ADVERSE REACTIONS
Common Adverse Events Leading to Discontinuation
In clinical trials, approximately 17% of the 2706 patients who received Cognex® and 5% of the 1886 patients who received placebo withdrew permanently because of adverse events. It should be noted that some of the placebo-treated patients were exposed to Cognex® prior to receiving placebo due to the variety of study designs used, including crossover studies. Transaminase elevations were the most common reason for withdrawals during Cognex® treatment (8% of all Cognex®-treated patients, or 212 of 456 patients withdrawn). The controlled clinical trial protocols required that any patient with an ALT/SGPT elevation >3 X ULN be withdrawn, because of concern about potential hepatotoxicity. Apart from withdrawals due to transaminase elevations, 244 patients (9%) withdrew for adverse events while receiving Cognex®.
Other adverse events that most frequently led to the withdrawal of tacrine-treated patients in clinical trials were nausea and/or vomiting (1.5%), agitation (0.9%), rash (0.7%), anorexia (0.7%), and confusion (0.5%). These adverse events also most frequently led to the withdrawal of placebo-treated patients, although at lower frequencies (0.1% to 0.2%).
Most Frequent Adverse Clinical Events Seen in Association With the Use of Tacrine
The events identified here are those that occurred at an absolute incidence of at least 5% of patients treated with Cognex®, and at a rate at least 2-fold higher in patients treated with Cognex® than placebo.
The most common adverse events associated with the use of Cognex® were elevated transaminases, nausea and/or vomiting, diarrhea, dyspepsia, myalgia, anorexia, and ataxia. Of these events, nausea and/or vomiting, diarrhea, dyspepsia, and anorexia appeared to be dose-dependent.
Adverse Events Reported in Controlled Trials
The events cited in the tables below reflect experience gained under closely monitored conditions of clinical trials with a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.
Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with Alzheimer's disease in placebo-controlled trials and who received the recommended regimen for dose introduction and titration of Cognex ® (see DOSAGE AND ADMINISTRATION).
Table 3. Adverse Events Occurring in at Least 2% of Patients Receiving Cognex at a Starting Dose of 40 mg/day with Titration in 40 mg/day Increments Every 6 Weeks in Controlled Clinical Trials [Number (%) of Patients] | BODY SYSTEM/ | Cognex® | Placebo |
| Adverse Events | N = 634 | N = 342 |
| LABORATORY DEVIATIONS | | |
| Elevated TransaminaseALT or AST value of approximately 3 X ULN or greater or that resulted in a change in patient management. Patients were monitored weekly. | 184 (29) | 5 (2) |
| BODY AS A WHOLE | | |
| Headache | 67 (11) | 52 (15) |
| Fatigue | 26 (4) | 9 (3) |
| Chest Pain | 24 (4) | 18 (5) |
| Weight Decrease | 21 (3) | 4 (1) |
| Back Pain | 15 (2) | 14 (4) |
| Asthenia | 15 (2) | 7 (2) |
| DIGESTIVE SYSTEM | | |
| Nausea and/or Vomiting | 178 (28) | 29 (9) |
| Diarrhea | 99 (16) | 18 (5) |
| Dyspepsia | 57 (9) | 22 (6) |
| Anorexia | 54 (9) | 11 (3) |
| Abdominal Pain | 48 (8) | 24 (7) |
| Flatulence | 22 (4) | 5 (2) |
| Constipation | 24 (4) | 8 (2) |
| HEMIC AND LYMPHATIC SYSTEM | | |
| Purpura | 15 (2) | 8 (2) |
| MUSCULOSKELETAL SYSTEM | | |
| Myalgia | 54 (9) | 18 (5) |
| NERVOUS SYSTEM | | |
| Dizziness | 73 (12) | 39 (11) |
| Confusion | 42 (7) | 24 (7) |
| Ataxia | 36 (6) | 12 (4) |
| Insomnia | 37 (6) | 18 (5) |
| Somnolence | 22 (4) | 11 (3) |
| Tremor | 14 (2) | 2 (<1) |
| PSYCHOBIOLOGIC FUNCTION | | |
| Agitation | 43 (7) | 30 (9) |
| Depression | 22 (4) | 14 (4) |
| Thinking Abnormal | 17 (3) | 14 (4) |
| Anxiety | 16 (3) | 7 (2) |
| Hallucination | 15 (2) | 12 (4) |
| Hostility | 15 (2) | 5 (2) |
| RESPIRATORY SYSTEM | | |
| Rhinitis | 51 (8) | 22 (6) |
| Upper Respiratory Infection | 18 (3) | 11 (3) |
| Coughing | 17 (3) | 18 (5) |
| SKIN AND APPENDAGES | | |
| RashIncludes COSTART terms: rash, rash-erythematous, rash-maculopapular, urticaria, petichial rash, rash-vesiculobullous, and pruritus. | 46 (7) | 18 (5) |
| Facial Flushing, Skin Flushing | 16 (3) | 3 (<1) |
| UROGENITAL SYSTEM | | |
| Urination Frequency | 21 (3) | 12 (4) |
| Urinary Tract Infection | 21 (3) | 20 (6) |
| Urinary Incontinence | 16 (3) | 9 (3) |
Other Adverse Events Observed During All Clinical Trials
Cognex® has been administered to 2706 individuals during clinical trials. A total of 1471 patients were treated for at least 3 months, 1137 for at least 6 months, and 773 for at least 1 year. Any untoward reactions that occurred during these trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary. These categories are used in the listing below. The frequencies represent the proportion of the 2706 individuals exposed to Cognex® who experienced that event while receiving Cognex®. All adverse events are included except those already listed on the previous table and those COSTART terms too general to be informative. Events are further classified by body system categories and listed 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; and rare adverse events are those occurring in less than 1/1000 patients. These adverse events are not necessarily related to Cognex® treatment. Only rare adverse events deemed to be potentially important are included.
