Fetal/Neonatal Morbidity and Mortality:The product information for aliskiren contains a Black Box Warning for use in pregnancy. Administration of medications that act at the RAAS during pregnancy has resulted in neonatal morbidity and mortality; therefore, aliskiren should be discontinued as soon as possible after a patient becomes pregnant. In patients where medications that affect the RAAS have been administered during the second or third trimester of pregnancy, hypotension, neonatal skull hypoplasia, anuria, kidney failure (reversible or irreversible), and death have occurred in the fetus. Deficiency in the amount of amniotic fluid (i.e., oligohydramnios) has been reported and was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Although not clear if related to the medication, premature birth, intrauterine growth retardation, and patent ductus arteriosus have been reported. In addition, data from an observational study in pregnant women receiving an ACEI in the first trimester reported an increase in the rate of fetal abnormalities compared to infants not exposed to ACEIs or other antihypertensive agents throughout pregnancy (refer to http://www.pbm.va.gov/ezminutes/EZ-MinutesApr-June06.pdf). Patients receiving aliskiren should be instructed to discontinue the medication as soon as possible, and an alternative medication considered. Studies of aliskiren in pregnant rats did not appear to have an adverse effect on the fetus at daily doses up to 600 mg/kg (20 times the maximum recommended human dose), or in pregnant rabbits at daily doses up to 100 mg/kg (7 times the maximum recommended human dose). At daily doses of 50 mg/kg, there was an adverse effect on birth weight in pregnant rabbits. Aliskiren was also reported to be present in the placenta, amniotic fluid, and fetuses of pregnant rabbits. Aliskiren has not been studied in pregnant women.
Angioedema: Angioedema (occurring in the face, lips, tongue, glottis and/or larynx, and extremities) has been reported in patients receiving treatment with aliskiren. It is unknown if the incidence of angioedema occurs more frequently in African American patients as has been seen with the ACEIs. Angioedema occurring in the tongue and glottis/larynx require prompt attention as there is a higher likelihood of airway obstruction.
Hypotension: Symptomatic hypotension may occur in patients who may be sodium or volume depleted (e.g., in patients receiving diuretic therapy) upon initial therapy with aliskiren. It is recommended to correct the volume depletion prior to starting aliskiren, otherwise therapy should be initiated under close medical supervision. Significant hypotension has been reported in 0.1% of patients with essential HTN receiving monotherapy with aliskiren, and in < 1% of patients on aliskiren in combination with other antihypertensive medications. Transient hypotension may occur and is not considered a contraindication to therapy with aliskiren.
Precautions1,2 Impaired Kidney Function: Aliskiren should be used with caution in the following patients: those with greater than moderate kidney dysfunction (defined as serum creatinine > 1.7 mg/dL for women and > 2.0 mg/dL for men, or estimated GFR < 30 mL/min), on dialysis, with a history of nephrotic syndrome or renovascular HTN; as these patients were not included in the clinical trials with aliskiren.
Hyperkalemia: Patients with DM receiving therapy with an ACEI are more likely to experience an increase in potassium levels when receiving concomitant aliskiren. It is recommended that electrolytes and kidney function be routinely monitored in this patient population.
Carcinogenesis, Mutagenesis, Fertility Impairment: Oral doses of aliskiren of up to 1500 mg/kg/day were studied in rats (4 times the maximum recommended human dose for 2 years) and mice (1.5 times the maximum recommended human dose for 6 months). In both species, mucosal epithelial hyperplasia was seen in the lower gastrointestinal tract at dose up to 750 mg/kg/day. A colonic adenoma was seen in one rat and a cecal adenocarcinoma in another rat; although, there was not a statistically significant increase in tumor incidence with aliskiren. Mucosal hyperplasia was also seen in the cecum or colon in rats at a dose of 250 mg/kg/day, and at higher doses in studies of 4 and 13 weeks duration. In male or female rats, fertility was not affected with aliskiren at doses of up to 8 times the maximum recommended dose in humans.
Pregnancy: Aliskiren is Pregnancy Category C for the first trimester and Category D for the second and third trimesters (see Warnings).
Nursing Mothers: It is unknown if aliskiren is excreted in human milk. The drug has been detected in the milk of lactating rats. Due to the potential for adverse effects in the infant, it is recommended that a decision be made to either discontinue nursing or the medication after consideration of the risk vs. benefit of the drug for the mother.
Drug Interactions: It has been reported that the blood concentrations of furosemide are significantly reduced when given in combination with aliskiren; therefore, the clinical effects of furosemide may be decreased after initiation of aliskiren.
Patient Information:Pregnancy: Women of child-bearing potential should be informed of the risks to the fetus with administration of medications that act at the RAAS during the second and third trimesters (although not apparent in patients where the use was limited to the first trimester), and should be instructed to inform their provider immediately when pregnancy is detected. Angioedema: Patients should be informed of the risk for angioedema at any time during treatment with aliskiren, and to immediately report any signs of swelling in the face, tongue, lips, or extremities, or any difficulty breathing or swallowing.
Demographics (Age):According to the manufacturer, the AUC of aliskiren is increased in older patients (pharmacokinetics studied in patients > 65 years of age); although, dose adjustment is not necessary in this patient population. In clinical trials, 19% of patients studied were > 65 years of age, with 3.4% > 75 years of age. Safety and efficacy were reported to be similar in these patients as in younger patients. Aliskiren has not been studied in pediatric patients.
Drug Interactions1,2 Aliskiren is metabolized by cytochrome (CYP) 3A4. Aliskiren does not inhibit CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor does it induce CYP 3A4. Repeated concomitant administration of irbesartan decreased Cmax aliskiren up to 50%. The Cmax and AUC of aliskiren were increased approximately 50% in patients receiving multiple concomitant doses of artorvastatin. Concomitant administration of ketoconazole 200 mg twice daily increased plasma levels of aliskiren by approximately 80%. The manufacturer reports a decrease in Cmax (~50%) and in AUC (~30%) of furosemide when administered in combination with aliskiren. There was not a clinically significant increase in aliskiren exposure or a significant effect on the pharmacokinetics of the following medications during concomitant administration: amlodipine, atenolol, celecoxib, digoxin, furosemide, hydrochlorothiazide, metformin, ramipril, or valsartan. There was not a significant increase in aliskiren with concomitant administration of warfarin, although the manufacturer states that the effect of aliskiren on the pharmacokinetics of warfarin has not been evaluated in a controlled clinical trial.