ADVERSE REACTIONS
The most commonly observed AEs associated with the use of RILUTEK more frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and circumoral paresthesia were dose related.
Approximately 14% (n = 141) of the 982 individuals with ALS who received RILUTEK in pre-marketing clinical trials discontinued treatment because of an adverse experience. Of those patients who discontinued due to adverse events, the most commonly reported were: nausea, abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, the rates of discontinuation of RILUTEK for asthenia, nausea, abdominal pain, and ALT elevation were dose related.
Incidence in Controlled ALS Clinical Studies
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with ALS treated with RILUTEK (n=794) participating in placebo-controlled trials and were numerically greater in the patients treated with RILUTEK 100 mg/day than with placebo or for which a dose response relationship is suggested.
The prescriber should be aware that these figures cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the AE incidences in the population studied.
Table 1 Adverse Events Occurring in Placebo-Controlled Clinical Trials Body System /
Adverse EventPercentage of patients reporting events | Riluzole
50 mg/day
(N=237) | Riluzole
100 mg/day
(N=313) | Riluzole
200 mg/day
(N=244) | Placebo
(N=320) |
|---|
| Body as a Whole | | | | |
| Asthenia | 14.8 | 19.2 | 20.1 | 12.2 |
| Headache | 8.0 | 7.3 | 7.0 | 6.6 |
| Abdominal pain | 6.8 | 5.1 | 7.8 | 3.8 |
| Back pain | 1.7 | 3.2 | 4.1 | 2.5 |
| Aggravation reaction | 0.4 | 1.3 | 2.0 | 0.9 |
| Malaise | 0.4 | 0.6 | 1.2 | 0.0 |
| Digestive | | | | |
| Nausea | 12.2 | 16.3 | 20.5 | 10.6 |
| Vomiting | 4.2 | 4.2 | 4.5 | 1.6 |
| Dyspepsia | 2.5 | 3.8 | 6.1 | 5.0 |
| Anorexia | 3.8 | 3.2 | 8.6 | 3.8 |
| Diarrhea | 5.5 | 2.9 | 9.0 | 3.1 |
| Flatulence | 2.5 | 2.6 | 2.0 | 1.9 |
| Stomatitis | 0.8 | 1.0 | 1.2 | 0.0 |
| Tooth disorder | 0.0 | 1.0 | 1.2 | 0.3 |
| Oral Moniliasis | 0.4 | 0.6 | 1.2 | 0.3 |
| Nervous | | | | |
| Hypertonia | 5.9 | 6.1 | 5.3 | 5.9 |
| Depression | 4.2 | 4.5 | 6.1 | 5.0 |
| Dizziness | 5.1 | 3.8 | 12.7 | 2.5 |
| Dry mouth | 3.0 | 3.5 | 2.0 | 3.4 |
| Insomnia | 2.1 | 3.5 | 2.9 | 3.4 |
| Somnolence | 0.8 | 1.9 | 4.1 | 1.3 |
| Vertigo | 2.5 | 1.9 | 4.5 | 0.9 |
| Circumoral paresthesia | 1.3 | 1.6 | 3.3 | 0.0 |
| Skin and Appendages | | | | |
| Pruritus | 3.8 | 3.8 | 2.5 | 3.1 |
| Eczema | 0.8 | 1.6 | 1.6 | 0.6 |
| Alopecia | 0.0 | 1.0 | 1.2 | 0.6 |
| Exfoliative dermatitis | 0.0 | 0.6 | 1.2 | 0.0 |
| Respiratory | | | | |
| Decreased lung function | 13.1 | 10.2 | 16.0 | 9.4 |
| Rhinitis | 8.9 | 6.4 | 7.8 | 6.3 |
| Increased cough | 2.1 | 2.6 | 3.7 | 1.6 |
| Sinusitis | 0.4 | 1.0 | 1.6 | 0.9 |
| Cardiovascular | | | | |
| Hypertension | 6.8 | 5.1 | 3.3 | 4.1 |
| Tachycardia | 1.3 | 2.6 | 2.0 | 1.3 |
| Phlebitis | 0.4 | 1.0 | 0.8 | 0.3 |
| Palpitation | 0.4 | 0.6 | 1.2 | 0.9 |
| Postural hypotension | 0.8 | 0.0 | 1.6 | 0.6 |
| Metabolic and Nutritional Disorders | | | | |
| Weight loss | 4.6 | 4.8 | 3.7 | 4.7 |
| Peripheral edema | 4.2 | 2.9 | 3.3 | 2.2 |
| Musculoskeletal System | | | | |
| Arthralgia | 5.1 | 3.5 | 1.6 | 3.4 |
| Urogenital System | | | | |
| Urinary tract infection | 2.5 | 2.6 | 4.5 | 2.2 |
| Dysuria | 0.0 | 1.0 | 1.2 | 0.3 |
Other Adverse Events Observed
Other events which occurred in more than 2% of patients treated with RILUTEK 100 mg/day but equally or more frequently in the placebo group included: accidental injury, apnea, bronchitis, constipation, death, dysphagia, dyspnea, flu syndrome, heart arrest, increased sputum, pneumonia, and respiratory disorder.