Body As a Whole: Frequent: Chill, fever, malaise, peripheral edema. Infrequent: Face edema, dehydration, weight increase, cachexia, edema (generalized), lipoma. Rare: Heat exhaustion, sepsis, cholingeric crisis, death.
Cardiovascular System: Frequent: Hypotension, hypertension. Infrequent: Heart failure, myocardial infarction, angina pectoris, cerebrovascular accident, transient ischemic attack, phlebitis, venous insufficiency, abdominal aortic aneurysm, atrial fibrillation or flutter, palpitation, tachycardia, bradycardia, pulmonary embolus, migraine, hypercholesterolemia. Rare: Heart arrest, premature atrial contractions, A-V block, bundle branch block.
Digestive System: Infrequent: Glossitis, gingivitis, mouth or throat dry, stomatitis, increased salivation, dysphagia, esophagitis, gastritis, gastroenteritis, GI hemorrhage, stomach ulcer, hiatal hernia, hemorrhoids, stools bloody, diverticulitis, fecal impaction, fecal incontinence, hemorrhage (rectum), cholelithiasis, cholecystitis, increased appetite. Rare: Duodenal ulcer, bowel obstruction.
Endocrine System: Infrequent: Diabetes. Rare: Hyperthyroid, hypothyroid.
Hemic and Lymphatic: Infrequent: Anemia, lymphadenopathy. Rare: Leukopenia, thrombocytopenia, hemolysis, pancytopenia.
Musculoskeletal: Frequent: Fracture, arthralgia, arthritis, hypertonia. Infrequent: Osteoporosis, tendinitis, bursitis, gout. Rare: Myopathy.
Nervous System: Frequent: Convulsions, vertigo, syncope, hyperkinesia, paresthesia. Infrequent: Dreaming abnormal, dysarthria, aphasia, amnesia, wandering, twitching, hypesthesia, delirium, paralysis, bradykinesia, movement disorder, cogwheel rigidity, paresis, neuritis, hemiplegia, Parkinson's disease, neuropathy, extrapyramidal syndrome, reflexes decreased/absent. Rare: Tardive dyskinesia, dysesthesia, dystonia, encephalitis, coma, apraxia, oculogyric crisis, akathisia, oral facial dyskinesia, Bell's palsy, exacerbation of Parkinson's disease.
Psychobiologic Function: Frequent: Nervousness. Infrequent: Apathy, increased libido, paranoia, neurosis. Rare: Suicidal, psychosis, hysteria.
Respiratory System: Frequent: Pharyngitis, sinusitis, bronchitis, pneumonia, dyspnea. Infrequent: Epistaxis, chest congestion, asthma, hyperventilation, lower respiratory infection. Rare: Hemoptysis, lung edema, lung cancer, acute epiglottitis.
Skin and Appendages: Frequent: Sweating increased. Infrequent: Acne, alopecia, dermatitis, eczema, skin dry, herpes zoster, psoriasis, cellulitis, cyst, furunculosis, herpes simplex, hyperkeratosis, basal cell carcinoma, skin cancer. Rare: Desquamation, seborrhea, squamous cell carcinoma, ulcer (skin), skin necrosis, melanoma.
Urogenital System: Infrequent: Hematuria, renal stone, kidney infection, glycosuria, dysuria, polyuria, nocturia, pyuria, cystitis, urinary retention, urination urgency, vaginal hemorrhage, pruritus (genital), breast pain, impotence, prostate cancer. Rare: Bladder tumor, renal tumor, renal failure, urinary obstruction, breast cancer, epididymitis, carcinoma (ovary).
Special Senses: Frequent: Conjunctivitis. Infrequent: Cataract, eyes dry, eye pain, visual field defect, diplopia, amblyopia, glaucoma, hordeolum, deafness, earache, tinnitus, inner ear infection, otitis media, unusual taste. Rare: Vision loss, ptosis, blepharitis, labyrinthitis, inner ear disturbance.
Postintroduction Reports
Voluntary reports of adverse events temporally associated with Cognex® that have been received since market introduction, that are not listed above, and that may have no causal relationship with the drug include the following: pancreatitis, perforated peptic ulcer, and falling.
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