Aliskiren

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# Black Box Warning

# Overview
Aliskiren is a renin inhibitor that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include diarrhea, dizziness, headache, and elevated serum creatinine.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Aliskiren 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 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 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 Programs 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.
- Aliskiren may be administered with some other antihypertensive agents. In diabetics, do not use in combination with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs). Concomitant use of aliskiren with an ARB or ACEI is not recommended in patients with GFR <60 ml/min. 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 aliskiren is used with angiotensin-converting enzyme inhibitors (ACEIs) or beta blockers (BB).
- Patients should establish a routine pattern for taking Aliskiren with regard to meals. High fat meals decrease absorption substantially.
- Dosing Information
- The usual recommended starting dose 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in adult patients.

### NonGuideline-Supported Use
- Dosing Information
- 300 mg PO qd

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of aliskiren in pediatric patients <18 years have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aliskiren in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Aliskiren in pediatric patients.

# Contraindications
- Do not use aliskiren with ARBs or ACEIs in patients with diabetes.

# Warnings
- 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.
- Aliskiren is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension.
- Avoid use of Aliskiren with ARBs or ACEIs in patients with moderate renal impairment (GFR <60 ml/min).
- 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 ACE inhibitors or angiotensin receptor antagonists. Anaphylactic reactions have been reported from post-marketing 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 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.
- 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. 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.
- 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-aldosterone system. Patients whose renal function may depend in part on the activity of the renin-angiotensin-aldosterone system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAID) 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.
- Monitor serum potassium periodically in patients receiving Aliskiren. Drugs that affect the renin-angiotensin-aldosterone system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs, NSAIDs, or potassium supplements or potassium sparing diuretics.
- 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.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
- Data described below reflect the evaluation of the safety of Aliskiren in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 patients for longer than 1 year. In placebo controlled clinical trials, discontinuation of therapy due to a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with Aliskiren vs. 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs.
- Two cases of angioedema with respiratory symptoms were reported with Aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with Aliskiren use including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with Aliskiren compared with 0.5% with placebo. In a long term active control study with Aliskiren and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms.
- Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age  65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2.0-2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation.
- Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the Aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms.
- Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with Aliskiren in the clinical trials. One of these patients did have predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures (for the other patient EEG and imaging results were not reported). Aliskiren was discontinued and there was no re-challenge.
- Other adverse effects with increased rates for Aliskiren compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%) and renal stones (0.2% vs. 0%).
- Aliskirens effect on ECG intervals was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12 lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen.

### Clinical Laboratory Findings
- In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Aliskiren in patients with hypertension not concomitantly treated with an ARB or ACEI. In multiple-dose studies in hypertensive patients, Aliskiren had no clinically important effects on total cholesterol, HDL, fasting triglycerides, or fasting glucose.
- In patients with hypertension not concomitantly treated with an ARB or ACEI, minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 7% of patients treated with Aliskiren alone vs. 6% on placebo.
- Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.08 g/dL and 0.16 volume percent, respectively, for all aliskiren monotherapy) were observed. The decreases were dose-related and were 0.24 g/dL and 0.79 volume percent for 600 mg daily. This effect is also seen with other agents acting on the renin angiotensin system, such as angiotensin inhibitors and angiotensin receptor blockers and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT1 receptor. These decreases led to slight increases in rates of anemia with aliskiren compared to placebo were observed (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, vs 0% for placebo). No patients discontinued therapy due to anemia.
- In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium >5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo).
- Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 mol/L) while HCTZ produced larger increases (about 30 mol/L). The combination of aliskiren with HCTZ appears to be additive (about 40 mol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% vs 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs 0%).
- Increases in creatine kinase of >300% were recorded in about 1% of aliskiren monotherapy patients vs. 0.5% of placebo patients. Five cases of creatine kinase rises, three leading to discontinuation and one diagnosed as subclinical rhabdomyolysis, and another as myositis, were reported as adverse events with aliskiren use in the clinical trials. No cases were associated with renal dysfunction.

## Postmarketing Experience
- The following adverse reactions have been reported in aliskiren post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
- Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization
- Urticaria
- Peripheral edema
- Hepatic enzyme increase with clinical symptoms of hepatic dysfunction
- Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis
- Pruritus
- Erythema

# Drug Interactions
- 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aliskiren in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Aliskiren during labor and delivery.

