Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, Tekturna® (aliskiren) should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
In addition, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin system, has been associated with a potential risk of birth defects in retrospective data. Healthcare professionals that prescribe drugs acting directly on the renin-angiotensin system should counsel women of childbearing potential about the potential risks of these agents during pregnancy.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, Tekturna should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in-utero exposure to a renin inhibitor should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
There is no clinical experience with the use of Tekturna in pregnant women. 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 (seven 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.
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren. This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients, but whether angioedema rates are higher in Blacks with aliskiren is not known. Tekturna should be promptly discontinued and appropriate therapy and monitoring provided until complete and sustained resolution of signs and symptoms has occurred. Experience with ACE inhibitors indicates that even in those instances where only swelling of the tongue is seen initially, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Very rarely, fatalities have been reported in patients with angioedema associated with laryngeal edema or tongue edema with ACE inhibitors. Patients with involvement of the tongue, glottis or larynx are more likely to experience airway obstruction, especially those with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures necessary to ensure a patent airway should be promptly provided (see ADVERSE REACTIONS).
An excessive fall in blood pressure was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Tekturna alone. Hypotension was also infrequent during combination therapy with other antihypertensive agents (<1%). In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those receiving high doses of diuretics), symptomatic hypotension could occur after initiation of treatment with Tekturna. This condition should be corrected prior to administration of Tekturna, or the treatment should start under close medical supervision.
If an excessive fall in blood pressure occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (see DOSAGE AND ADMINISTRATION). 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 Functio n
Patients with greater than moderate renal dysfunction (creatinine 1.7 mg/dL for women and 2.0 mg/dL for men and/or estimated GFR <30 mL/min), a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of Tekturna® (aliskiren) in hypertension. Caution should be exercised in these patients because of the paucity of safety information with Tekturna in these patients and the potential for other drugs acting on the renin-angiotensin system to increase serum creatinine and blood urea nitrogen.
Increases in serum potassium >5.5 meq/L were infrequent with Tekturna alone (0.9% compared to 0.6% with placebo). However, when used in combination with an ACE inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%). Routine monitoring of electrolytes and renal function is indicated in this population. Concomitant use of Tekturna with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium. If concomitant use is considered necessary, caution should be exercised.
Renal Artery Stenosis
No data are available on the use of Tekturna in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Information for Patients
Female patients of childbearing age should be told about the consequences of exposure to drugs that act on the renin-angiotensin system. Discuss other treatment options with female patients planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Angioedema, including laryngeal edema, may occur at any time during treatment with Tekturna. Patients should be so advised and told to report immediately any signs or symptoms suggesting 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 physician.
Patients should report any medications they take with aliskiren.
When aliskiren was given with furosemide, the blood concentrations of furosemide were reduced significantly. Patients receiving furosemide could find its effect diminished after starting aliskiren.
When aliskiren was given with cyclosporine, the blood concentrations of aliskiren were significantly increased. Concomitant use of aliskiren with cyclosporine is not recommended.
Carcinogenesis/Mutagenesis/Impairment of Fertilit y
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 or more 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 is 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 oral 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 Tekturna/60 kg on a mg/m2 basis.
Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).
It is not known whether aliskiren is excreted in human 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.
Safety and effectiveness of aliskiren in pediatric patients have not been established.
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. Blood pressure responses and adverse effects were generally similar to those in younger patients.