tacrine hydrochloride
Cognex

Available forms
Available by prescription only
Capsules: 10 mg, 20 mg, 30 mg, 40 mg

Indications and dosages
 Mild to moderate dementia of the Alzheimer’s type. Adults: Initially, 40 mg daily (10 mg P.O. q.i.d.). Maintain therapy for at least 4 weeks. After 4 weeks of therapy, begin every-other-week monitoring of transaminase levels. If patient tolerates treatment and transaminase levels remain normal, increase to 80 mg daily (20 mg P.O. q.i.d.). Adjust to higher dose at 4-week intervals to a total of 120 to 160 mg daily (30 to 40 mg P.O. q.i.d.).
≡ Dosage adjustment. For patients with an ALT level two to three times the upper limit of normal, monitor ALT level weekly.
If ALT level is three to five times the upper limit of normal, reduce dose by 40 mg daily and monitor ALT level weekly. Resume usual pattern of dose adjustment and every-other-week monitoring when ALT level returns to normal.
If ALT level is above five times the upper limit of normal, stop treatment and monitor ALT level. Monitor patient for signs and symptoms related to hepatitis. Rechallenge when ALT level is normal, and monitor ALT level weekly.

Pharmacodynamics
Psychotherapeutic action: Tacrine presumably slows degradation of acetylcholine released by still-intact cholinergic neurons, thereby elevating acetylcholine levels in the cerebral cortex. If this theory is correct, the effects of tacrine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. No evidence suggests that tacrine alters the course of the underlying dementia.

Pharmacokinetics
Absorption: Rapidly absorbed after oral administration. Absolute bioavailability of tacrine is about 17%. Food reduces tacrine bioavailability by about 30% to 40% if taken less than 1 hour before a meal.
Distribution: About 55% bound to plasma proteins.
Metabolism: Undergoes first-pass metabolism, which is dose dependent. It’s extensively metabolized by the cytochrome P-450 system to multiple metabolites, not all of which have been identified.
Excretion: Elimination half-life is about 2 to 4 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or acridine derivatives and in patients with hypersensitivity reactions related to elevated ALT level. Also contraindicated in patients with tacrine-related jaundice that’s been confirmed with an elevated total bilirubin level of more than 3 mg/dl.
  Use cautiously in patients with sick sinus syndrome, bradycardia, renal disease, Parkinson’s disease, asthma, prostatic hyperplasia, or other urinary outflow impairment. Also use cautiously in patients with a history of hepatic disease and in those at risk for peptic ulcer.

Interactions
Drug-drug. Anticholinergics: Decreases anticholinergic effectiveness. Monitor patient closely.
Cholinergics, cholinesterase inhibitors: Causes additive effects. Monitor patient for signs of toxicity.
Cimetidine: Increases tacrine level (by 54%). Monitor patient.
Drugs that undergo extensive metabolism via cytochrome P-450: May cause drug interactions. Use together cautiously.
NSAIDs: May contribute to GI irritation and gastric bleeding. Monitor patient carefully.
Theophylline: Doubles theophylline elimination half-life and average plasma levels. Monitor plasma theophylline level.
Drug-food. Any food: May delay drug absorption. Give drug 1 hour before meals.
Drug-lifestyle. Smoking: Significantly decreases drug levels. Discourage smoking.

Adverse reactions
CNS: agitation, ataxia, insomnia, abnormal thinking, somnolence, depression, anxiety, headache, dizziness, fatigue, confusion, seizures.
CV: bradycardia, hypertension, palpitations, chest pain.
EENT: rhinitis.
GI: nausea, vomiting, diarrhea, dyspepsia, loose stools, changes in stool color, anorexia, abdominal pain, flatulence, constipation.
Metabolic: hyperglycemia, weight loss.
Musculoskeletal: myalgia.
Respiratory: upper respiratory tract infection, cough.
Skin: rash, jaundice, facial flushing.
Other: increased sweating.

Effects on lab test results
• May increase ALT and AST levels.

Overdose and treatment
Overdose with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, and seizures. Increasing muscle weakness may occur and can result in death if respiratory muscles are involved.
 Provide supportive care. Tertiary anticholinergics, such as atropine, may be used as an antidote for tacrine overdose. I.V. atropine sulfate titrated to effect is recommended (initial dose of 1 to 2 mg I.V. in adults, with subsequent doses based on clinical response). In children, may give 0.05 mg/kg I.V. or I.M., repeated q 10 to 30 minutes until muscarinic signs and symptoms subside. It isn’t known whether tacrine or its metabolites can be eliminated by dialysis.

Special considerations
• Tacrine as a cholinesterase inhibitor is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
• Drug may have vagotonic effects on the heart rate, such as bradycardia. Use cautiously in patients with sick sinus syndrome.
• Dose escalation may be slowed if patient is intolerant to recommended dosage adjustment schedule. Acceleration of dosage adjustment schedule is never recommended.
• Cognitive function can worsen after abrupt discontinuation of tacrine or after a reduction in total daily dose of 80 mg or more.
• If drug is discontinued for 4 weeks or longer, restart dosage adjustment and monitoring schedule.
• The risk of transaminase elevations is higher among women. There are no other known predictors of risk of hepatocellular injury.
• Monitor serum ALT levels every other week from at least week 4 to week 16 following start of therapy, after which monitoring may be decreased to every 3 months if ALT level is less than or equal to two times the upper limit of normal. After each dosage adjustment, resume monitoring schedule.
• Monitor patient for dose tolerance and cognitive changes.

Patient education
• Instruct caregiver to give drug between meals. If GI upset occurs, drug may be taken with food but plasma levels may be reduced.
• Inform caregiver that drug can alleviate symptoms but doesn’t alter the underlying degenerative disease.
• Inform caregiver that effectiveness of therapy depends on drug administration at regular intervals.
• Caution caregiver that dosage adjustment is an integral part of the safe use of drug. Abrupt discontinuation or a large reduction in daily dose (80 mg or more) may precipitate behavioral disturbances and a decline in cognitive function.
• Advise caregiver to promptly report significant adverse effects or changes in status.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use