The most commonly observed, treatment-emergent adverse events associated with the use of dexfenfluramine in double-blind, placebo-controlled clinical trials were diarrhea (17.5%), dry mouth (12.5%), and somnolence (7.1%). These and other commonly observed adverse reactions were generally mild and transient. (Commonly observed is defined as incidence of 5% or greater and incidence in dexfenfluramine group at least twice that of placebo group, as derived from the Table 3 below.)
Associated with Discontinuation of Treatment
Seven percent of the 1159 patients who received dexfenfluramine in double-blind, placebo-controlled clinical trials discontinued treatment because of an adverse event. The most common adverse events resulting in discontinuation included asthenia, insomnia, headache, and depression. Five percent of the 1138 placebo-treated patients discontinued because of an adverse event.
Incidence in Controlled Clinical Trials
The following Table 3 lists treatment-emergent adverse events from several double-blind, placebo-controlled trials that occurred at a frequency of 2% or more among patients treated with dexfenfluramine and occurred at least as frequently as the placebo group, regardless of relationship to study medication.
Other Events Observed in Controlled Clinical Trials
The events below are classified within body system categories and enumerated in order of decreasing frequency using the following definitions. Frequent adverse events are those occurring in more than 1/100 patients but were not described above because the frequency in dexfenfluramine-treated patients was less than that in placebo-treated patients or they occurred at a rate less than 2%. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare adverse events are those occurring in only one patient during placebo-controlled clinical trials.
Body as a whole:
Frequent: infection, flu syndrome, pain,back pain, fever, allergic reaction.
Infrequent: malaise, neck pain, chest pain, generalized edema, stress, face edema, neoplasm, pelvic pain.
Rare: adenoma, immune system disorder, neck rigidity, suicide attempt.
Frequent: hypertension, angina pectoris, palpitation, vasodilation, migraine.
Infrequent: cardiovascular disorder, tachycardia, postural hypotension, hypotension, peripheral vascular disorder, syncope, arrhythmia, extrasystoles, hemorrhage, thrombophlebitis, varicose vein.
Rare: heart block, pulmonary embolus, thrombosis.
Frequent: constipation, nausea, dyspepsia, increased appetite, rectal disorder, gastritis, gastroenteritis, flatulence.
Infrequent: colitis, eructation, gastrointestinal hemorrhage, enteritis, peptic ulcer, hepatitis, hepatomegaly.
Rare: appendicitis, cholelithiasis, fecal incontinence, melena, mouth ulceration, pancreatitis, rectal hemorrhage, sialoadenitis.
Infrequent: goiter, diabetes mellitus, thyroid disorder.
Hemic and lymphatic system:
Infrequent: anemia, lymphedema.
Rare: coagulation disorder, lymphadenopathy, polycythemia, thrombocythemia.
Metabolic and nutritional:
Infrequent: edema, gout, hypoglycemia, hypokalemia.
Rare: hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia.
Frequent: arthralgia, myalgia, arthritis.
Infrequent: leg cramps, joint disorder, bone disorder, tenosynovitis, myasthenia, rheumatoid arthritis.
Rare: bursitis, tetany.
Frequent: nervousness, anxiety, increased libido, hypertonia, paresthesia.
Infrequent: tremor, amnesia, euphoria, decreased libido, incoordination, neuralgia, speech disorder, ataxia, hypokinesia, sleep disorder, abnormal gait, agitation, confusion, depersonalization, diplopia, hostility, hyperesthesia, hyperkinesia, peripheral neuritis.
Rare: apathy, dementia, hallucinations, hypotonia, neuritis, neurosis, paralysis.
Frequent: rhinitis, sinusitis. Infrequent: asthma, dyspnea, epistaxis, laryngitis.
Rare: apnea, hyperventilation.
Skin and appendages:
Frequent: sweating, alopecia, urticaria, pruritus.
Infrequent: skin disorder, fungal dermatitis, hirsutism, eczema, psoriasis.
Rare: skin hypertrophy.
Frequent: taste perversion, amblyopia.
