Fetal/Neonatal Morbidity and Mortality
Valturna can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.
Drugs that act directly on the renin-angiotensin-aldosterone system can cause
fetal and neonatal morbidity and death when administered to pregnant women.
If this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, apprise the patient of the potential hazard to the fetus [see
Use In Specific Populations]. In several dozen published cases, use of
ACE inhibitors during the second and third trimesters of pregnancy was associated
with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. In addition, first
trimester use of ACE inhibitors has been associated with birth defects in retrospective
data.
Head and Neck Angioedema
Aliskiren
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has 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. 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 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 angioedema and do not readminister.
Hypotension
An excessive fall in blood pressure (hypotension) was rarely seen ( < 0.5%) in patients with uncomplicated hypertension treated with Valturna in controlled trials.
In patients with an activated renin-angiotensin-aldosterone system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving renin-angiotensin-aldosterone system (RAAS) blockers. Correct these conditions prior to the administration of Valturna, or start the treatment under close medical supervision.
Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
If an excessive fall in blood pressure occurs with Valturna, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Patients with Severe Renal Impairment
Valturna
Patients with severe renal impairment were excluded from clinical trials with Valturna in hypertension.
Aliskiren
Patients with severe 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 aliskiren in hypertension. Safety information with aliskiren and the potential for other drugs acting on the renin-angiotensin-aldosterone system to increase serum creatinine and blood urea nitrogen are not available.
Valsartan
In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 hypertensive patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may occur particularly in volume depleted patients. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure or death. Similar outcomes have been reported with valsartan.
Patients with Hepatic Impairment
Valsartan
As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs).
Patients with Congestive Heart Failure and Post-Myocardial Infarction
Valsartan
Some patients with heart failure have developed increases in blood urea nitrogen, serum creatinine, and potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required. In the Valsartan Heart Failure Trial, in which 93% of patients were on concomitant ACE inhibitors, treatment was discontinued for elevations in creatinine or potassium (total of 1.0% on valsartan vs. 0.2% on placebo). In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), discontinuation due to various types of renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. Include assessment of renal function when evaluating patients with heart failure or post-myocardial infarction.
Serum Electrolyte Abnormalities
Valturna
In the short-term controlled trials of various doses of Valturna, the incidence of hyperkalemia (serum potassium > 5.5 mEq/L) was about l%-2% higher in the combination treatment group compared with the monotherapies aliskiren and valsartan, or with placebo.
In a long-term, uncontrolled study with median treatment duration of about
one year, about 4% of the patients had at least one serum potassium > 5.5
mEq/L at some time during the study; about 0.8% of patients discontinued study
treatment and had a high serum potassium at some point during the study. Patients
with hyperkalemia were older (median age 65 vs. 55) with slightly lower mean
baseline estimated creatinine clearance compared to patients without hyperkalemia.
While about 25% of the hyperkalemic episodes occurred in the first two months,
other initial episodes were reported throughout the study.
Periodic determinations of serum electrolytes to detect possible electrolyte imbalances is advised, particularly in patients at risk for hyperkalemia such as those with renal impairment.
Caution is advised with concomitant use of Valturna with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium.
Renal Artery Stenosis
Aliskiren
No data are available on the use of aliskiren in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Valsartan
In studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 hypertensive patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.
Cyclosporine or Itraconazole
Aliskiren
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 [See DRUG INTERACTIONS].
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION)
Healthcare professionals should instruct their patients to read the Patient Package Insert before starting Valturna and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
Pregnancy
Tell female patients of childbearing age about the consequences of exposure to drugs that act on the renin-angiotensin-aldosterone system. Discuss other treatment options with female patients planning to become pregnant. Ask these patients to report pregnancies to their physicians as soon as possible.
Symptomatic Hypotension
Caution patients receiving Valturna that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell the patients that if syncope occurs, discontinue Valturna until the physician has been consulted.
Caution all patients 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
Tell patients receiving Valturna 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 Valturna with regard to meals. High-fat meals decrease absorption substantially.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Valturna
No carcinogenicity, mutagenicity or fertility studies have been conducted for Valturna alone as these studies have been conducted for each individual component. Valturna has been studied in 2- and 13-week toxicity studies and was generally well-tolerated. Findings were primarily attributable to the exaggerated pharmacological effects of each component.
Aliskiren
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 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 Tekturna/60 kg on a mg/m2
basis).
Valsartan
There was no evidence of carcinogenicity when valsartan was administered in
the diet to mice and rats for up to 2 years at concentrations calculated to
provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice
and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on
a mg/m2 basis. (Calculations based on a 60 kg patient.)
Mutagenicity assays did not reveal any valsartan-related effects at either
the gene or chromosome level. These assays included bacterial mutagenicity tests
with Salmonella and E. coli, a gene mutation test with Chinese
hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and
a rat micronucleus test.
Use In Specific Populations
Pregnancy
Pregnancy Category D [See WARNINGS AND PRECAUTIONS.].
Valturna contains both aliskiren (a direct renin inhibitor) and valsartan (an angiotensin II receptor blocker). When administered during the second or third trimester of pregnancy, drugs that act directly on the renin-angiotensin-aldosterone system can cause fetal and neonatal morbidity and death. Valturna can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.
Angiotensin II receptor antagonists, like valsartan, and angiotensin-converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin-aldosterone system. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios was also reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also 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-aldosterone system, has been associated with a potential risk of birth defects in retrospective data.
When pregnancy occurs in a patient using Valturna, discontinue Valturna treatment as soon as possible. Inform the patient about potential risks to the fetus based on the time of gestational exposure to Valturna (first trimester only or later). If exposure occurs beyond the first trimester, perform an ultrasound examination.
In rare cases when another antihypertensive agent cannot be used to treat the
pregnant patient, perform serial ultrasound examinations to assess the intraamniotic
environment. Routine fetal testing with non-stress tests, biophysical profiles,
and/or contraction stress tests may be appropriate based on gestational age
and standards of care in the community. If oligohydramnios occurs in these situations,
individualized decisions about continuing or discontinuing Valturna treatment
and about pregnancy management should be made by the patient, her physician,
and experts in the management of high risk pregnancy. Patients and physicians
should be aware that oligohydramnios may not appear until after the fetus has
sustained irreversible injury.
Closely observe infants with histories of in utero exposure to Valturna
for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these infants
may require blood pressure and renal perfusion support. Exchange transfusion
or dialysis may be required to reverse hypotension or support decreased renal
function.
No reproductive toxicity studies have been conducted with the combination of
aliskiren and valsartan. However, these studies have been conducted for aliskiren
as well as valsartan alone [See Nonclinical Toxicology].
Nursing Mothers
It is not known whether aliskiren is excreted in human milk, but aliskiren was secreted in the milk of lactating rats. It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. 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 Valturna in pediatric patients have not been established.
Geriatric Use
In the short-term controlled clinical trials of Valturna, 99 (15.9%) patients treated with Valturna were ≥ 65 years and 14 (2.2%) were ≥ 75 years.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and 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.
Last reviewed on RxList: 10/31/2011
This monograph has been modified to include the generic and brand name in many instances.