Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
ATACAND has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with ATACAND was well tolerated. The overall incidence of adverse events reported with ATACAND was similar to placebo.
The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (ie, 108 of 3260) of patients treated with ATACAND as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with ATACAND and 3.4% (ie, 35 of 1027) of patients treated with placebo.
The most common reasons for discontinuation of therapy with ATACAND were headache (0.6%) and dizziness (0.3%).
The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with ATACAND and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).
The following adverse events occurred in placebo-controlled clinical trials at a more than 1% rate but at about the same or greater incidence in patients receiving placebo compared to ATACAND: fatigue, peripheral edema, chest pain, headache, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia, albuminuria.
Other potentially important adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% or greater from the 3260 patients worldwide treated in clinical trials with ATACAND are listed below. It cannot be determined whether these events were causally related to ATACAND. Body as a Whole: asthenia, fever; Central and Peripheral Nervous System: paresthesia, vertigo; Gastrointestinal System Disorder: dyspepsia, gastroenteritis; Heart Rate and Rhythm Disorders: tachycardia, palpitation; Metabolic and Nutritional Disorders: creatine phosphokinase increased, hyperglycemia, hypertriglyceridemia, hyperuricemia; Musculoskeletal System Disorders: myalgia; Platelet/Bleeding-Clotting Disorders: epistaxis; Psychiatric Disorders: anxiety, depression, somnolence; Respiratory System Disorders: dyspnea; Skin and Appendages Disorders: rash, sweating increased; Urinary System Disorders: hematuria.
Other reported events seen less frequently included angina pectoris, myocardial infarction, and angioedema.
Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.
Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded.
The adverse event profile of ATACAND in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing ATACAND in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued ATACAND for adverse events vs. 16.1% of placebo patients.
The following adverse reactions were identified during post-approval use of ATACAND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following have been very rarely reported in post-marketing experience:
Digestive: Abnormal hepatic function and hepatitis.
Hematologic: Neutropenia, leukopenia, and agranulocytosis.
Metabolic and Nutritional Disorders: hyperkalemia, hyponatremia.
Renal: renal impairment, renal failure.
Skin and Appendages Disorders: Pruritus and urticaria.
Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Laboratory Test Findings
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with the administration of ATACAND.
Creatinine, Blood Urea Nitrogen
Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed infrequently.
Hyperuricemia was rarely found (19 or 0.6% of 3260 patients treated with ATACAND and 5 or 0.5% of 1106 patients treated with placebo).
Hemoglobin and Hematocrit
Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.2 grams/dL and 0.5 volume percent, respectively) were observed in patients treated with ATACAND alone but were rarely of clinical importance. Anemia, leukopenia, and thrombocytopenia were associated with withdrawal of one patient each from clinical trials.
A small increase (mean increase of 0.1 mEq/L) was observed in patients treated with ATACAND alone but was rarely of clinical importance. One patient from a congestive heart failure trial was withdrawn for hyperkalemia (serum potassium = 7.5 mEq/L). This patient was also receiving spironolactone [see WARNINGS AND PRECAUTIONS].
Liver Function Tests
Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients assigned to ATACAND in clinical trials were withdrawn because of abnormal liver chemistries. All had elevated transaminases. Two had mildly elevated total bilirubin, but one of these patients was diagnosed with Hepatitis A.
In the CHARM program, small increases in serum creatinine (mean increase 0.2 mg/dL in candesartan-treated patients and 0.1 mg/dL in placebo-treated patients) and serum potassium (mean increase 0.15 mEq/L in ATACAND-treated patients and 0.02 mEq/L in placebo-treated patients), and small decreases in hemoglobin (mean decrease 0.5 gm/dL in ATACAND-treated patients and 0.3 gm/dL in placebo-treated patients) and hematocrit (mean decrease 1.6% in ATACAND-treated patients and 0.9% in placebo-treated patients) were observed.