6 ADVERSE REACTIONS
6.1 Clinical Trials 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 clinical practice.
In the controlled trial of Exforge HCT, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse reactions was similar between men and women, younger (<65 years) and older (> 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with Exforge HCT 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Exforge HCT were dizziness (1.0%) and hypotension (0.7%).
The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with Exforge HCT are presented in the table below:
| Preferred term | Aml/Val/HCTZ
10/320/25 mg
N=582
n (%) | Val/HCTZ
320/25 mg
N=559
n (%) | Aml/Val
10/320 mg
N=566
n (%) | HCTZ/Aml
25/10 mg
N=561
n (%) |
| Dizziness | 48 (8.2) | 40 (7.2) | 14 (2.5) | 23 (4.1) |
| Edema | 38 (6.5) | 8 (1.4) | 65 (11.5 ) | 63 (11.2) |
| Headache | 30 (5.2) | 31 (5.5) | 30 (5.3) | 40 (7.1) |
| Dyspepsia | 13 (2.2) | 5 (0.9) | 6 (1.1) | 2 (0.4) |
| Fatigue | 13 (2.2) | 15 (2.7) | 12 (2.1) | 8 (1.4) |
| Muscle spasms | 13 (2.2) | 7 (1.3) | 7 (1.2) | 5 (0.9) |
| Back pain | 12 (2.1) | 13 (2.3) | 5 (0.9) | 12 (2.1) |
| Nausea | 12 (2.1) | 7 (1.3) | 10 (1.8) | 12 (2.1) |
| Nasopharyngitis | 12 (2.1) | 13 (2.3) | 13 (2.3) | 12 (2.1) |
Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Other adverse reactions that occurred in clinical trials with Exforge HCT (>0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge HCT.
Cardiac Disorders: tachycardia
Ear and Labyrinth Disorders: vertigo, tinnitus
Eye Disorders: vision blurred
Gastrointestinal Disorders: diarrhea, abdominal pain upper, vomiting, abdominal pain, toothache, dry mouth, gastritis, hemorrhoids
General Disorders and Administration Site Conditions: asthenia, non-cardiac chest pain, chills, malaise
Infections and Infestations: upper respiratory tract infection, bronchitis, influenza, pharyngitis, tooth abscess, gastroenteritis viral, respiratory tract infection, rhinitis, urinary tract infection
Injury, Poisoning and Procedural Complications: back injury, contusion, joint sprain, procedural pain
Investigations: blood uric acid increased, blood creatine phosphokinase increased, weight decreased
Metabolism and Nutrition Disorders: hypokalaemia, diabetes mellitus, hyperlipidemia, hyponatremia
Musculoskeletal and Connective Tissue Disorders: pain in extremity, arthralgia, musculoskeletal pain, muscular weakness, musculoskeletal weakness, musculoskeletal stiffness, joint swelling, neck pain, osteoarthritis, tendonitis
Nervous System Disorders: paraesthesia, somnolence, syncope, carpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, head discomfort, lethargy, sinus headache, tremor
Psychiatric Disorders: anxiety, depression, insomnia
Renal and Urinary Disorders: pollakiuria
Reproductive System and Breast Disorders: erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders: dyspnea, nasal congestion, cough, pharyngolaryngeal pain
Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, night sweats, rash
Vascular Disorders: hypotension
Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: anorexia, constipation, dehydration, dysuria, increased appetite, viral infection.
Amlodipine
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Other adverse reactions not listed above that have been reported in <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
Musculoskeletal System: arthrosis, muscle cramps
Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization
Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
Urinary System: micturation frequency, micturation disorder, nocturia
Autonomic Nervous System: sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Hemopoietic: leukopenia, purpura, thrombocytopenia
Other adverse reactions 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 its full prescribing information.
Valsartan
Valsartan 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 reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:
Digestive: flatulence
Respiratory: sinusitis, pharyngitis
Urogenital: impotence
Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.
Hydrochlorothiazide
Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole : weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
Hematologic: aplastic anemia, agranulocytosis, hemolytic anemia
Hypersensitivity: photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: glycosuria, hyperuricemia
Nervous System/Psychiatric: restlessness
Renal: renal failure, renal dysfunction, interstitial nephritis
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: transient blurred vision, xanthopsia.
6.2 Post-Marketing Experience
Amlodipine
With 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 post-marketing experience with valsartan or valsartan/hydrochlorothiazide:
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
Vascular: Vasculitis
Nervous System: Syncope
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. 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.
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