FDA label 0daaca03-de52-425a-a1e6-784f5c83e200

WARNINGS Anesthesia Cognex®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Cardiovascular Conditions Because of its pharmacological action, Cognex® may have vagotonic effects on the sinoatrial and atrioventricular nodes possibly leading to bradycardia and/or heart block. These effects may be particularly harmful to patients with conduction abnormalities, bradyarrhythmias, or a sick sinus syndrome, but may also occur in patients without known preexisting cardiac disease. Gastrointestinal Disease and Dysfunction Cognex® is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients are at increased risk for developing ulcers. Those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) should be monitored closely for symptoms of active or occult gastrointestinal disease. Cognex®, also as a predictable consequence of its pharmacological properties, can cause nausea, vomiting, and loose stools at recommended doses. Liver Injury Cognex® should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and gamma-glutamyl transpeptidase (GGT) levels (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections). The use of tacrine in patients without a prior history of liver disease is commonly associated with serum aminotransferase elevations, some to levels ordinarily considered to indicate clinically important hepatic injury (see Table 2). Experience gained in more than 12,000 patients who received tacrine in clinical studies and the treatment IND program indicates that if tacrine is promptly withdrawn following detection of these elevations, clinically evident signs and symptoms of liver injury are rare. Long-term follow up of patients who experience transaminase elevations, however, is limited and it is impossible, therefore, to exclude, with certainty, the possibility of chronic sequelae. Controlled Clinical Trials, Treatment IND and Post Marketing Experience: Experience with tacrine in controlled trials and in a large, less closely monitored experience (a treatment IND) is summarized below: Clinically evident liver toxicity : One of more than 12,000 patients exposed to tacrine in clinical studies and the treatment IND program had documented elevated bilirubin (5.3 X Upper Limit of Normal, ULN) and jaundice with transaminase levels (AST/SGOT) nearly 20 X ULN. Rare cases of liver toxicity associated with jaundice, raised serum bilirubin, pyrexia, hepatitis and liver failure have been reported in post-marketing experience. Most of these cases have been reversible but some deaths have occurred. Since there was multiple pathology including infection, gallstones and carcinoma it was not possible to clearly establish the relationship to Cognex® treatment. Blood chemistry signs of liver injury : Experience from the 30-week clinical study (described earlier) provides a representative estimate of the frequency of ALT/SGPT elevations expected for patients whose transaminase levels are monitored weekly and who receive Cognex® according to the recommended regimen for dose introduction and titration (Table 2). A dosing regimen employing a more rapid escalation of the daily dose of tacrine may be associated with more serious clinical events (see Monitoring of Liver function and the Management of the patient who develops transaminase elevations). Table 2. Cumulative Incidence of ALT/SGPT Elevations Based on Maximum Values with Weekly Monitoring During the 30-Week Study [Number and (%) of Patients] Maximum ALT Males N = 229 Females N = 250 Total N = 479 Within Normal Limits 121 (53) 100 (40) 221 (46) >ULN 108 (47) 150 (60) 258 (54) >2 times ULN 77 (34) 104 (42) 181 (38) >3 times ULN 58 (25) 81 (32) 139 (29) >10 times ULN 12 (5) 19 (8) 31 (6) >20 times ULN 3 (1) 6 (2) 9 (2) Experience in 2446 patients who participated in all clinical trials, including the 30-week study, indicates approximately 50% of patients treated with Cognex® can be expected to have at least 1 ALT/SGPT level above ULN; approximately 25% of patients are likely to develop elevations >3 X ULN, and about 7% of patients may develop elevations >10 X ULN. Data collected from the treatment IND program were consistent with those obtained during clinical studies, and showed 3% of 5665 patients experiencing an ALT/SGPT elevation >10 X ULN. In clinical trials where transaminases were monitored weekly, the median time to onset of the first ALT/SGPT elevation above ULN was approximately 6 weeks, with maximum ALT/SGPT occurring 1 week later, even in instances when Cognex® treatment was stopped. Under the conditions of forced slow upwards dose titration (increases of 40 mg a day every 6 weeks) employed in clinical studies, 95% of transaminase elevations >3 X ULN occurred within the first 18 weeks of Cognex® therapy, and 99% of the 10-fold elevations occurred by the 12th week and on not more than 80 mg; note, however, that for most patients ALT was monitored weekly and Cognex®was stopped when liver enzymes exceeded 3 X ULN. A total of 276 patients were monitored for ALT/SGPT levels every other week in two double-blind clinical studies, an open-label study, and amended treatment IND. The incidence, severity, time to onset, peak and recovery of ALT/SGPT levels were similar to weekly monitoring. With less frequent monitoring than every other week or the less stringent discontinuation criteria recommended below (see DOSAGE AND ADMINISTRATION), it is possible that marked elevations might be more common. It must also be appreciated that experience with prolonged exposure to the high dose (160 mg/day) is limited. In all cases, transaminase levels returned to within normal limits upon discontinuation of Cognex® treatment or following dosage reduction, usually within 4 to 6 weeks. This relatively benign experience may be the consequence of careful laboratory monitoring that facilitated the discontinuation of patients early on after the onset of their transaminase elevations. Consequently, frequent monitoring of serum transaminase levels is recommended (see DOSAGE AND ADMINISTRATION, WARNINGS: Liver Injury: Monitoring of Liver Function and the Management of the Patient Who Develops Transaminase Elevations and PRECAUTIONS: Laboratory Tests). Liver biopsy experience: Liver biopsy results in 7 patients who received tacrine (1 in a Parke-Davis sponsored study and 6 in studies reported in the literature) revealed hepatocellular necrosis in 6 patients, and granulomatous changes in the seventh. In all cases, liver function tests returned to normal with no evidence of persisting hepatic dysfunction. Experience with the rechallenge of patients with transaminase elevations following recovery: Two hundred and twelve patients among the 866 patients assigned to tacrine in the 12 and 30 week studies were withdrawn because they developed transaminase elevations >3 X ULN. One hundred and forty-five of these patients were subsequently rechallenged with weekly monitoring of ALT/SGPT. During their initial exposure to tacrine, 20 of these 145 had experienced initial elevations >10 times ULN, while the remainder had experienced elevations between 3 and 10 X ULN. Upon rechallenge with an initial dose of 40 mg/day, only 48 (33%) of the 145 patients developed transaminase elevations greater than 3 X ULN. Of these patients, 44 had elevations that were between 3 and 10 X ULN and 4 had elevations that were > 10 X ULN. The mean time to onset of elevations occurred earlier on rechallenge than on initial exposure (22 versus 48 days). Of the 145 patients rechallenged, 127 (88%) were able to continue Cognex® treatment, and 91 of these 127 patients titrated to doses higher than those associated with the initial transaminase elevation. Predictors of the risk of transaminase elevations: The incidence of transaminase elevations is higher among females. There are no other known predictors of the risk of hepatocellular injury. Monitoring of Liver function and the Management of the patient who develops transaminase elevations. (See also DOSAGE AND ADMINISTRATION and PRECAUTIONS: Laboratory Tests.) Blood chemistries: Serum transaminase levels (specifically ALT/SGPT) should be monitored every other week from at least week 4 to week 16 following initiation of treatment, after which monitoring may be decreased to every 3 months. For patients who develop ALT/SGPT elevations greater than two times the upper limit of normal, the dose and monitoring regimen should be modified as described in Table 4 (see DOSAGE AND ADMINISTRATION). A full monitoring sequence should be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks. If ALT/SGPT elevations occur, the frequency of monitoring and the dose of Cognex® should be modified according to the table shown below in DOSAGE AND ADMINISTRATION. Rechallenge: Patients with clinical jaundice confirmed by a significant elevation in total bilirubin (> 3 mg/dL) and/or those exhibiting clinical signs and/or symptoms of hypersensitivity (e.g. rash or fever) in association with ALT/SGPT elevations should immediately and permanently discontinue Cognex® and not be rechallenged. Other patients who are required to discontinue Cognex® treatment because of ALT/SGPT elevations may be rechallenged once ALT/SGPT levels return to within normal limits. (See DOSAGE AND ADMINISTRATION.) Rechallenge of patients with ALT/SGPT elevations less than 10 X ULN has not resulted in serious liver injury. However, because experience in the rechallenge of patients who had elevations greater than 10 X ULN is limited, the risks associated with the rechallenge of these patients are not well characterized. Careful, frequent (weekly) monitoring of serum ALT/SGPT should be undertaken when rechallenging such patients. If rechallenged, patients should be given an initial dose of 40 mg/day (10 mg QID) and ALT/SGPT levels monitored weekly. If, after 6 weeks on 40 mg/day, the patient is tolerating the dosage with no unacceptable elevations in ALT/SGPT, recommended dose-titration may be resumed. Weekly monitoring of the ALT/SGPT levels should continue for a total of 16 weeks after which monitoring may be decreased to monthly for 2 months and every 3 months thereafter. Liver biopsy: Liver biopsy is not indicated in cases of uncomplicated transaminase elevation . Genitourinary Cholinomimetics may cause bladder outflow obstruction. Neurological Conditions Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions; seizure activity may, however, also be a manifestation of Alzheimer's disease . Sudden worsening of the degree of cognitive impairment: Worsening of cognitive function has been reported following abrupt discontinuation of Cognex® or after a large reduction in total daily dose (80 mg/day or more). Pulmonary Conditions Because of its cholinomimetic action, Cognex® should be prescribed with care to patients with a history of asthma.

