Clinical Studies Experience: Since clinical studies are conducted under widely varying conditions, adverse reactions rates reported 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.
Adult Hypertension: Safety evaluation of valsartan has been reported for more than 4000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions were reportedly mild and transient in nature and only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan was reported to be similar to placebo.
The overall frequency of adverse reactions was reported to be neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was reported in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with valsartan were headache and dizziness.
The adverse reactions reported placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan than placebo patients included viral infection, fatigue, and abdominal pain.
Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia reported at a more than 1% rate but at about the same incidence in placebo and valsartan patients.
In reported trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was reported to be significantly greater in the ACE-inhibitor group than in the groups who received valsartan or placebo. In a reported study 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).
Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness has been reported in patients treated with valsartan 320 mg as compared to 10 to 160 mg.
Valsartan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.
Other adverse reactions that occurred in reported controlled clinical trials of patients treated with valsartan (>0.2%) are listed as follows. It cannot be determined whether these events were causally related to valsartan.
Body as a Whole: Allergic reaction and asthenia.
Dermatologic: Pruritus and rash.
Digestive: Constipation, dry mouth, dyspepsia, and flatulence.
Musculoskeletal: Back pain, muscle cramps, and myalgia.
Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence.
Special Senses: Vertigo.
Other reported events seen less frequently in clinical studies include chest pain, syncope, anorexia, vomiting, and angioedema.
Pediatric Hypertension: With the exception of isolated gastrointestinal disorders (like abdominal pain, nausea, vomiting) and dizziness, no relevant differences in terms of type, frequency and severity of adverse reactions were identified between the safety profile for hypertensive pediatric patients aged 6 to 18 years and that previously reported for adult patients.
Valsartan has been reported for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were reported between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most commonly reported adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly reported in children with underlying renal/chronic kidney disease.
Valsartan is not recommended for pediatric patients under 6 years of age. In a study of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment liver transaminase elevations were reported in a one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant comorbidities. A causal relationship to valsartan has not been reported. In a another 1 year open-label extension randomized study involving children aged 1 to 6 years, one case of marked liver transaminase elevations was reported.
Heart Failure: The adverse experience profile of valsartan in heart failure patients is reported to be consistent with the pharmacology of the drug and the health status of the patients. In a reported clinical study, comparing valsartan in total daily doses up to 320 mg to placebo, 10% of valsartan-treated patients reportedly discontinued for adverse reactions vs. 7% of placebo-treated patients.
The table as follows shows adverse reactions in reported double-blind short-term heart failure studies, including the first 4 months of the clinical study, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients reportedly received standard drug therapy for heart failure including multiple medications, which could include diuretics, digitalis, beta-blockers, or ACE inhibitors. Majority of patients reported to have received concomitant ACE inhibitors. (See Table 1.)
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Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.
Other adverse reactions reported with a greater incidence than 1% and greater than placebo included headache NOS, nausea, renal impairment NOS, syncope, blurred vision, upper abdominal pain and vertigo (NOS = not otherwise specified).
From the long-term data in the reported clinical study, there did not appear to be any significant adverse reactions not previously identified.
Post-Myocardial Infarction: The safety profile of valsartan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table as follows shows the percentage of patients discontinued in the valsartan and captopril-treated groups in a reported clinical study with a rate of at least 0.5% in either of the treatment groups.
Discontinuations due to renal dysfunction have been reported in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. (See Table 2.)
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Post-Marketing Experience: The following additional adverse reactions have been reported in innovator's post-marketing experience: Hypersensitivity: Hypersensitivity including serum sickness has been reported. There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should not be re-administered to patients who have had angioedema.
Digestive: Elevated liver enzymes/liver function values including serum bilirubin and very rare reports of hepatitis.
Renal: Impaired renal function, renal failure and impairment.
Clinical Laboratory Tests: Hyperkalemia.
Dermatologic: Alopecia, Bullous Dermatitis.
Blood and Lymphatic: There are very rare reports of thrombocytopenia.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Since 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.
Other adverse events: reported include decrease in hemoglobin, decrease in hematocrit, neutropenia, hyponatremia, cardiac failure, orthostatic hypotension, acute renal failure and increase in blood urea nitrogen.