Clinical Trials Experience
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 the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Studies with Exforge
Exforge has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The hazards [see WARNINGS AND PRECAUTIONS] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Exforgetreated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Exforge were peripheral edema (0.4%), and vertigo (0.2%).
The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with Exforge but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs. 3.0%), nasopharyngitis (4.3% vs. 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).
Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.
Other adverse reactions that occurred in placebo-controlled clinical trials with Exforge ( ≥ 0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge.
Blood and Lymphatic System Disorders: Lymphadenopathy
Cardiac Disorders: Palpitations, tachycardia
Ear and Labyrinth Disorders: Ear pain
Gastrointestinal Disorders: Diarrhea, nausea, constipation, dyspepsia, abdominal pain, abdominal pain upper, gastritis, vomiting, abdominal discomfort, abdominal distention, dry mouth, colitis
General Disorders and Administration Site Conditions: Fatigue, chest pain, asthenia, pitting edema, pyrexia, edema
Immune System Disorders: Seasonal allergies
Infections and Infestations: Nasopharyngitis, sinusitis, bronchitis, pharyngitis, gastroenteritis, pharyngotonsillitis, bronchitis acute, tonsillitis
Injury and Poisoning: Epicondylitis, joint sprain, limb injury
Metabolism and Nutrition Disorders: Gout, non-insulin-dependent diabetes mellitus, hypercholesterolemia
Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, muscle spasms, pain in extremity, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain
Nervous System Disorders: Headache, sciatica, paresthesia, cervicobrachial syndrome, carpal tunnel syndrome, hypoesthesia, sinus headache, somnolence
Psychiatric Disorders: Insomnia, anxiety, depression
Renal and Urinary Disorders: Hematuria, nephrolithiasis, pollakiuria
Reproductive System and Breast Disorders: Erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders: Cough, pharyngolaryngeal pain, sinus congestion, dyspnea, epistaxis, productive cough, dysphonia, nasal congestion
Skin and Subcutaneous Tissue Disorders: Pruritus, rash, hyperhidrosis, eczema, erythema
Vascular Disorders: Flushing, hot flush
Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension.
Studies with Amlodipine
Norvasc®* has been evaluated for safety in more than 11000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis
Central and Peripheral Nervous System: neuropathy peripheral, tremor
Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia
General: allergic reaction, hot flushes, malaise, rigors, weight gain, weight loss
Musculoskeletal System: arthrosis, muscle cramps
Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization
Respiratory System: dyspnea
Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Hemopoietic: leukopenia, purpura, thrombocytopenia
Other events reported with amlodipine at a frequency of ≤ 0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc.
Studies with Valsartan
Diovan® has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. 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 Lab Test Findings
Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 0.4% of patients receiving Exforge and 0.6% receiving placebo. In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Exforgetreated patients.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 2.8% of Exforge-treated patients compared to 3.4% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 5.5% of Exforge-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.
Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Valsartan: The following additional adverse reactions have been reported in postmarketing experience with valsartan:
Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia,
Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Exforge should not be re-administered to patients who have had angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis
Renal: Impaired renal function, renal failure
Clinical Laboratory Tests: Hyperkalemia
Dermatologic: Alopecia, bullous dermatitis
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.