Infrequent: abnormal vision, conjunctivitis, eye disorder, glaucoma, tinnitus, vestibular disorder, dry eyes, mydriasis.
Rare: abnormality of accommodation, anisocoria, lacrimation disorder, miosis, parosmia, retinal disorder.
Frequent: menstrual disorder, urinary tract infection, nocturia, dysmenorrhea.
Infrequent: amenorrhea, dysuria, oliguria, albuminuria, breast pain, kidney calculus, kidney pain.
Rare: spontaneous abortion, threatened abortion, breast neoplasm, endometrial disorder, female lactation, hematuria, impotence, mastitis, nephritis, prostatic disorder, testis disorder, urinary incontinence, urinary retention, uterine hemorrhage.
In controlled clinical trials, there has been no consistent pattern of laboratory abnormalities in patients treated with dexfenfluramine.
Voluntary reports of adverse events temporally associated with dexfenfluramine that have been received since market introduction in countries other than the US, for which the association with the drug is unknown, and which are not included in descriptions of adverse events elsewhere in this labeling, include the following:
Body as a whole: anaphylaxis, congenital anomaly, eventration, hypothermia, laryngeal edema, peritonitis, reaction aggravation, retroperitoneal fibrosis, scleroderma, sudden death.
Cardiovascular system: pulmonary hypertension (see WARNINGS), atrial fibrillation, cardiomyopathy, cerebral vasculitis, ECG abnormal, heart arrest, heart failure, myocardial infarction, myocarditis, shock, tachycardia, ventricular fibrillation, ventricular tachycardia.
Digestive system: dysphagia, gastrointestinal disorder, tongue disorder. Endocrine system--diabetic coma.
Gastrointestinal system: hepatic failure, jaundice, liver damage.
Hemic and lymphatic system: agranulocytosis, antinuclear antibody present, bone marrow depression, ecchymosis, hemolytic anemia, pancytopenia.
Metabolic and nutritional: dehydration, elevated lipases, increased prolactin, thyroid disease, weight increase.
Nervous system: antisocial reaction, apathy, cerebellar ataxia, cerebrovascular accident (including cerebral hemorrhage, cerebral infarction, cerebral ischemia and cochlear infarction), choreoathetosis, convulsions, decreased reflexes, delirium, drug dependence, dyslexia, encephalopathy, grand mal convulsions, Guillain-Barré syndrome, hemiplegia, hypoesthesia, manic-depressive psychosis, manic reaction, memory loss, meningism, meningitis, neuropathy, papilledema, paraplegia, personality disorder, reflexes increased, retrobulbar neuritis, schizophrenic reaction, stupor, subdural hematoma, twitch, withdrawal syndrome.
Respiratory system: pulmonary hypertension (see WARNINGS), diffuse interstitial pneumonitis, dyspnea, hiccup, lung edema.
Skin and appendages: angioedema, bullous eruption, erythema multiforme, lower extremity purpura, purpura annularis telangiectodes, Stevens-Johnson syndrome (erythema multiforme major).
Special Senses: ophthalmoplegia, photophobia, transitory deafness, visual field defects.
Urogenital system: breast enlargement, carcinoma (breast), carcinoma (cervix), ejaculation abnormal, gynecomastia, hypomenorrhea, kidney failure, placenta previa, urinary tract disorder.
Adverse Events Occurring After Discontinuation
In controlled clinical trials and/or in post-marketing reports, symptoms have been reported within a few days after discontinuation of dexfenfluramine. These include one or more of the following: abdominal pain, anxiety, asthenia, delusion, depression, diarrhea, dizziness, hypertension, insomnia, nausea and vomiting.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Dexfenfluramine is a controlled substance in Schedule IV.
Abuse and Physical and Psychological Dependence
Dexfenfluramine is not an amphetamine or a stimulant. There is no evidence of addictive or drug-seeking behavior in pre-marketing clinical studies. Dexfenfluramine was inactive in rat and monkey self-administration, drug-discrimination, and place-preference models of abuse potential.