The ADAS cog is a multi-item test battery administered by a psychometrician that examines aspects of memory, attention, praxis, reason, and language. The worst possible score is 70. Elderly, normal adults may score as low as 0 or 1 unit, but individuals judged not to be demented can score higher. The mean score of patients entering each study was approximately 28 units (range 7 to 62). The ADAS cog score is reported to deteriorate at a rate of about 6 to 10 units per year for untreated patients at this stage of dementia.
 
The clinician's global assessments used in the two studies relied on a clinician's judgment about the overall clinical change observed in patients over the course of the study. Although the conditions for obtaining the clinical assessment differed in each study, the global assessment was rated on a 7-point scale in both studies. A rating of four (4) represents no change; lower ratings indicate improvement from baseline and higher ratings deterioration.

Twelve-Week Study

In one study of 12 weeks duration, patients were randomized to sequences that provided a comparison between placebo, 20, 40, and 80 mg/day by study's end. Statistically significant drug-placebo differences were detected on both primary outcome measures for the group titrated to 80 mg/day. Estimates of the size of the treatment effect varied between 2 and 4 ADAS cog units. The imprecision in these estimates reflects the fact that different analyses, conducted in attempts to account for the effects of the failure of a substantial fraction of the patients randomized to complete the full 12 weeks of the study, yielded different results.
 
The placebo-80 mg/day comparison also achieved statistical significance on the clinician's global impression of change (CGIC) with a 0.3 to 0.4 unit mean difference. The following diagram illustrates the percentages of patients falling into each global category at trial's end for the patients given placebo or 80 mg/day.

FIGURE 1. Percent of Patients in Each of the Seven Outcome Categories on the Clinician-Rated CGIC for Patients Completing 12 Weeks of Treatment (83% of patients randomized to placebo completed 12 weeks of treatment and are represented above; 56% of those randomized to the 80 mg/day Cognex® sequence completed 12 weeks).

Thirty-Week Study

The second study was 30 weeks long. Six hundred sixty-three patients were randomized to 4 treatment sequences (placebo and 3 drug groups) that called for the daily dose of tacrine to be increased at 6-week intervals, starting with a 40-mg/day dose. By study's end, a comparison between placebo, 80, 120, and 160 mg/day was possible. Patients in the 160 mg group received this dose for the final 12 weeks; the 120 mg group received that dose for  18 weeks.
 
The study showed statistically significant drug-placebo differences for the 80 and 120 mg/day groups at 18 weeks and for the 120 and 160 mg/day groups at 30 weeks on both a performance-based test of cognitive function (the ADAS cog) and a clinician's assessment of global change (Clinician Interview Based Impression: CIBI). Because many patients failed to complete 30 weeks on treatment, analyses that used each patient's last on-study value or retrieved patients' (see below) 30-week value, even if they were no longer in the study ("intent-to-treat” analysis) were also carried out. All analyses confirmed the effectiveness of tacrine, although the estimated mean treatment effect was different in each analysis.

Effects on ADAS Cog:

The results for the ADAS cog are shown in Figure 2 for the subset of patients actually completing the full 30 weeks of the study. They show that individual patients, whether assigned to tacrine or to placebo, had a wide range of responses. This variability in response is illustrated in the display that follows (Figure 2).

FIGURE 2. Cumulative Percent of Patients Completing 30 Weeks of Treatment Who Attained a Change in ADAS Cog Score From Baseline at Least as Large as the Value on the X Axis. The display is based on scores obtained from a subset of patients (ie, 64% of the 184 randomized to placebo and 27% of the 239 randomized to the 160 mg/daytreatment group).

The results on the CIBI are shown in Figure 3.

FIGURE 3. Percent of Patients in Each of the Seven Outcome Categories of the CIBI Among Those Completing 30 Weeks. The display is based on scores obtained from the same subset of patients as Figure 2.

Cognex® is rapidly absorbed after oral administration; maximal plasma concentrations occur within 1 to 2 hours. The rate and extent of tacrine absorption following administration of tacrine capsules and solution are virtually indistinguishable. Absolute bioavailability of tacrine is approximately 17 (SD ± 13) %. Food reduces tacrine bioavailability by approximately 30-40%; however, there is no food effect if tacrine is administered at least an hour before meals. The effect of achlorhydria on the absorption of tacrine is unknown.

