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 [s
ee Warnings and Precautions]
- Head and neck angioedema [s
ee Warnings and Precautions]
- Hypotension [s
ee 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%).
Hyperkalemia has been observed as a serum electrolyte abnormality in Valturna clinical trials [see Warnings and Precautions].
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.
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.
Other adverse reactions with increased rates for aliskiren compared to placebo included rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs. 0%).
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.
The following adverse events occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with aliskiren, but also occurred at about the same or greater incidence in patients receiving placebo: headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain and cough.
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:
Body as a Whole:
allergic reaction, asthenia
Musculoskeletal: muscle cramps
Neurologic and Psychiatric: paresthesia
Respiratory: sinusitis, pharyngitis
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)/
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.
Post-M arketing Experience
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
Blood creatinine increased