Tacrine Hydrochloride

Class: Parasympathomimetic (Cholinergic) Agents
VA Class: AU300
Chemical Name: 9-Acridinamine, 1,2,3,4-tetrahydro-,monohydrochloride
CAS Number: 1684-40-8
Brands: Cognex

Warning(s)

Special Alerts:

This drug was removed from the US market in May, 2012.

Introduction

Centrally active, reversible anticholinesterase agent.2 3 4 5 6 12

Uses for Tacrine Hydrochloride

Alzheimer’s Disease

Palliative treatment of mild to moderate dementia of the Alzheimer’s type (Alzheimer’s Disease, presenile or senile dementia).1 3 5 12 13 14 15 16 17 18 24 46 47 53

Slideshow: Flashback: FDA Drug Approvals 2013

Tacrine Hydrochloride Dosage and Administration

General

  • Carefully adjust dose according to individual response and tolerance (e.g., serum ALT concentrations).1

  • Observe for adverse effects following initiation of therapy or an increase in dosage.1 46 47 48

  • Monitoring of ALT concentrations needed; adjustment in the treatment regimen may be needed in patients with ALT elevations.1

Liver Function Monitoring

  • Monitor serum ALT concentrations every other week from at least week 4 to week 16 and every 3 months thereafter.1

  • If serum ALT concentrations are >2 times to ≤3 times the ULN, monitor weekly until serum concentrations return to within normal limits.1

  • If serum ALT concentrations are >3 times to ≤5 times the ULN, reduce dosage and monitor weekly until serum concentrations return to within normal limits.1

  • If serum ALT concentrations are >5 times the ULN, discontinue therapy, at least temporarily, and monitor until serum concentrations return to normal.1

  • During rechallenge, monitor ALT concentrations every week for 16 weeks, every month for 2 months, then every 3 months thereafter.1

Administration

Administration

Administer orally1 12 13 14 15 16 17 25 27 28 between (i.e., ≥1 hour before) meals whenever possible.1 53 (See Food under Pharmacokinetics.) If mild GI upset occurs, administer with meals.1 53

Therapy should be initiated using a low dosage for the first 4 weeks.1 Increase dosage based on response and tolerance.1

Do not attempt dosage escalation during initial 4-week period due to possible delayed-onset liver function abnormalities.1 Decrease rate of dosage escalation if patient does not tolerate the recommended titration schedule; acceleration of recommended schedule is not advisable.1

Administer highest tolerated dosage; cognitive improvement is more likely to occur at higher dosages.46 Discontinue therapy if there is no improvement in clinical status after 3–6 months.46

Dosage adjustment or temporary discontinuance may be necessary in patients with serum ALT elevations.1

If tacrine therapy is interrupted for >4 weeks and reinitiation of the drug is not contraindicated, resume therapy using the lowest dosage and titrate upward.1

Rechallenge

When therapy is withheld due to elevated serum ALT concentrations, rechallenge with the drug when ALT concentrations have returned to within normal limits.1

Rechallenge in patients with elevations <10 times the ULN not associated with serious hepatic injury.1

Carefully weigh risks against the possible benefits in patients with elevations >10 times the ULN.1

Elevations in ALT concentrations (≥3 times the ULN) reported in patients who are rechallenged; time to onset of such elevations may be more rapid than with initial therapy.1

Dosage

Available as tacrine hydrochloride; dosage expressed in terms of tacrine.1

Adjust dosage or discontinue therapy in patients with serum ALT elevations as required.1 53

Adults

Alzheimer’s Disease
Initiation and Titration
Oral

Initially, 10 mg 4 times daily for at least 4 weeks.1 46 47 53

If well tolerated and increased serum ALT concentrations have not occurred, increase dosage to 20 mg 4 times daily;1 if tolerated, increase dosage in 40-mg daily increments (divided into 4 doses daily) at 4-week intervals1 up to a maximum of 160 mg daily (40 mg 4 times daily).1 46 47

Dosage Adjustment for ALT Elevations
Oral

If serum ALT concentrations are ≤3 times the ULN, continue usual dosages.1

If serum ALT concentrations are >3 times to ≤5 times the ULN, reduce dosage by 40 mg daily.1 Resume usual dosages when ALT concentrations have returned to within normal limits.1

If serum ALT concentrations are >5 times the ULN, withhold tacrine.1 Consider rechallenge when ALT concentrations have returned to within normal limits.1

Rechallenge
Oral

Initially, 10 mg 4 times daily for at least 6 weeks.1 If tolerated with no unacceptable changes in serum ALT concentrations, resume recommended dosage titration schedule.1

Prescribing Limits

Adults

Alzheimer’s Disease
Oral

Maximum 160 mg daily (40 mg 4 times daily).1 46 47

Special Populations

Hepatic Impairment

Reduced clearance is likely; dosage adjustments should be considered.1 b (See Hepatic Impairment under Cautions.)

Cautions for Tacrine Hydrochloride

Contraindications

  • Known hypersensitivity to tacrine or acridine derivatives.1

  • Jaundice, serum total bilirubin concentration >3 mg/dL, and/or clinical signs and/or symptoms of hypersensitivity (e.g., rash, fever) associated with elevations of ALT attributed to tacrine.1

Warnings/Precautions

Warnings

Permanently discontinue therapy in patients with clinical evidence of jaundice confirmed by elevations in serum total bilirubin concentration >3 mg/dL and/or clinical signs and/or symptoms of hypersensitivity (e.g., rash, fever) associated with elevations of ALT; do not rechallenge with the drug.1

Anesthesia

Potential for exaggerated succinylcholine-type muscle relaxation during anesthesia.1

Cardiovascular Effects

Possible bradycardia or other vagotonic effects on the heart.a Use with caution in patients with conduction abnormalities, bradyarrhythmias, or sick sinus syndrome.a

GI Effects

Possible diarrhea, nausea, and vomiting at recommended dosages.1

Potential for increased gastric acid secretion.1

Carefully monitor patients, especially those at increased risk for developing ulcers (e.g., those with history of peptic ulcer disease, those receiving concomitant NSAIA therapy), for symptoms of active or occult GI disease.1

Hepatic Effects

Increased serum ALT concentrations reported in >50% of patients receiving tacrine.1 37 Risk of increased ALT higher in women than men.1 37 Serum ALT concentrations return to normal following discontinuance or dosage reduction.1 37 Clinically evident hepatic injury occurs rarely.1 31 (See Hepatic Impairment under Cautions.)

Frequent monitoring of ALT needed.1 (See Liver Function Monitoring under Dosage and Administration.)

GU Effects

Potential urinary obstruction secondary to cholinergic activity.1

Nervous System Effects

Possible increased risk of seizures secondary to cholinergic activity or possibly as a manifestation of Alzheimer’s disease.1

Abrupt discontinuance or rapid dosage reduction (e.g., by ≥80 mg daily) may result in sudden worsening of the degree of cognitive impairment.1

Respiratory Effects

Use with caution in patients with a history of asthma.1

General Precautions

Hematologic Effects

Possible decreased ANC; however, serious hematologic abnormalities attributable to tacrine not reported.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether tacrine is distributed into milk.1

Pediatric Use

Safety and efficacy not established.1 31

Hepatic Impairment

Possible reduced clearance.1

Use with caution in patients with current evidence or history of liver function abnormalities (i.e., clinically important elevations in serum ALT, AST, bilirubin, and/or γ-glutamyltransferase [γ-glutamyltranspeptidase, GT, GGTP]).1 31 32 48 Discontinue therapy, at least temporarily, if ALT concentrations are >5 times the ULN.1

Renal Impairment

Possible fluid and electrolyte disturbances resulting from adverse GI effects.32 Use with caution.32

Common Adverse Effects

Elevated aminotransferases (ALT, AST), nausea, vomiting, diarrhea, anorexia, dyspepsia, myalgia, ataxia.1

Interactions for Tacrine Hydrochloride

Metabolized primarily by CYP1A2.1 Dosage adjustments may be necessary with concomitant administration of drugs that affect or are metabolized by this system.1 53

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs metabolized by CYP1A2.1 53

Smoking

Pharmacokinetic interaction (decreased tacrine concentrations).1

Specific Drugs

Drug

Interaction

Comments

Antacids (magnesium- or aluminum-containing)

Change in tacrine bioavailability unlikely1

Anticholinergic agents

Possible interference with activity of anticholinergic agents1

Cholinergic agonists

Synergistic effect1

Cholinesterase inhibitors

Synergistic effect1

Cimetidine

Increased tacrine concentrations and AUC1

Diazepam

Pharmacokinetic interaction unlikely1

Digoxin

Pharmacokinetic interaction unlikely1

Fluvoxamine

Increased tacrine concentrations and AUCa

Neuromuscular blocking agents (e.g., succinylcholine)

Exaggerated muscle relaxation1

Theophylline

Increased theophylline elimination half-life and theophylline concentrations1

Monitor plasma theophylline concentrations and adjust theophylline dosage as required1

Warfarin

Effect on anticoagulant activity unlikely1

Tacrine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; undergoes dose-dependent, first-pass metabolism.1 Absolute bioavailability is approximately 17%.1

Peak plasma concentrations are attained in 1–2 hours.1 Plasma concentrations are approximately 50% higher in women than men.1

Food

Food reduces bioavailability by approximately 30–40%.1

Distribution

Extent

Not evaluated.1

Not known whether tacrine is distributed into milk.1

Plasma Protein Binding

About 55%.1

Elimination

Metabolism

Extensively metabolized, principally via CYP1A2 to multiple metabolites.1

Elimination Route

Not known whether tacrine undergoes biliary excretion or enterohepatic circulation.1

Half-life

2–4 hours.1

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment to date; however, clearance may be reduced.1 Clearance not altered in patients with renal impairment.1

Stability

Storage

Oral

Capsules

15–30°C. Protect from moisture.1

Actions

  • Precise mechanism(s) of action in patients with dementia of the Alzheimer’s type not fully elucidated.1 Binds reversibly with and inactivates cholinesterases (e.g., acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine1 4 5 6 7 13 and resulting in increased acetylcholine concentrations at cholinergic synapses.1 4 5 6 7

Advice to Patients

  • Risk of adverse effects (e.g., nausea, vomiting, loose stools, diarrhea).1 Importance of caregivers monitoring for adverse effects and informing clinicians if they occur.1

  • Importance of clinicians informing caregivers that potential beneficial effects of therapy depend on administration of the drug at regular intervals.1

  • Need for periodic laboratory monitoring (i.e., liver function tests).1

  • Importance of clinicians informing caregivers that abrupt discontinuation or large decrease in total daily dose may cause a sudden worsening of the degree of cognitive impairment.1

  • Importance of informing clinicians of any new events or any increase in severity of existing adverse clinical events.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tacrine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

10 mg (of tacrine)

Cognex

First Horizon

20 mg (of tacrine)

Cognex

First Horizon

30 mg (of tacrine)

Cognex

First Horizon

40 mg (of tacrine)

Cognex

First Horizon

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cognex 10MG Capsules (SHIONOGI PHARMA): 120/$315.99 or 360/$893.99

Cognex 20MG Capsules (SHIONOGI PHARMA): 120/$315.99 or 360/$879.92

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Parke-Davis. Cognex (tacrine hydrochloride) capsules prescribing information. Morris Plains, NJ; 1997 Oct.

2. Parke-Davis. Cognex treatment IND investigator’s brochure. Morris Plains, NJ; 1992.

3. Cooper JK. Drug treatment of Alzheimer’s disease. Arch Intern Med. 1991; 151:245-9. [IDIS 277908] [PubMed 1992951]

4. Kumar V, Becker RE. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent for Alzheimer’s disease. Int J Clin Pharmacol Ther Toxicol. 1989; 27:478-85. [PubMed 2684868]

5. Volger BW. Alternatives in the treatment of memory loss in patients with Alzheimer’s disease. Clin Pharm. 1991; 10:447-56. [IDIS 281504] [PubMed 2065522]

6. Freeman SE, Dawson RM. Tacrine: a pharmacological review. Prog Neurobiol. 1991; 36:257-77. [PubMed 1714613]

7. Drukarch B, Kits KS, Van der Meer EG et al. 9-Amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer’s disease, inhibits acetylcholinesterase activity and slow outward K+current. Eur J Pharmacol. 1987; 141:153-7. [PubMed 2444444]

8. Rogawski MA. Tetrahydroaminoacridine blocks voltage-dependent ion channels in hippocampal neurons. Eur J Pharmacol. 1987; 142:169-72. [PubMed 2446884]

9. Freeman SE, Law WM, Szilagyi M. Blockade of a cardiac K+ channel by tacrine: interactions with muscarinic and adenosine receptors. Eur J Pharmacol. 1988; 154:59-65. [PubMed 3181293]

10. Mozar HN, Bal DG, Howard JT. Perspectives on the etiology of Alzheimer’s disease. JAMA. 1987; 257:1503-7. [PubMed 2950247]

11. Parke-Davis, Morris Plains, NJ: Personal communication.

12. Parke-Davis. Cognex treatment IND protocol 970-58. Morris Plains, NJ; 1992.

13. Farlow M, Gracon SI, Hershey LA et al. A controlled trial of tacrine in Alzheimer’s disease. JAMA. 1992; 268:2523-9. [IDIS 304558] [PubMed 1404819]

14. Davis KL, Thal LJ, Gamzu ER et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. New Engl J Med. 1992; 327:1253-9. [IDIS 303816] [PubMed 1406817]

15. Peripheral and Central Nervous System Drugs Advisory Committee Meeting, July 7, 1989. Rockville, MD: Dept. of Health and Human Services, Public Health Service, Food and Drug Administration; 1989:227.

16. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer’s disease. Lancet. 1991; 337:989-92. [IDIS 280218] [PubMed 1673209]

17. Anon. Tacrine for Alzheimer’s disease. Med Lett Drugs Ther. 1993; 35:87-8. [PubMed 8361451]

18. Small GW. Tacrine for treating Alzheimer’s disease. JAMA. 1992; 268:2564-5. [IDIS 304559] [PubMed 1404825]

19. Dom R. Tacrine in Alzheimer’s disease. JAMA. 1993; 269:2848-9. [IDIS 315101] [PubMed 8497088]

20. Cutler NR, Sramek JJ. Tacrine in Alzheimer’s disease. New Engl J Med. 1993; 328:808. [IDIS 310606] [PubMed 8437603]

21. Growdon JH. Treatment for Alzheimer’s disease? New Engl J Med. 1992; 327:1306-8. Editorial.

22. Pirozzolo FJ, Baskin DS, Swihart AA et al. Oral tetrahydroaminoacridine in the treatment of senile dementia, Alzheimer’s type. New Engl J Med. 1987; 316:1603. [IDIS 230804] [PubMed 3587295]

23. Lachs M. Tacrine in Alzheimer’s disease. New Engl J Med. 1993; 328:810. [IDIS 310609] [PubMed 8437607]

24. Food and Drug Administration Division of Neuropharmacological Drug Products. Tacrine as a treatment for Alzheimer’s dementia: an interim report from the FDA. N Engl J Med. 1991; 324:349-52. [IDIS 277140] [PubMed 1986300]

25. Summers WK, Majovski LV, Marsh GM et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med. 1986; 315:1241-5. [IDIS 222579] [PubMed 2430180]

26. Relman AS. Tacrine as a treatment for Alzheimer’s dementia: editor’s note. N Engl J Med. 1991; 324:349. [IDIS 277140] [PubMed 1986300]

27. Gauthier S, Bouchard R, Lamontagne A et al. Tetrahydroaminoacridine–lecithin combination treatment in patients with intermediate-stage Alzheimer’s disease: results of a Canadian double-blind, cross-over, multicenter study. N Engl J Med. 1990; 322:1272-6. [IDIS 265329] [PubMed 2183056]

28. Chatellier G, Lacombez L, and Groupe Francais d’Etude de la Tetrahydroaminoacridine. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. Br Med J. 1990; 300:495-9.

29. Ulus IH, Wurtman RJ. Prevention by choline of the depletion of membrane phosphatidylcholine by a cholinesterase inhibitor. N Engl J Med. 1988; 318:191. [PubMed 3336410]

30. Gauthier S. Tetrahydroaminoacridine and lecithin for Alzheimer’s disease. N Engl J Med. 1990; 323:920. [IDIS 272229] [PubMed 1697647]

31. Parke-Davis, Morris Plains, NJ: Personal communication.

32. Reviewers’ comments (personal observations).

33. Osterrieder W. 9-amino-1,2,3,4-tetrahydroacridine (THA) is a potent blocker of cardiac potassium channels. Br J Pharmacol. 1987; 92:521-5. [PubMed 2447986]

34. Schauf CL, Settin A. Tetrahydroaminoacridine blocks potassium channels and inhibits sodium inactivation in Myxicola. Soc Neurosci Abstract. 1987; 13:566.

35. Drukarch B, Kits KS, Vander Meer EG et al. 9-Amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer’s disease, inhibits acetylcholinesterase activity and slows outward K+current. Eur J Pharmacol. 1987; 141:153-7. [PubMed 2444444]

36. Knapp MJ, Knopman DS, Soloman PR et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA. 1994; 217:985-91.

37. Watkins PB, Zimmerman HJ, Knapp MJ et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994; 217:992-8.

38. Winker MA. Tacrine for Alzheimer’s disease: which patient, what dose? JAMA. 1994; 271:1023-4. Editorial.

39. Byrne EJ, Arie T. Tetrahydroaminoacridine and Alzheimer’s disease: for the few, but we don’t know which few. BMJ. 1994; 308:868-9. [IDIS 327976] [PubMed 8173360]

40. Maltby N, Broe GA, Creasey H et al. Efficacy of tacrine in mild to moderate Alzheimer’s disease: double blind trial. BMJ. 1994; 308:879-83. [IDIS 327979] [PubMed 8173365]

41. Pendlebury WW, Soloman PR. Tacrine is safe and effective. BMJ. 1994; 308:1506.

42. Levy R. Patient heterogeneity explains varied response. BMJ. 1994; 308:1506. [PubMed 8019288]

43. Roberts C, Ford J, Mäkelä P et al. Serum tacrine concentrations too low. BMJ. 1994; 308:1506.

44. Wilcock GK. Negative conclusions not justified. BMJ. 1994; 308:1507. [PubMed 8019291]

45. Broe GA, Creasey H, Maltby N et al. Author’s reply. BMJ. 1994; 308:1507.

46. American Psychiatric Association. Practice guidelines for the treatment of patients with Alzheimer’s disease and other dementias of late life. Am J Psychiatry. 1997; 154(Suppl):1-39.

47. Small GW, Rabins PV, Barry PP et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997; 278:1363-71. [IDIS 393115] [PubMed 9343469]

48. Watkins PB, Zimmerman HJ, Knapp MJ et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994; 271:992-8. [IDIS 327345] [PubMed 8139084]

49. Mos RC. Donepezil: a viewpoint. Drugs Aging. 1997; 10:240.

50. Whitehouse PJ. Donepezil: a viewpoint. Drugs Aging. 1997; 10:240-1.

51. Solomon PR, Knapp MJ, Gracon SI et al. Long-term tacrine treatment in patients with Alzheimer’s disease. Lancet. 1996; 348:275-6. [IDIS 370167] [PubMed 8684234]

52. Knopman D, Schneider L, Davis K et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality. Neurology. 1996; 47:166-77. [IDIS 370441] [PubMed 8710072]

53. Samuels SC, Davis KL. A risk-benefit assessment of tacrine in the treatment of Alzheimer’s disease. Drug Saf. 1997; 16:66-77. [PubMed 9010644]

54. Doody Rs, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2001; 56:1154-66. [IDIS 463599] [PubMed 11342679]

a. First Horizon. Cognex (tacrine hydrochloride) capsules prescribing information. Roswell, GA; 2002 Jan.

b. AHFS drug information 2006. McEvoy GK, ed. Tacrine. Bethesda, MD: American Society of Health-System Pharmacists; 2006:1251-4

Hide
(web1)