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Tacrine Hydrochloride

( Tetrahydroaminoacridine ; THA )

Pronunciation: TAK-reen HIGH-droe-KLOR-ide
Class: Cholinesterase inhibitor

Trade Names

Cognex
- Capsules 10 mg
- Capsules 20 mg
- Capsules 30 mg
- Capsules 40 mg

Pharmacology

Believed to inhibit (reversibly) cholinesterase in CNS, leading to increased concentrations of acetylcholine.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Tacrine is rapidly absorbed after oral administration. T max is 1 to 2 h. Tacrine bioavailability is approximately 17%; food reduces bioavailability about 30% to 40%; however, there is no food effect if given at least 1 h before meals. Steady state is achieved within 24 to 36 h.

Distribution

Vd is about 349 L and it is approximately 55% bound to plasma proteins.

Metabolism

Extensively metabolized by the cytochrome P450 system. Cytochrome P450 1A2 is the principal isozyme involved in metabolism. The extent of first-pass metabolism depends on the dose administered.

Elimination

The t ½ is approximately 2 to 4 h.

Special Populations

Hepatic Function Impairment

Hepatic impairment may reduce Cl.

Gender

Plasma concentrations are about 50% higher in women than men.

Smoking

Mean plasma concentrations in people who currently smoke are approximately one third the concentrations in nonsmokers.

Indications and Usage

Treatment of mild to moderate dementia of Alzheimer type.

Contraindications

Hypersensitivity to acridine derivatives; previous treatment with tacrine that resulted in jaundice (confirmed by elevated total bilirubin greater than 3 mg/dL); signs or symptoms of hypersensitivity (eg, rash, fever) in association with ALT elevations.

Dosage and Administration

Adults Initial dose

PO 40 mg/day (10 mg 4 times daily). Maintain this dose for at least 4 wk with every-other-week monitoring of transaminase levels beginning at week 4 of therapy.

Titration

PO Increase the dose to 80 mg/day (20 mg 4 times daily), providing there are no significant transaminase elevations and the patient is tolerating treatment. Titrate patients to higher doses (120 and 160 mg/day in divided doses on a 4 times daily schedule) at 4-wk intervals on the basis of tolerance.

Dose adjustment

If transaminase levels are greater than 2 to 3 × ULN or less, continue treatment according to recommended titration. Monitor transaminase levels weekly until levels return to normal limits. If transaminase levels are greater than 3 to 5 × ULN or less, reduce the daily dose by 40 mg/day. Monitor ALT levels weekly. Resume dose titration and every other wk monitoring when transaminase levels return to within normal limits. If transaminase levels are greater than 5 × ULN, stop treatment. Monitor the patient closely for signs and symptoms associated with hepatitis and follow transaminase levels until within normal limits.

Rechallenge

Initial dose of 40 mg/day (10 mg 4 times daily) and monitor transaminase levels weekly. If after 6 wk on 40 mg/day the patient is tolerating the dosage with no unacceptable elevations in transaminases, recommended dose titration and transaminase monitoring may be resumed.

Storage/Stability

Store capsules at controlled room temperature (59° to 86°F). Protect from moisture.

Drug Interactions

Cimetidine, fluvoxamine

Increased tacrine concentrations.

Levodopa

The antiparkinsonism effects of levodopa may be inhibited.

Theophylline

Increased theophylline concentrations.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension, hypertension (at least 1%).

CNS

Dizziness (12%); headache (11%); agitation, confusion (7%); ataxia, insomnia (6%); depression, fatigue, somnolence (4%); abnormal thinking, anxiety (3%); tremor, hallucinations, hostility (2%); convulsions, vertigo, syncope, hyperkinesias, paresthesia, nervousness (at least 1%).

Dermatologic

Rash (7%); facial/skin flushing (3%); increased sweating (at least 1%).

EENT

Rhinitis (8%); conjunctivitis, pharyngitis, sinusitis (at least 1%).

GI

Nausea/vomiting (28%); diarrhea (16%); dyspepsia, anorexia (9%); abdominal pain (8%); flatulence, constipation (4%).

Genitourinary

Urinary incontinence, urinary frequency, UTI (3%).

Metabolic-Nutritional

Weight decrease (3%).

Musculoskeletal

Myalgia (9%); fracture, arthralgia, arthritis, hypertonia (at least 1%).

Respiratory

Coughing, upper respiratory tract infection (3%); bronchitis, pneumonia, dyspnea (at least 1%).

Miscellaneous

Elevated transaminases (29%); chest pain (4%); back pain, asthenia, purpura (2%); chills, fever, malaise, peripheral edema (at least 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in any dementing illness.

Hepatic Function

Use drug with caution in patients with history of abnormal liver function.

Carcinogenesis

May be carcinogenic.

Anesthesia

Use of muscle relaxants (eg, succinylcholine) during anesthesia, while receiving tacrine, may lead to exaggerated effects.

Concomitant medical conditions

Increases cholinergic activity and therefore can affect other organ systems, possibly leading to bradycardia, bladder outflow obstruction, increased gastric acid secretion, or bronchoconstriction. Use drug with caution in patients susceptible to these effects.

Hematology

An absolute neutrophil count (ANC) less than 500/mcL occurred in 4 patients who received tacrine during the course of clinical trials.

Neurologic conditions

Drug may contribute to seizures. Cognitive function may worsen after discontinuation or large dose reductions.

Overdosage

Symptoms

Cholinergic crisis, severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, convulsions.

Patient Information

  • Advise patient or caregiver that this drug does not alter the Alzheimer process and that effectiveness of the medication may lessen over time.
  • Instruct patient or caregiver to continue using other medications for dementia or behavior as prescribed by health care provider.
  • Advise patient or caregiver that medication is started at a low dose and gradually increased (no more often than every 4 wk) as tolerated until max benefit is obtained.
  • Advise patient or caregiver to take prescribed doses at regular intervals between meals but to take with food if GI upset occurs. Encourage consistency in dosage schedule (eg, either always between meals or always with food) to prevent fluctuations in effectiveness and side effects.
  • Caution patient or caregiver not to discontinue the drug or change the dose unless advised by health care provider.
  • Caution patient or caregiver that if medication is discontinued for more than 1 wk to notify health care provider before restarting the medication.
  • Advise patient or caregiver that nausea, vomiting, and diarrhea are common side effects and to notify health care provider if they occur and are intolerable.
  • Advise patient that drug may cause drowsiness or dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise patient or caregiver to notify health care provider immediately if any of the following are noted: rash, fever, persistent nausea or vomiting, yellowing of skin or eyes.
  • Advise patient or caregiver to report changes in thinking or behavior, bothersome side effects, or unexplained feelings or symptoms.

Copyright © 2009 Wolters Kluwer Health.

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