Tacrine

Pronunciation

(TAK reen)

U.S. Brand Names

Cognex®

Synonyms

Tacrine Hydrochloride; Tetrahydroaminoacrine; THA

Generic Available

Use

Treatment of mild to moderate dementia of the Alzheimer's type

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to tacrine, acridine derivatives, or any component of the formulation; patients previously treated with tacrine who developed jaundice

Warnings/Precautions

The use of tacrine has been associated with elevations in serum transaminases; serum transaminases (specifically ALT) must be monitored throughout therapy; use extreme caution in patients with current evidence of a history of abnormal liver function tests; use caution in patients with urinary tract obstruction (bladder outlet obstruction or prostatic hyperplasia), asthma, and sick-sinus syndrome, bradycardia, or conduction abnormalities (tacrine may cause bradycardia and/or heart block). Also, patients with cardiovascular disease, asthma, or peptic ulcer should use cautiously. Adverse cardiovascular events may also occur in patients without known cardiac disease. Use with caution in patients with a history of seizures. May cause nausea, vomiting, or loose stools. Abrupt discontinuation or dosage decrease may worsen cognitive function. May be associated with neutropenia.

Adverse Reactions

>10%:

Central nervous system: Headache, dizziness

Gastrointestinal: Nausea, vomiting, diarrhea

Miscellaneous: Transaminases increased

1% to 10%:

Cardiovascular: Flushing

Central nervous system: Confusion, ataxia, insomnia, somnolence, depression, anxiety, fatigue

Dermatologic: Rash

Gastrointestinal: Dyspepsia, anorexia, abdominal pain, flatulence, constipation, weight loss

Neuromuscular & skeletal: Myalgia, tremor

Respiratory: Rhinitis

Overdosage/Toxicology

Provide general supportive measures. Can cause cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increased 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 overdose. I.V. atropine sulfate titrated to effect is recommended at an initial dose of 1-2 mg I.V. with subsequent doses based upon clinical response. Atypical increases in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate.

Drug Interactions

Substrate of CYP1A2 (major); Inhibits CYP1A2 (weak)

Anticholinergic agents: Tacrine may antagonize the therapeutic effect of anticholinergic agents (benztropine, trihexphenidyl); a peripherally-acting agent (glycopyrrolate) has been reported to reduce tacrine-associated gastrointestinal complaints

Beta-blockers: Tacrine in combination with beta-blockers may produce additive bradycardia

Calcium channel blockers: Tacrine in combination with heart rate lowering calcium channel blockers (diltiazem and verapamil) may produce additive bradycardia

Cholinergic agents: Tacrine in combination with other cholinergic agents (eg, ambenonium, edrophonium, neostigmine, pyridostigmine, bethanechol), will likely produce additive cholinergic effects

CYP1A2 inducers: May decrease the levels/effects of tacrine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of tacrine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

Digoxin: Tacrine, in combination with digoxin, may produce additive bradycardia

Haloperidol: Tacrine may worsen Parkinson's disease and inhibit the effects of haloperidol.

Levodopa: Tacrine may worsen Parkinson's disease and inhibit the effects of levodopa

Neuromuscular blocking agents (nondepolarizing): Theoretically, tacrine may antagonize the effect of nondepolarizing neuromuscular blocking agents

Succinylcholine: Tacrine may prolong the effect of succinylcholine

Theophylline: Tacrine may inhibit the metabolism of theophylline resulting in elevated plasma levels; dose adjustment will likely be needed

Ethanol/Nutrition/Herb Interactions

Food: Food decreases bioavailability.

Mechanism of Action

Centrally-acting cholinesterase inhibitor. It elevates acetylcholine in cerebral cortex by slowing the degradation of acetylcholine.

