Aliskiren Drug Information

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.

Relationship to Meals Patients should establish a routine pattern for taking Aliskiren

with regard to meals. High-fat meals decrease absorption substantially.

Clinical Trials Experience

The following serious adverse reactions are discussed in greater detail in other sections of the label: Fetal Toxicity Anaphylactic Reactions and Head and Neck Angioedema Hypotension 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. Adult Hypertension 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 versus 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. Angioedema: 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 hydrochlorothiazide (HCTZ) arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms.

Gastrointestinal: 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 years and older) 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% to 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. Cough: Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any Aliskiren use versus 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. Seizures: Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 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 rechallenge. Other adverse effects with increased rates for Aliskiren compared to placebo included rash (1% versus 0.3%), elevated uric acid (0.4% versus 0.1%), gout (0.2% versus 0.1%) and renal stones (0.2% versus 0%). Aliskiren's 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.

Pediatric Hypertension Aliskiren has been evaluated for safety in 267 pediatric hypertensive patients 6 to 17 years of age; including 208 patients treated for 52 weeks . These studies did not reveal any unanticipated adverse reactions. Adverse reactions in pediatric patients 6 years of age and older are expected to be similar to those seen in adults. 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.

Blood Urea Nitrogen, Creatinine : 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 versus 6% on placebo . Hemoglobin and Hematocrit : 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 ARBs, 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, versus 0% for placebo). No patients discontinued therapy due to anemia. Serum Potassium : In patients with hypertension not concomitantly treated with an ARB or ACEI, increases in serum potassium greater than 5.5 mEq/L were infrequent (0.9% compared to 0.6% with placebo) . Serum Uric Acid : Aliskiren monotherapy produced small median increases in serum uric acid levels (about 6 micromol/L) while HCTZ produced larger increases (about 30 micromol/L). The combination of aliskiren with HCTZ appears to be additive (about 40 micromol/L increase). The increases in uric acid appear to lead to slight increases in uric acid-related AEs: elevated uric acid (0.4% versus 0.1%), gout (0.2% versus 0.1%), and renal stones (0.2% versus 0%). Creatine Kinase : Increases in creatine kinase of greater than 300% were recorded in about 1% of aliskiren monotherapy patients versus 0.5% of placebo patients. Five cases of creatine kinase rises, 3 leading to discontinuation and 1 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 postmarketing 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 Hyponatremia Nausea, Vomiting

• Cyclosporine: Avoid coadministration of cyclosporine with aliskiren .
• Itraconazole: Avoid coadministration of itraconazole with aliskiren. Nonsteroidal Anti-Inflammatory Drugs (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, coadministration of NSAIDs, including selective COX-2 inhibitors with agents that affect the RAAS, 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 (RAAS): The concomitant use of aliskiren with other agents acting on the RAAS 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. Most patients receiving the combination of two drugs that inhibit the renin-angiotensin system do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min. Monitor blood pressure, renal function, and electrolytes in patients taking aliskiren and other agents that affect the RAAS. The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated.
• Furosemide: Oral coadministration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is coadministered with aliskiren.
• Cyclosporine or Itraconazole: Avoid concomitant use.
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Increased risk of renal impairment and loss of antihypertensive effect.

Pregnancy Risk Summary Aliskiren can cause fetal harm when administered to a pregnant woman. 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 . 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. When pregnancy is detected, discontinue Aliskiren as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15- 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death.

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. In patients taking Aliskiren during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.

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. If oliguria or hypotension occur in neonates with a history of in utero exposure to aliskiren, support blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function. Data Animal Data In developmental toxicity studies, pregnant rats and rabbits received oral aliskiren hemifumarate during organogenesis at doses up to 20 and 7 times the maximum recommended human dose (MRHD) based on body surface area (mg/m 2 ), respectively, in rats and rabbits. (Actual animal doses were up to 600 mg/kg/day in rats and up to 100 mg/kg/day in rabbits.) No teratogenicity was observed; however, fetal birth weight was decreased in rabbits at doses 3.2 times the MRHD based on body surface area (mg/m 2 ). Aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits.

Pediatric Use Aliskiren is contraindicated in patients less than 2 years of age. Aliskiren is indicated for treatment of hypertension in pediatric patients 6 years of age and older weighing 50 kg or more. The safety and effectiveness of aliskiren have been established in pediatric patients 6 years of age and older weighing 20 kg or more, but Aliskiren is not approved in patients 6 years of age and older weighing 20 kg to less than 50 kg because of the lack of an appropriate dosage form.

Use of Aliskiren in pediatric patients 6 years and older is supported by evidence from a pharmacokinetic trial and two randomized, double-blind clinical trials in pediatric patients with hypertension 6 years to 17 years of age weighing 20 kg or more. The safety and effectiveness of Aliskiren have not been established in pediatric patients younger than 6 years of age and patients less than 20 kg. Avoid use in patients 2 years to less than 6 years and patients weighing less than 20 kg due to the limited information about aliskiren metabolism and exposures in this age group.

No data are available in pediatric patients weighing less than 20 kg or in pediatric patients with a glomerular filtration rate <30 mL/min/1.73 m 2. Juvenile Animal Toxicity Data Toxicology studies in juvenile animals the approximate human age equivalent of children less than 2 years of age identified 85- to 385-fold increased systemic exposure to aliskiren compared to adult rats. The increased aliskiren exposure in juvenile rats was attributed to immaturity in aliskiren drug transporters and metabolizing enzymes. Increased aliskiren exposures were associated with premature deaths.

Although a definitive pathology-based cause of death could not be ascertained, the premature deaths were attributed to the immaturity in aliskiren metabolism. The nonclinical findings suggest a distinct age-dependent relationship between dose and exposure. 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.

Do not use Aliskiren with ARBs or ACEIs in patients with diabetes. Aliskiren is contraindicated in patients with known hypersensitivity to any of the components. 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.

Do not use with angiotensin receptor blockers (ARBs) or angiotensin- converting enzyme inhibitors (ACEIs) in patients with diabetes. Hypersensitivity to any of the components. Aliskiren is contraindicated in pediatric patients less than 2 years of age.

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.

Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure .