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Cognex®
(tacrine hydrochloride) Capsules, USP

DESCRIPTION

Cognex® (tacrine hydrochloride) is a reversible cholinesterase inhibitor, known chemically as 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate. Tacrine hydrochloride is commonly referred to in the clinical and pharmacological literature as THA. It has an empirical formula of C13H14N2•HCl•H2O and a molecular weight of 252.74.

The molecular formula of tacrine hydrochloride is:

Tacrine hydrochloride is a white solid and is freely soluble in distilled water, 0.1N hydrochloric acid, acetate buffer (pH 4.0), phosphate buffer (pH 7.0 to 7.4), methanol, dimethylsulfoxide (DMSO), ethanol, and propylene glycol. The compound is sparingly soluble in linoleic acid and PEG 400.

Each capsule of Cognex® contains tacrine as the hydrochloride. Inactive ingredients are hydrous lactose, magnesium stearate, and microcrystalline cellulose. The hard gelatin capsules contain gelatin, NF; silicon dioxide, NF; sodium lauryl sulfate, NF; and the following dyes: 10 mg: D&C Yellow #10, FD&C Green #3, titanium dioxide; 20 mg: D&C Yellow #10, FD&C Blue #1, titanium dioxide; 30 mg: D&C Yellow #10, FD&C Blue #1, FD&C Red #40, titanium dioxide; 40 mg: D&C Yellow #10, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide.

Each 10-, 20-, 30-, and 40-mg Cognex® (tacrine) capsule for oral administration contains 12.75, 25.50, 38.25, and 51.00 mg of tacrine HCl, respectively.

INDICATIONS

Cognex® (tacrine hydrochloride capsules) is indicated for the treatment of mild to moderate dementia of the Alzheimer's type.

Evidence of Cognex® (tacrine) 's effectiveness in the treatment of dementia of the Alzheimer's type derives from results of two adequate and well-controlled clinical investigations that compared tacrine and placebo on both a performance based measure of cognition and a clinician's global assessment of change. (See CLINICAL PHARMACOLOGY Section: Clinical Trial Data).

DOSAGE AND ADMINISTRATION

The recommendations for dose titration are based on experience from clinical trials. The rate of dose escalation may be slowed if a patient is intolerant to the titration schedule recommended below. It is not advisable, however, to accelerate the dose incrementation plan.

Following initiation of therapy, or any dosage increase, patients should be observed carefully for adverse effects. Cognex® (tacrine) should be taken between meals whenever possible; however, if minor GI upset occurs, Cognex® (tacrine) may be taken with meals to improve tolerability. Taking Cognex® (tacrine) with meals can be expected to reduce plasma levels approximately 30% to 40%.

Initiation of Treatment

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® (tacrine) 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 whodevelop ALT/SGPTelevations 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

Patients who are required to discontinue Cognex® (tacrine) treatment because of ALT/SGPT elevations may be rechallenged once ALT/SGPT levels return to normal limits. Rechallenge of patients exposed to 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, the 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.

HOW SUPPLIED

Cognex® is supplied as capsules of tacrine hydrochloride containing 10, 20, 30, and 40 mg of tacrine. The capsule logo is "Cognex® (tacrine) " with the strength (eg, 10, 20, 30, or 40) printed underneath

Storage

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.

Revised June 2006. Distributed by: Sciele Inc., Atlanta, GA 30328. FDA rev date: 6/19/2003

SIDE EFFECTS

Common Adverse Events Leading to Discontinuation

In clinical trials, approximately 17% of the 2706 patients who received Cognex® (tacrine) 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® (tacrine) 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® (tacrine) treatment (8% of all Cognex® (tacrine) -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® (tacrine) .

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® (tacrine) , and at a rate at least 2-fold higher in patients reated with Cognex (tacrine) ®than placebo.

The most common adverse events associated with the use of Cognex® (tacrine) 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® (tacrine) 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]