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Clinical Studies Experience
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Risk of fetal/neonatal morbidity and mortality [See WARNINGS AND PRECAUTIONS].
- Head and neck angioedema [See WARNINGS AND PRECAUTIONS].
- Hypotension [See WARNINGS AND PRECAUTIONS].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Valturna has been evaluated for safety in more than 1,225 patients, including over 316 patients for over 1 year. In placebo-controlled clinical trials, discontinuation of therapy because of a clinical adverse event (including uncontrolled hypertension) occurred in 1.4% of patients treated with Valturna versus 2.7% of patients given placebo.
Adverse events in placebo-controlled trials that occurred in at least 1% of patients treated with Valturna and at a higher incidence than placebo included fatigue (2.6% vs. 1.4%), nasopharyngitis (2.6% vs. 2.2%), diarrhea (1.4% vs 0.9%), upper respiratory tract infection (1.4% vs. 1.1%), urinary tract infection (1.4% vs. 0.6%), influenza (1.1% vs 0.2%), and vertigo (1.1% vs. 0.3%).
Aliskiren has been evaluated for safety in 6,460 patients, including 1,740 treated for longer than 6 months, and 1,250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy because of a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with aliskiren, versus 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEI [see CONTRAINDICATIONS, WARNINGS, and Clinical Trials].
Two cases of angioedema with respiratory symptoms were reported with aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%.
In addition, 26 other cases of edema involving the face, hands, or whole body were reported with aliskiren use, including 4 leading to discontinuation.
In the placebo-controlled studies, however, the incidence of edema involving the face, hands, or whole body was 0.4% with aliskiren compared with 0.5% with placebo. In a long-term active-controlled study with aliskiren and HCTZ arms, the incidence of edema involving the face, hands, or whole body was 0.4% in both treatment arms.
Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age ≥65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg similar to those seen at 300 mg for men or younger patients (all rates about 2%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation.
Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use vs. 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms.
Single episodes of tonic-clonic seizures with loss of consciousness were reported in two patients treated with aliskiren in the clinical trials. One patient had predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures; for the other patient, EEG and imaging results were not reported. Aliskiren was discontinued and there was no rechallenge in either case.
No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren.
Valsartan has been evaluated for safety in more than 4,000 hypertensive patients in clinical trials, including over 400 treated for over 6 months, and more than 160 for over 1 year.
In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129 patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p<0.001).
Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:
Musculoskeletal: muscle cramps
Neurologic and Psychiatric: paresthesia
Other reported events seen less frequently in clinical trials were: angioedema.
Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.
Clinical Laboratory Test Abnormalities
RBC count, hemoglobin and hematocrit:
Small mean decreases from baseline were seen in RBC count, hemoglobin and hematocrit in both monotherapies and combination therapy. These changes were small, but changes in hemoglobin were slightly more pronounced with the combination therapy (-0.26 g/dL) than with monotherapy regimens (-0.04 g/dL in aliskiren or -0.13 g/dL in valsartan) or placebo (+0.07 g/dL).
Blood Urea Nitrogen (BUN)/Creatinine:
In patients without renal dysfunction, elevations in BUN (>40 mg/dL) and creatinine (>2.0 mg/dL) in any treatment group were less than 1.0%. For creatinine, 0.5% (3/599) of patients on combination treatment had a creatinine level >1.5 mg/dL at the end of the study and a 30% increase from baseline compared to none in either monotherapy or placebo [see WARNINGS].
The following adverse reactions have been reported in aliskiren post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity: angioedema requiring airway management and hospitalization
Skin: Severe cutaneous adverse reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis Peripheral edema
Read the Valturna (aliskiren and valsartan, usp tablets) Side Effects Center for a complete guide to possible side effects
No drug interaction studies have been conducted with Valturna and other drugs, although studies with the individual aliskiren and valsartan components are described below.
Cyclosporine: Avoid co-administration of cyclosporine with aliskiren.
Itraconazole: Avoid co-administration of itraconazole with aliskiren [See CLINICAL PHARMACOLOGY].
No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with aliskiren, amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Warfarin: Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies have indicated that CYP450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of low extent of metabolism [see Pharmacokinetics - Valsartan].
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine.
Aliskiren and Valsartan
Non-Steroidal Anti-Inflammatory Agents(NSAIDS) including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors with agents that affect the renin-angiotensin system, including aliskiren and valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren, valsartan and NSAID therapy.
The antihypertensive effect may be attenuated by NSAIDS.
Read the Valturna Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/7/2012
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