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Pregnancy Category D
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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Valturna as soon as possible, [see Use in Specific Populations]
Renal Impairment/Hyperkalemia/Hypotension when Valturna is used in patients with diabetes
Avoid use of Valturna in patients with moderate renal impairment (GFR <60 ml/min).
Head and Neck Angioedema
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.
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.
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 Function
Monitor renal function periodically in patients treated with Valturna. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or non-steroidal anti-inflammatory (NSAID) therapy may be at particular risk for developing acute renal failure on Valturna [see CONTRAINDICATIONS, WARNINGS, Clinical Trials]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.
Patients with Hepatic Impairment
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
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
Monitor serum potassium periodically in patients receiving Valturna. Drugs that affect the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes [see CONTRAINDICATIONS, WARNINGS, and Clinical Trials], NSAIDs, potassium supplements or potassium sparing diuretics.
In the short-term controlled trials of various doses of Valturna, in patients without renal insufficiency 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.
Cyclosporine or Itraconazole
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.
Female patients of childbearing age should be told about the consequences of exposure to Valturna during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
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.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
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).
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 Category D
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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Valturna as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
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. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Valturna, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. 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 Valturna for hypotension, oliguria, and hyperkalemia.
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].
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.
Safety and effectiveness of Valturna in pediatric patients have not been established.
Neonates with a history of in utero exposure to Valturna: 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.
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.
Safety and effectiveness of aliskiren in patients with severe renal impairment (CrCL <30 ml/min) have not been established as patients with eGFR <30ml/min were excluded in clinical trials [see WARNINGS, Clinical Trials].
Last reviewed on RxList: 5/7/2012
This monograph has been modified to include the generic and brand name in many instances.
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