Pharmacodynamics/Kinetics

Absorption: Oral: Rapid

Distribution: Vd: Mean: 349 L; reduced by food

Protein binding, plasma: 55%

Metabolism: Extensively by CYP450 to multiple metabolites; first pass effect

Bioavailability: Absolute: 17%

Half-life elimination, serum: 2-4 hours; Steady-state: 24-36 hours

Time to peak, plasma: 1-2 hours

Dosage

Adults: Initial: 10 mg 4 times/day; may increase by 40 mg/day adjusted every 6 weeks; maximum: 160 mg/day; best administered separate from meal times.

Dose adjustment based upon transaminase elevations:

ALT 3 times ULN*: Continue titration

ALT >3 to 5 times ULN*: Decrease dose by 40 mg/day, resume when ALT returns to normal

ALT >5 times ULN*: Stop treatment, may rechallenge upon return of ALT to normal

*ULN = upper limit of normal

Patients with clinical jaundice confirmed by elevated total bilirubin (>3 mg/dL) should not be rechallenged with tacrine

Monitoring Parameters

ALT (SGPT) levels and other liver enzymes weekly for at least the first 18 weeks, then monitor once every 3 months

Reference Range

In clinical trials, serum concentrations >20 ng/mL were associated with a much higher risk of development of symptomatic adverse effects

Dietary Considerations

Give with food if GI side effects are intolerable.

Patient Education

This medication will not cure the disease, but may help reduce symptoms. Use as directed; do not increase dose or discontinue without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause dizziness, sedation, or hypotension (rise slowly from sitting or lying position and use caution when driving or climbing stairs); vomiting or loss of appetite (small, frequent meals, frequent mouth care, or chewing gum, or sucking lozenges may help); or diarrhea (boiled milk, yogurt, or buttermilk may help). Report persistent abdominal discomfort; significantly increased salivation, sweating, tearing, or urination; flushed skin; chest pain or palpitations; acute headache; unresolved diarrhea; excessive fatigue, insomnia, dizziness, or depression; increased muscle, joint, or body pain; vision changes or blurred vision; shortness of breath or wheezing; or signs of jaundice (yellowing of eyes or skin, dark colored urine or light colored stool, abdominal pain, or easy fatigue). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Nursing Implications

Monitor ALT levels and other liver enzymes weekly for at least the first 18 weeks, then monitor once every 3 months

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Capsule, as hydrochloride: 10 mg, 20 mg, 30 mg, 40 mg

References

Byrne J and Arie T, "Tetrahydroaminoacridine (THA) in Alzheimer's Disease," BMJ , 1989, 298(6677):845-6.

Crismon ML, "Tacrine: First Drug Approved for Alzheimer's Disease," Ann Pharmacother , 1994, 28(6):744-51.

Davis KL and Powchik P, "Tacrine," Lancet , 1995, 345(8950):625-30.

Davis KL, Thal LJ, Gamzu ER, et al, "A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease," N Engl J Med , 1992, 327(18):1253-9.

Eagger SA, Levy R, Sahakian BJ, et al, "Tacrine in Alzheimer's Disease," Lancet , 1991, 338(8758):50-1.

Farlow M, Gracon SI, Hershey LA, et al, "A Controlled Trial of Tacrine in Alzheimer's Disease," JAMA , 1992, 268(18):2523-9.

Knapp MJ, Knopman DS, Solomon PR, et al, "A 30-Week Randomized Controlled Trial of High-Dose Tacrine in Patients With Alzheimer's Disease," JAMA , 1994, 271(13):985-91.

Madden S, Spaldin V, and Park BK, "Clinical Pharmacokinetics of Tacrine," Clin Pharmacokinet , 1995, 28(6):449-57.

Watkins PB, Zimmerman HJ, Knapp MJ, et al, "Hepatotoxic Effects of Tacrine Administration in Patients With Alzheimer's Disease," JAMA , 1994, 271(13):992-8.

International Brand Names

Cognex® (AR, AT, AU, BE, BR, CL, ES, FR, NZ); Cognitiv® (AR); Tacrinal® (BR); Talem® (AR); THA® (AU)

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