Distribution:

Mean volume of distribution of tacrine is approximately 349 (SD ± 193) L. Tacrine is about 55% bound to plasma proteins. The extent and degree of tacrine's distribution within various body compartments has not been systematically studied. However, 336 hours after the administration of a single radiolabeled dose, approximately 25% of the radiolabel was not recovered in a mass balance study, suggesting the possibility that tacrine and/or one or more of its metabolites may be retained.

Metabolism:

Tacrine is extensively metabolized by the cytochrome P450 system to multiple metabolites, not all of which have been identified. The vast majority of radiolabeled species present in the plasma following a single dose of 14C radiolabeled tacrine are unidentified (ie, only 5% of radioactivity in plasma has been identified [tacrine and 3-hydroxylated metabolites; 1-, 2-, and 4-hydroxytacrine]).
 
Studies utilizing human liver preparations demonstrated that cytochrome P450 IA2 is the principal isozyme involved in tacrine metabolism. These findings are consistent with the observation that tacrine and/or one of its metabolites inhibits the metabolism of theophylline in humans (see PRECAUTIONS: Drug-Drug Interactions: theophylline). Results from a study utilizing quinidine to inhibit cytochrome P450 IID6 indicate that tacrine is not metabolized extensively by this enzyme system.
 
Following aromatic ring hydroxylation, tacrine's metabolites undergo glucuronidation. Whether tacrine and/or its metabolites undergo biliary excretion or entero-hepatic circulation is unknown.

Special Populations:

Age: Based on pooled pharmacokinetic studies (n = 192), there is no clinically relevant influence of age (50 to 84 years) on tacrine clearance. Gender: Average tacrine plasma concentrations are approximately 50% higher in females than in males. This is not explained by differences in body surface area or elimination half-life. The difference is probably due to higher systemic availability after oral dosing and may reflect the known lower activity of cytochrome P450 IA2 in women. Race: The effect of race on tacrine clearance has not been studied. Smoking: Mean plasma tacrine concentrations in current smokers are approximately one third the concentrations in nonsmokers. Cigarette smoking is known to induce cytochrome P450 IA2. Renal disease: Renal disease does not appear to affect the clearance of tacrine. Liver disease: Although studies in patients with liver disease have not been done, it is likely that functional hepatic impairment will reduce the clearance of tacrine and its metabolites.

Presystemic Clearance/Elimination/Excretion:

Tacrine undergoes presystemic clearance (ie, first pass metabolism). The extent of this first pass metabolism depends upon the dose of tacrine administered. Because the enzyme system involved can be saturated at relatively low doses, a larger fraction of a high dose of tacrine will escape first pass elimination than of a smaller dose. Thus, when a 40 mg daily dose is increased by 40 mg, the average plasma concentration will be increased by approximately 6 ng/mL. However, when a daily dose of 80 or 120 mg is increased by 40 mg, the increment in average plasma concentration is approximately 10 ng/mL.
 
Elimination of tacrine from the plasma, however, is not dose dependent (ie, the half-life is independent of dose or plasma concentration). The elimination half-life is approximately 2 to 4 hours. Following initiation of therapy or a change in daily dose, steady state tacrine plasma concentration should be attained within 24 to 36 hours.

Drug Interactions (See PRECAUTIONS)

INDICATIONS AND USAGE

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:

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:

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 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.

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]

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:

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.

OVERDOSAGE

The initial dose of Cognex® brand of tacrine hydrochloride is 40 mg/day (10 mg QID). This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment. It is important that the dose not be increased during this period because of the potential for delayed onset of transaminase elevations.

Dose Titration

Following 4 weeks of treatment at 40 mg/day (10 mg QID), the dose of Cognex® should then be increased to 80 mg/day (20 mg QID), providing there are no significant transaminase elevations and the patient is tolerating treatment. Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a QID schedule) at 4- week intervals on the basis of tolerance.

Dose Adjustment

Serum 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.
 
A full monitoring and dose titration sequence must be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks.
 
Table 4. Recommended Dose and Monitoring Regimen
Modification in Response to ALT/SGPT Elevations

Rechallenge

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Protect from moisture.