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patients who received tacrine in clinical studies and the treatment IND program indicates that if tacrine is promptly withdrawn following detection of these elevations, clinically evident signs and symptoms of liver injury are rare.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] | Males | Females | Total |
| Maximum ALT | N = 229 | N = 250 | 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.
PRECAUTIONS
General
Liver Injury: see WARNINGS
Hematology
An absolute neutrophil count (ANC) less than 500/æL occurred in 4 patients who received Cognex® during the course of clinical trials. Three of the 4 patients had concurrent medical conditions commonly associated with a low ANC; 2 of these patients remained on Cognex®. The fourth patient, who had a history of hypersensitivity (penicillin allergy), withdrew from the study as a result of a rash and also developed an ANC <500/æL, which returned to normal; this patient was not rechallenged and, therefore, the role played by Cognex® in this reaction is unknown.
Six patients had an absolute neutrophil count ≤1500/æL, associated with an elevation of ALT/SGPT.
The total clinical experience in more than 12,000 patients does not indicate a clear association between Cognex® treatment and serious white blood cell abnormalities.
Information for Patients and Caregivers
Patients and caregivers should be advised that the effect of Cognex® (brand of tacrine hydrochloride) therapy is thought to depend upon its administration at regular intervals, as directed.
The caregiver should be advised about the possibility of adverse effects. Two types should be distinguished: (1) those occurring in close temporal association with the initiation of treatment or an increase in dose (eg, nausea, vomiting, loose stools, diarrhea, etc) and (2) those with a delayed onset (eg, rash, jaundice, changes in the color of stool—black, very dark or light [ie, acholic]).
Patients and caregivers should be encouraged to inform the physician about the emergence of new events or any increase in the severity of existing adverse clinical events.
Caregivers should be advised that abrupt discontinuation of Cognex® or a large reduction in total daily dose (80 mg/day or more) may cause a decline in cognitive function and behavioral disturbances. Unsupervised increases in the dose of tacrine may also have serious consequences. Consequently, changes in dose should not be undertaken in the absence of direct instruction of a physician.
Laboratory Tests (see WARNINGS: Liver Injury and DOSAGE AND ADMINISTRATION)
Serum transaminase levels (specifically ALT/SGPT) should be monitored in patients given Cognex® (see WARNINGS: Liver Injury).
Drug-Drug Interactions
Possible metabolic basis for interactions . Tacrine is primarily eliminated by hepatic metabolism via cytochrome P450 drug metabolizing enzymes. Drug-drug interactions may occur when Cognex® is given concurrently with agents such as theophylline that undergo extensive metabolism via cytochrome P450 IA2.
Theophylline. Coadministration of tacrine with theophylline increased theophylline elimination half-life and average plasma theophylline concentrations by approximately 2-fold. Therefore, monitoring of plasma theophylline concentrations and appropriate reduction of theophylline dose are recommended in patients receiving tacrine and theophylline concurrently. The effect of theophylline on tacrine pharmacokinetics has not been assessed.
Cimetidine . Cimetidine increased the Cmax and AUC of tacrine by approximately 54% and 64%, respectively.
Anticholinergics . Because of its mechanism of action, Cognex® has the potential to interfere with the activity of anticholinergic medications.
Cholinomimetics and Cholinesterase Inhibitors. A synergistic effect is expected when Cognex® is given concurrently with succinylcholine (see WARNINGS), cholinesterase inhibitors, or cholinergic agonists such as bethanechol.
Fluvoxamine. In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine.
Other Interactions . Rate and extent of tacrine absorption were not influenced by the coadministration of an antacid containing magnesium and aluminum. Tacrine had no major effect on digoxin or diazepam pharmacokinetics or the anticoagulant activity of warfarin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tacrine was mutagenic to bacteria in the Ames test. Unscheduled DNA synthesis was induced in rat and mouse hepatocytes in vitro. Results of cytogenetic (chromosomal aberration) studies were equivocal. Tacrine was not mutagenic in an in vitro mammalian mutation test. Overall, the results of these tests, along with the fact that tacrine belongs to a chemical class (acridines) containing some members which are animal carcinogens, suggest that tacrine may be carcinogenic.
Studies of the effects of tacrine on fertility have not been performed.
Pregnancy
Category C: Animal reproduction studies have not been conducted with tacrine. It is also not known whether Cognex® can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
Nursing Mothers
It is not known whether this drug is excreted in human milk.
Pediatric Use
There are no adequate and well-controlled trials to document the safety and efficacy of tacrine in any dementing illness occurring in pediatric patients.
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