Anesthesia Cognex®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Cardiovascular Conditions Because of its pharmacological action, Cognex® may have vagotonic effects on the sinoatrial and atrioventricular nodes possibly leading to bradycardia and/or heart block. These effects may be particularly harmful to patients with conduction abnormalities, bradyarrhythmias, or a sick sinus syndrome, but may also occur in patients without known preexisting cardiac disease.

Gastrointestinal Disease and Dysfunction Cognex® is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients are at increased risk for developing ulcers. Those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) should be monitored closely for symptoms of active or occult gastrointestinal disease. Cognex®, also as a predictable consequence of its pharmacological properties, can cause nausea, vomiting, and loose stools at recommended doses.

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 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/Adverse Events Cognex®N = 634 PlaceboN = 342 LABORATORY DEVIATIONS Elevated Transaminase a 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 Rash b 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) a ALT or AST value of approximately 3 X ULN or greater or that resulted in a change in patient management. Patients were monitored weekly. b Includes COSTART terms: rash, rash-erythematous, rash-maculopapular, urticaria, petechial rash, rash-vesiculobullous, and pruritus. 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.

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 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/Adverse Events Cognex®N = 634 PlaceboN = 342 LABORATORY DEVIATIONS Elevated Transaminase a 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 Rash b 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) a ALT or AST value of approximately 3 X ULN or greater or that resulted in a change in patient management. Patients were monitored weekly. b Includes COSTART terms: rash, rash-erythematous, rash-maculopapular, urticaria, petechial rash, rash-vesiculobullous, and pruritus.