Cognex

General

see WARNINGS.

An absolute neutrophil count (ANC) less than 500/µL 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/µL, 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/µL, 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 stoolblack, 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

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.

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 increased the Cmax and AUC of tacrine by approximately 54% and 64%, respectively.

Because of its mechanism of action, Cognex® has the potential to interfere with the activity of anticholinergic medications.

A synergistic effect is expected when Cognex® is given concurrently with succinylcholine (see WARNINGS), cholinesterase inhibitors, or cholinergic agonists such as bethanechol.

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.

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.

Applies to tacrine: oral capsule

Hepatic

Elevations in LFTs (liver function tests) have been reported in as many as 50% of patients started on tacrine (the active ingredient contained in Cognex) therapy. LFTs should be closely monitored while patients are treated with tacrine, particularly when therapy is initiated and when dosages are altered.

Specific recommendations for LFT monitoring are as follows:

Every-other-week monitoring of LFTs, particularly ALT, is recommended during the first sixteen weeks of tacrine therapy.

If modest elevations of up to two times the ULN (upper limit of normal) occur, continued every-other-week LFTs are recommended.

If elevations of up to three times ULN occur, weekly LFT monitoring is recommended until LFTs return to normal.

If elevations of up to five times ULN occur, a daily dosage reduction of 40 mg and weekly LFT monitoring is recommended until LFTs return to normal.

If elevations greater than five times ULN occur, discontinuation of tacrine therapy is recommended until LFTs return to normal.

Rechallenge may be attempted in patients who have discontinued tacrine therapy as a result of elevated LFTs (but rechallenge is contraindicated in patients with a history tacrine-induced jaundice). Rechallenge should only proceed once LFTs have returned to normal. A daily dose of 40 mg may be attempted. LFTs should be monitored weekly during rechallenge. Limited experience is available concerning rechallenge in patients with a history of tacrine-induced LFT elevations greater than 10 times ULN.[Ref]

Twenty-five percent of patients may experience a rise in ALT to three times normal. Seven percent may experience a rise in ALT to 10 times normal. Large rises in LFTs have been associated with hepatocellular injury rarely. Pathologic findings associated with tacrine-induced hepatotoxicity include granulomatous changes and hepatocellular necrosis.[Ref]

Other

Cholinergic adverse effects occur in as many as 68% of treated patients and include nausea, vomiting, diarrhea, dyspepsia, anorexia, restlessness, tremors, myalgia, arthralgia, excessive sweating, rash and frequent micturition. Hypotension, hypertension, bradycardia, syncope, ataxia and confusion have also been reported less frequently.[Ref]

The cholinomimetic effects of tacrine may result in an increase in gastric acid secretion and may therefore increase the risk of gastric ulceration in some patients.

Because of the potential vagotonic effects of cholinomimetic therapy, use in patients with "sick sinus syndrome" should be undertaken, if at all, with caution.[Ref]

Hematologic

Agranulocytosis has been reported in four of 8000 treated patients. Three of the four patients had medical conditions associated with agranulocytosis.[Ref]

Nervous system

A case of exacerbation of parkinsonism has been reported. Some clinicians have also reported vertigo and paresthesias as nervous system effects. Six cases of generalized tonic or tonic-clonic seizures have also been reported.[Ref]

Some side effects of Cognex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Tacrine has been assigned to pregnancy category C by the FDA. Animal studies have not yet been conducted. Tacrine has been used with suxamethonium historically to reduce postoperative respiratory depression in women undergoing Cesarean section. In one study, tacrine was recovered in the urine of neonates whose mothers received suxamethonium and tacrine. No serious effects were reported. There are no controlled data in human pregnancy or data concerning the use of tacrine during embryogenesis. Tacrine should only be given in pregnancy when benefit outweighs risk.