Drug: Cognex

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.

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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withdrawals during Cognex® (tacrine) treatment (8% of all Cognex® (tacrine) -treated patients, or 212 of 456 patients withdrawn).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 3 X ULN be withdrawn, because of concern about potential hepatotoxicity.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]
BODY SYSTEM/
Adverse Events Cognex®
N = 634 Placebo
N = 342 LABORATORY DEVIATIONS   Elevated Transaminasea 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 (

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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
ALT/SGPT Level Treatment and Monitoring Regimen 2 X ULN Continue treatment according to recommended titration and monitoring schedule. > 2 to 3 X ULN Continue treatment according to recommended titration. Monitor ALT/SGPT levels weekly until levels return to normal limits. > 3 to 5 X ULN Reduce the daily dose of Cognex® by 40 mg/day. Monitor ALT/SGPT levels weekly. Resume dose titration and every other week monitoring when the levels of the ALT/SGPT return to normal limits. > 5 X ULN Stop Cognex® treatment. Monitor the patient closely for signs and symptoms associated with hepatitis and follow ALT/SGPT levels until within normal limits. See Rechallenge section below. Experience is limited in patients with ALT/SGPT >10 X ULN. The risk of rechallenge must be considered against demonstrated clinical benefit. 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® (tacrine) and not be rechallenged. 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.

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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® (tacrine) 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 approx-i mately 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® (tacrine) has the potential to interfere with the activity of anticholinergic medications. Cholinomimetics and Cholinesterase Inhibitors. A synergistic effect is expected when Cognex® (tacrine) 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. Read the Cognex Drug Interactions Center for a complete guide to possible interactions Learn More »

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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).

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Cognex® (tacrine) is contraindicated in patients with known hypersensitivity to tacrine or acridine derivatives. Cognex® (tacrine) is contraindicated in patients previously treated with Cognex® (tacrine) who developed treatment-associated jaundice; a serum bilirubin > 3 mg/dL; and/or those exhibiting clinical signs or symptoms of hypersensitivity (eg, rash or fever) in association with ALT/SGPT elevations. Last reviewed on RxList: 6/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for Cognex® (tacrine) overdosage. Intravenous atropine sulfate titrated to effect is recommended: in adults, nitial dose of 1.0 to 2.0 mg IV with subsequent doses based on clinical response. In children, the usual IM or IV dose is 0.05 mg/kg, repeated every 10-30 minutes until muscarinic signs and symptoms subside and repeated if they reappear. Atypical increases in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate. It is not known whether Cognex® (tacrine) or its metabolites can be eliminated by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). The estimated median lethal dose of tacrine following a single oral dose in rats is 40 mg/kg, or approximately 12 times the maximum recommended human dose of 160 mg/day. Dose-related signs of cholinergic stimulation were observed in animals and included vomiting, diarrhea, salivation, lacrimation, ataxia, convulsions, tremor, and stereotypic head and body movements.

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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 10 mg (yellow/dark green) Bottles of 120 (NDC 59630-190-12) 20 mg (yellow/light blue) Bottles of 120 (NDC 59630-191-12) 30 mg (yellow/swedish orange) Bottles of 120 (NDC 59630-192-12) 40 mg (yellow/lavender) Bottles of 120 (NDC 59630-193-12) 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 Last reviewed on RxList: 6/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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General Liver Injury: see WARNINGS. Hematology An absolute neutrophil count (ANC) less than 500/µL occurred in 4 patients who received Cognex® (tacrine) 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 (tacrine) .® 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/µL, which returned to normal; this patient was not rechallenged and, therefore, the role played by Cognex® (tacrine) in this reaction is unknown. Six patients had an absolute neutrophil count 1500/µ L, 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® (tacrine) treatment and serious white blood cell abnormalities. Laboratory Tests (see WARNINGS: Liver Injury and DOSAGE AND ADMINISTRATION) Serum transaminase levels (specifically ALT/SGPT) should be monitored in patients given Cognex® (tacrine) (see WARNINGS: Liver Injury). 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® (tacrine) 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. Last reviewed on RxList: 6/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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