Coadministration of 200 mg twice-daily ketoconazole with aliskiren resulted in an approximate 80% increase in plasma levels of aliskiren. A 400-mg once-daily dose was not studied but would be expected to increase aliskiren blood levels further.|For more Interactions (Complete) data for Aliskiren (11 total), please visit the HSDB record page.

The plasma protein binding of aliskiren ranges from 47-51%.

Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control.|FDA Label|Treatment of essential hypertension.|Treatment of essential hypertension in adults.Rasilez HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone.Rasilez HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.|Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled with aliskiren or amlodipine used alone.|Rasitrio is indicated for the treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of aliskiren, amlodipine and hydrochlorothiazide given concurrently at the same dose level as in the combination.|Treatment of essential hypertension in adults.Riprazo HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone.Rirpozo HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.|Treatment of essential hypertension in adults.Sprimeo HCT is indicated in patients whose blood pressure is not adequately controlled on aliskiren or hydrochlorothiazide used alone.Sprimeo HCT is indicated as substitution therapy in patients adequately controlled with aliskiren and hydrochlorothiazide, given concurrently, at the same dose level as in the combination.|Treatment of essential hypertension|Heart Failure, Treatment of hypertension

Aliskiren is a unique antihypertensive agent that acts by direct inhibition of renin and has only recently been introduced into clinical practice. Aliskiren has been linked to rare instances of serum aminotransferase elevations during therapy and rare cases of idiosyncratic, clinically apparent liver injury.

Antihypertensive Agents

Antihypertensive Agent; Renin/antagonists and inhibitors|Tekturna is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Use with maximal doses of ACE inhibitors has not been adequately studied. /Included in US product label/

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Tekturna as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|Possible fetal and neonatal morbidity and mortality when used during pregnancy. Such potential risks occur throughout pregnancy, especially during the second and third trimesters.|Retrospective data indicate that angiotensin-converting enzyme (ACE) inhibitors, a class of drugs acting on the renin-angiotensin-aldosterone (RAA) system, have been associated with an increased risk of major congenital malformations when administered during the first trimester of pregnancy.|Excessive hypotension reported rarely in patients with uncomplicated hypertension receiving the drug alone and infrequently during combination therapy with other antihypertensive agents.|For more Drug Warnings (Complete) data for Aliskiren (21 total), please visit the HSDB record page.

Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction.

Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration.|Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route.|Unchanged aliskiren accounts for about 80% of the drug found in the plasma.|Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers.|Poorly absorbed; oral bioavailability is about 2.5%.|Steady state blood levels are reached in about 7-8 days.|Peak plasma concentrations usually attained within 1-3 hours following oral administration. Substantial proportion (85-90%) of antihypertensive effect attained within 2 weeks of initiation of therapy.|High-fat meal decreases mean AUC and peak plasma concentration by 71 and 85%, respectively; however, in clinical studies drug was administered without requiring a fixed relation of administration to meals.|For more Absorption, Distribution and Excretion (Complete) data for Aliskiren (12 total), please visit the HSDB record page.

About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma.|Amount of absorbed dose that undergoes metabolism not established; however, drug appears to undergo minimal hepatic metabolism. CYP isoenzyme 3A4 appears to be main enzyme responsible for metabolism of drug based on in vitro studies. Also, a substrate for p-glycoprotein.|The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.|... The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. ...

Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours.|Accumulation half-life is approximately 24 hours.|... Terminal half-lives for radioactivity and aliskiren in plasma were 49 hr and 44 hr, respectively. ...|Terminal half-life is approximately 24-40 hours; wide interpatient variability observed.

Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally increase blood pressure.|Aliskiren is a nonpeptide renin inhibitor. Renin catalyzes the conversion of angiotensinogen to angiotensin I, the initial and rate-limiting enzymatic reaction of the renin-angiotensin-aldosterone (RAA) system; angiotensin I is subsequently cleaved to angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II has vasoconstrictor and aldosterone-secreting effects, which increase blood pressure. All drugs that inhibit the RAA system, including renin inhibitors, suppress feedback inhibition of renin secretion, leading to a compensatory increase in plasma renin concentrations. When this increase occurs during therapy with ACE inhibitors or angiotensin II receptor antagonists, the result is increased plasma renin activity (PRA). Because aliskiren binds with high affinity to plasma renin, aliskiren inhibits effects of increased renin concentrations and conversion of angiotensinogen to angiotensin I, resulting in reduced PRA and reduced concentrations of angiotensin I, angiotensin II, and aldosterone; whether aliskiren affects other RAA system components (eg, ACE, non-ACE pathways) is not known.|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, eg, ACE or non-ACE pathways, is not known.|Aliskiren ... acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). ...|Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the 'escape' phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. /Investigators/ made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete 'upstream' inhibition of the renin-angiotensin-aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination half-life of aliskiren (about 40 hours) compared with ramiprilat (13-17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.|For more Mechanism of Action (Complete) data for Aliskiren (7 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.|/HUMAN EXPOSURE STUDIES/ ... Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, significant natriuresis on both diets /were found/. Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis.|/SIGNS AND SYMPTOMS/ Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension occurs, supportive treatment should be initiated.|/CASE REPORTS/ ... A case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren /is reported/. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.|For more Human Toxicity Excerpts (Complete) data for Aliskiren (7 total), please visit the HSDB record page.

2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-(4-methoxy-3-(3-methoxypropoxy)phenyl)octanamid hemifumarate

Aliskiren preparations: (AHFS, 2010)|Rasilez

Human drugs -> Rasilez -> EMA Drug Category|Agents acting on the renin-angiotensin system -> Human pharmacotherapeutic group|Human drugs -> Rasilez HCT -> EMA Drug Category|Human drugs -> Rasilamlo -> EMA Drug Category|Human drugs -> Riprazo -> EMA Drug Category|Human drugs -> Rasitrio -> EMA Drug Category|Cardiovascular system -> Human pharmacotherapeutic group|Human drugs -> Riprazo HCT -> EMA Drug Category|Human drugs -> Sprimeo HCT -> EMA Drug Category|Human drugs -> Sprimeo -> EMA Drug Category|Human drugs -> Enviage -> EMA Drug Category|Human drugs -> Tekturna -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients