ADVERSE REACTIONS
Exforge
Exforge® (amlodipine and valsartan) has been evaluated for safety in over 2,600 patients with hypertension; over 1,440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse experiences 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 Exforge-treated 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 experiences 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=1,437 ) 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 experiences 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 L ymphatic S ystem D isorders : Lymphadenopathy
Cardiac D isorders : Palpitations, tachycardia
Ear and L abyrinth D isorders : Ear pain
Gastrointestinal D isorders : Diarrhea, nausea, constipation, dyspepsia, abdominal pain, abdominal pain upper, gastritis, vomiting, abdominal discomfort, hemorrhoids, abdominal distention, dry mouth, flatulence, toothache, colitis
General D isorders and A dministration S ite C onditions : Fatigue, chest pain, asthenia, pitting edema, pyrexia, edema, pain
Immune S ystem D isorders : seasonal allergies
Infections and I nfestations : Nasopharyngitis, sinusitis, influenza, bronchitis, pharyngitis, urinary tract infection, gastroenteritis, pharyngotonsillitis, bronchitis acute, viral infection, tonsillitis, tooth abscess, cystitis, pneumonia
Injury, P oisoning and P rocedural C omplications : Contusion, epicondylitis, joint sprain, limb injury, post procedural pain
Investigations : Cardiac murmur
Metabolism and N utrition D isorders : Gout, non-insulin dependent diabetes mellitus, hypercholesterolemia
Musculoskeletal and C onnective T issue D isorders : Arthralgia, back pain, muscle spasms, pain in extremity, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain
Nervous S ystem D isorders : Headache, sciatica, parasthesia, cerviocobrachial syndrome, carpal tunnel syndrome, hypoaesthesia, sinus headache, somnolence
Psychiatric D isorders : Insomnia, anxiety, depression
Renal and U rinary D isorders : Hematuria, nephrolithiasis, pollakiuria
Reproductive S ystem and B reast D isorders : Erectile dysfunction
Respiratory, T horacic and M ediastinal D isorders : Cough, pharyngolaryngeal pain, sinus congestion, dyspnea, epistaxis, productive cough, dysphonia, nasal congestion
Skin and S ubcutaneous T issue D isorders : Pruritus, rash, hyperhidrosis, eczema, erythema
Vascular D isorders : Flushing, hot flush
Isolated cases of the following clinically notable adverse events were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension.
Amlodipine
Norvasc® has been evaluated for safety in more than 11,000 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 S ystem : micturation frequency, micturation 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®.
Post-Marketing Experience
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
Diovan® has been evaluated for safety in more than 4,000 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 events, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:
Body as a W hole: allergic reaction, asthenia
Musculoskeletal : muscle cramps
Neurologic and P sychiatric: paresthesia
Respiratory: sinusitis, pharyngitis
Urogenital: Impotence
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.
Post-Marketing Experience
The following additional adverse events have been reported in post-marketing experience with valsartan:
Blood and Lymphatic: There are very rare reports of thrombocytopenia.
Hypersensitivity : There are rare reports of angioedema.
Digestive : Elevated liver enzymes and very rare reports of hepatitis
Renal : Impaired renal function
Clinical Laboratory Tests : Hyperkalemia
Dermatologic : Alopecia
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
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