### Nursing Mothers
- 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.

### 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.

### Gender
There is no FDA guidance on the use of Aliskiren with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Aliskiren with respect to specific racial populations.

### Renal Impairment
- Safety and effectiveness of Aliskiren in patients with severe renal impairment (CrCl <30 ml/min) have not been established as patients with eGFR <30ml/min were excluded in clinical trials.

### Hepatic Impairment
There is no FDA guidance on the use of Aliskiren in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aliskiren in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Aliskiren in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- Monitor renal function periodically in patients treated with Aliskiren.
- Monitor serum potassium periodically in patients receiving Aliskiren.
- 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.
- Oral co-administration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is co-administered with aliskiren.

# IV Compatibility
There is limited information regarding IV Compatibility of Aliskiren in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension.

### Management
- If symptomatic hypotension occurs, supportive treatment should be initiated.
- Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Aliskiren in the drug label.

# Pharmacology

## 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 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.

## Structure
- Aliskiren contains aliskiren hemifumarate, a renin inhibitor, that is provided as tablets for oral administration. Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8--octanamide hemifumarate and its structural formula is:
- 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.

## Pharmacodynamics
- In placebo controlled clinical trials, plasma renin activity (PRA) was decreased in a range of 5080%. This reduction in PRA was not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

## Pharmacokinetics
- 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.
- 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.
- 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 CYP3A4. 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 this transporter.
- The effect of co-administered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on aliskiren) and Figure 2 (impact of aliskiren on co-administered drugs).
- Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.
- Furosemide: In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day.
- Renally Impaired Patients
- Aliskiren was evaluated in patients with varying degrees of renal insufficiency. The rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients. The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis was not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis.
- Hepatically Impaired Patients
- The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, adjustment of the starting dose is not required in these patients.
- Pediatric Patients
- The pharmacokinetics of aliskiren have not been investigated in patients <18 years of age.
- Geriatric Patients
- Exposure (measured by AUC) is increased in elderly patients 65 years. Adjustment of the starting dose is not required in these patients.
- Race
- The pharmacokinetic differences between Blacks, Caucasians, and the Japanese are minimal.

## Nonclinical Toxicology
- Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 mg/kg/day in both species, with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies.
- Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay.
- Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the maximum recommended human dose of 300 mg Aliskiren/60 kg on a mg/m2 basis.)
- Reproductive Toxicology Studies: Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose (MRHD) of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits.

# Clinical Studies
- The antihypertensive effects of Aliskiren have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 1.
- The studies included approximately 2,730 patients given doses of 75-600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increases at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9.
- Patients in the placebo-controlled trials continued open-label aliskiren for up to one year. A persistent blood pressure lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy.
- Aliskiren lowered blood pressure in all demographic subgroups, although Black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs.
- There are no studies of Aliskiren or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.
Hydrochlorothiazide
- Aliskiren 75, 150, and 300 mg and hydrochlorothiazide 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 2.
Valsartan
- Aliskiren 150 and 300 mg and valsartan 160 and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 and 160 mg, respectively, and increased at four weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3.
Amlodipine
- Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4.
ACE inhibitors
- Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction.
- Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month. After a median follow up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the table below.
- The risk of stroke (3.4% aliskiren vs 2.7% placebo) and death (8.4% aliskiren vs. 8.0% placebo) were also numerically higher in aliskiren treated patients.

# How Supplied
- Aliskiren 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.
- All strengths are packaged in bottles and unit-dose blister packages (10 strips or 10 tablets) as described below in Table 6.
- Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) . Protect from moisture.
- Dispense in original container.

## Storage
There is limited information regarding Aliskiren Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Pregnancy
- Female patients of child bearing age should be told about the consequences of exposure to Aliskiren during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
- Anaphylactic Reactions and Angioedema
- Patients should be advised and told to report immediately any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physicians. Angioedema, including laryngeal edema, may occur at any time during treatment with Aliskiren.
- Symptomatic Hypotension
- A patient receiving Aliskiren should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, Aliskiren should be discontinued until the physician has been consulted.
- All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Potassium Supplements
- A patient receiving Aliskiren should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
- Relationship to Meals
- Patients should establish a routine pattern for taking Aliskiren with regard to meals. High-fat meals decrease absorption substantially.

# Precautions with Alcohol
- Alcohol-Aliskiren interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Tekturna

# Look-Alike Drug Names
- N/A

# Drug Shortage Status

# Price