Adverse reactions : תופעות לוואי

8    ADVERSE REACTIONS

8.1 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.

Amlodipine has been evaluated for safety in more than 11,000 patients in clinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mg daily.
Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N = 1730) at doses up to 10 mg to placebo (N = 1250), discontinuation of amlodipine besylate because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Amlodipine                               Placebo
2.5mg              5mg                 10mg
N=275             N=296                N=268               N=520
Edema                    1.8                3.0                 10.8                0.6 Dizziness                1.1                3.4                 3.4                 1.5 Flushing                 0.7                1.4                  2.6                0.0 Palpitation              0.7                1.4                  4.5                0.6 
Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: 
Amlodipine (%)                      Placebo (%)
(N=1730)                           (N=1250)
Fatigue                                   4.5                                2.8 Nausea                                    2.9                                1.9 Abdominal Pain                            1.6                                0.3 Somnolence                                1.4                                0.6 
For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:

Amlodipine (%)                         Placebo (%)
Male = %         Female = %            Male = %        Female = %
(N=1218)           (N=512)             (N=914)          (N=336)
Edema                     5.6               14.6                1.4              5.1 Flushing                  1.5                4.5                0.3              0.9 Palpitations              1.4                3.3                0.9              0.9 Somnolence                1.3                1.6                0.8              0.3 
The following events occurred 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; they are listed to alert the physician to a possible relationship: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.

Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,1 epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus, 1 rash,1 rash erythematous, rash maculopapular.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System: micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.
1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.
In the CAMELOT and PREVENT studies of amlodipine in coronary artery disease, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

8.2 Postmarketing Experience

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 postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, 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.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well- compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.