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Valturna (Aliskiren Hemifumarate / Valsartan) - Warnings and Precautions

 
 



WARNING: AVOID USE IN PREGNANCY  

When pregnancy is detected, discontinue Valturna   as soon as possible. When used in pregnancy during the second and third trimesters, d rugs that act directly on the renin-angiotensin - aldosterone system can cause injury and death to the developing fetus.   [ See Warnings and Precautions (5.1) ] .

 

  WARNINGS AND PRECAUTIONS

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 Abnormalitie s

Valturna

In the short-term controlled trials of various doses of Valturna, the incidence of hyperkalemia (serum potassium >5.5 mEq/L) was about 1%-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. Concomitant use of aliskiren with cyclosporine or itraconazole is not recommended [see Drug Interactions].

  USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D   [s ee Warnings and Precautions (5.1) ].

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.

Page last updated: 2010-08-01

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