The overall adverse event profile for RILUTEK was similar between females and males, and was independent of age. Because the largest non-white racial subgroup was only 2% of patients exposed to RILUTEK (18/794) in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. In ALS studies, dizziness did occur more commonly in females (11%) than in males (4%). There was not a difference between females and males in the rates of discontinuation of RILUTEK for individual adverse experiences.
Other Adverse Events Observed During All Clinical Trials
RILUTEK has been administered to 1713 individuals during all clinical trials, some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 1713 individuals exposed to RILUTEK who experienced an event of the type cited on at least one occasion while receiving RILUTEK. All reported events are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug.
Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients.
Body as a Whole: Frequent: Hostility. Infrequent: Abscess, sepsis, photosensitivity reaction, cellulitis, face edema, hernia, peritonitis, attempted suicide, injection site reaction, chills, flu syndrome, intentional injury, enlarged abdomen, neoplasm. Rare: Acrodynia, hypothermia, moniliasis, rheumatoid arthritis.
Digestive System: Infrequent: Increased appetite, intestinal obstruction, fecal impaction, gastrointestinal hemorrhage, gastrointestinal ulceration, gastritis, fecal incontinence, jaundice, hepatitis, glossitis, gum hemorrhage, pancreatitis, tenesmus, esophageal stenosis. Rare: Cheilitis, cholecystitis, hematemesis, melena, biliary pain, proctitis, pseudomembranous enterocolitis, enlarged salivary gland, tongue discoloration, tooth caries.
Nervous System: Frequent: Agitation, tremor. Infrequent: Hallucinations, personality disorder, abnormal thinking, coma, paranoid reaction, manic reaction, ataxia, extrapyramidal syndrome, hypokinesia, urinary retention, emotional lability, delusions, apathy, hypesthesia, incoordination, confusion, convulsion, leg cramps, amnesia, dysarthria, increased libido, stupor, subdural hematoma, abnormal gait, delirium, depersonalization, facial paralysis, hemiplegia, decreased libido, myoclonus. Rare: Abnormal dreams, acute brain syndrome, CNS depression, dementia, cerebral embolism, euphoria, hypotonia, ileus, peripheral neuritis, psychosis, psychotic depression, schizophrenic reaction, trismus, wristdrop.
Skin and Appendages: Infrequent: Skin ulceration, urticaria, psoriasis, seborrhea, skin disorder, fungal dermatitis. Rare: Anaphylactoid reaction, angioedema, contact dermatitis, erythema multiforme, furunculosis, skin moniliasis, skin granuloma, skin nodule.
Respiratory System: Infrequent: Hiccup, pleural disorder, asthma, epistaxis, hemoptysis, yawn, hyperventilation, lung edema, hypoventilation, lung carcinoma, hypoxia, laryngitis, pleural effusion, pneumothorax, respiratory moniliasis, stridor.
Cardiovascular System: Infrequent: Syncope, hypotension, heart failure, migraine, peripheral vascular disease, angina pectoris, myocardial infarction, ventricular extrasystoles, cerebral hemorrhage, atrial fibrillation, bundle branch block, congestive heart failure, pericarditis, lower extremity embolus, myocardial ischemia, shock. Rare: Bradycardia, cerebral ischemia, hemorrhage, mesenteric artery occlusion, subarachnoid hemorrhage, supraventricular tachycardia, thrombosis, ventricular fibrillation, ventricular tachycardia.
Metabolic and Nutritional Disorders: Infrequent: Gout, respiratory acidosis, edema, thirst, hypokalemia, hyponatremia, weight gain. Rare: Generalized edema, hypercalcemia, hypercholesteremia.
Endocrine System: Infrequent: Diabetes mellitus, thyroid neoplasia. Rare: Diabetes insipidus, parathyroid disorder.
Hemic and Lymphatic System: Infrequent: Anemia, leukocytosis, leukopenia, ecchymosis. Rare: Neutropenia, aplastic anemia, cyanosis, hypochromic anemia, iron deficiency anemia, lymphadenopathy, petechiae, purpura.
Musculoskeletal System: Infrequent: Arthrosis, myasthenia, bone neoplasm. Rare: Bone necrosis, osteoporosis, tetany.
Special Senses: Infrequent: Amblyopia, ophthalmitis. Rare: Blepharitis, cataract, deafness, diplopia, ear pain, glaucoma, hyperacusis, photophobia, taste loss, vestibular disorder.
Urogenital System: Infrequent: Urinary urgency, urine abnormality, urinary incontinence, kidney calculus, hematuria, impotence, prostate carcinoma, kidney pain, metrorrhagia, priapism. Rare: Amenorrhea, breast abscess, breast pain, nephritis, nocturia, pyelonephritis, enlarged uterine fibroids, uterine hemorrhage, vaginal moniliasis.
Laboratory Tests: Infrequent: Increased gamma glutamyl transferase , abnormal liver function/tests, increased alkaline phosphatase, positive direct Coombs test, increased gamma globulins. Rare: increased lactic dehydrogenase.
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