Tacrine (Systemic)


VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Cognex.

Other commonly used names are
tetrahydroaminoacridine {09} {10} {11} {12} {13} {14} {15} {16} {23} {26} {34} and THA {06} {07} {08} {09} {10} {11} {12} {13} {14} {23} {24} {25} {28}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Dementia symptoms treatment adjunct{43}

Indications

Accepted

Dementia of the Alzheimer's type, mild to moderate (treatment)—Tacrine is indicated for the symptomatic treatment of mild to moderate dementia of the Alzheimer's type. {06} Clinical trials have found tacrine to be of limited efficacy in the treatment of this condition. {07} {08} {09} {10} {11} {12} {13} {16} {19} {21} {22} {23} {26} {29}
—In one high-dose, 30-week clinical trial of tacrine, approximately 43% of the 663 patients enrolled dropped out due to adverse medication effects, primarily elevated transaminase values and gastrointestinal effects {41}, and only 28% of patients randomized to the 160 mg per day (mg/day) treatment group were able to complete the study. {41} {42} Of those patients who achieved the maximum tacrine dosage of 160 mg/day, and completed the 30-week study, 42% showed improvement in the Clinician Interview–Based Impression (CIBI), a global evaluation of change; 42% showed improvement in the Final Comprehensive Consensus Assessment (FCCA), which was similar to the CIBI but included caregivers' impressions; and 40% showed at least a 4 point improvement on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), an objective 70-point evaluation of cognitive function. {41} The only significant improvement seen in the lower dosage treatment groups was on the FCCA in the 120 mg/day patients. {41} Among patients who received placebo, 18% showed improvement in the CIBI, 16% showed improvement in the FCCA, and 25% improved on the ADAS-Cog by at least 4 points. {41} The improvements seen in clinical trials of tacrine were comparable in magnitude to the decline that would be expected to occur over a 6-month period in a patient with Alzheimer's disease. {16} {19} {21} {42}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Acridines {03} {06}
Molecular weight—
    Tacrine hydrochloride monohydrate: 252.74 {06}

pKa—
    9.85 {29}

Mechanism of action/Effect:

While many neuronal systems are affected in Alzheimer's disease {07} {10} {11} {13} {19}, the decline in central cholinergic activity is one of the most pronounced neurotransmitter deficits {07} {19}. This deficit occurs early in the disease process {07} {18} and correlates with decreased scores on dementia ratings scales {07} {09} {10} {11} {12} {31}. Tacrine's primary effect is the reversible {07} {11} {14} {19} {21} {22} {23} {29} {40} inhibition of cholinesterase {07} {11} {14} {19} {21} {22} {23} {28} {29} {40}, butyrylcholinesterase more than acetylcholinesterase. {23} {28} {29} This inhibition is thought to increase the level of acetylcholine available in the central nervous system. {06} {07} {10} {11} {14} {23} In fact, increased levels of acetylcholine have been detected in the cerebrospinal fluid of patients receiving tacrine. {07} {10} {23}

Tacrine may also block potassium channels {07} {10} {11} {14} {16} {23} {28} {29} {30}, increasing the duration of the action potential {11} {23} {28} {29} {30} and augmenting acetylcholine release from cholinergic neurons {07} {10} {11} {14} {23} {28} {29} {30}.

In addition, tacrine may moderate cholinergic activity by acting as a partial agonist {07} {22} {28} or antagonist {07} {29} through direct binding {14} {23} {28} to nicotinic receptors {07} {11} {14} {16} {23} {29} and, with greater affinity {14} {23} {28} {29}, to muscarinic receptors {07} {11} {14} {16} {23} {29}.

Additionally, tacrine inhibits monoamine oxidase (MAO) {07} {16} {22} {28} {29}, MAO-A to a greater extent than MAO-B {07} {28} {29}. Tacrine may also inhibit the reuptake of norepinephrine {07} {22} {28}, serotonin {07} {22} {28}, and dopamine {22} {28}.

There is no evidence that tacrine alters the underlying dementing process {06}, and its effect may be expected to lessen as the disease progresses {06} {10}.


Other actions/effects:

Because of its cholinomimetic action, tacrine may have vagotonic effects on the heart, including bradycardia {06}, and may increase the activity of the gastrointestinal and urinary tracts. {44} {45}

Absorption:

Tacrine is rapidly absorbed {04} {06} {07} {10} {24} {32}. Probably due to a very high first-pass metabolism {06} {22} {24}, absolute bioavailability is about 17 ± 13% {06} {11} {24}. Bioavailability increases with increasing dose in a nonlinear manner {06} {07} {22}, and large interindividual variations are seen {04} {07} {24} {29}. Food decreases bioavailability {06} {22} by 30 to 40% {06}.

Distribution:

Mean volume of distribution (Vol D) is 349 ± 193 L {06} {24}.

In rats, tacrine readily penetrates the blood-brain barrier {10} {29} {30}, resulting in brain concentrations approximately 10 times those of plasma. {07} {28} {29}

Protein binding:

Moderate (55%). {06}

Biotransformation:

Hepatic {04} {06} {10}; cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. {06} {40} The major metabolite {07}, 1-hydroxy-tacrine {04} {07} {20} {24}, or velnacrine {04} {07}, has central cholinergic activity {04} {05} {07} {24}.

Half-life:


Elimination:

Tacrine: 1.5 to 4 hours. {06} {07} {11} {20} {22} {24} {32} {33}

1-hydroxy-tacrine (velnacrine): 2.5 to 3.1 hours. {05}


Time to peak concentration:

1 to 2 hours {06} {22} {23} {32} {33}.

Peak serum concentration:

Peak serum concentration increases nonlinearly with dose {06} {07} {22} {32} {33}. Because the enzyme system responsible for presystemic clearance (i.e., first-pass metabolism) can be saturated at relatively low doses {06}, a larger fraction of a high dose than of a low dose will reach the systemic circulation. {06} Also, peak serum concentration shows wide interindividual variation {20} {22}. Average tacrine plasma concentrations are approximately 50% higher in females than in males {55}; this increase may reflect the lower activity of cytochrome P450 1A2 in women {55}. Mean plasma concentrations of tacrine in current smokers of tobacco are approximately one third that of tacrine concentrations in nonsmokers {55}; this decrease is caused by the induction of cytochrome P450 1A2 by cigarette smoking {55}.

Elimination:
    Negligible amount excreted in urine {04} {22} {32}. In a mass balance study, 336 hours after a single radiolabeled dose was administered, approximately 25% of the radiolabel remained unrecovered, suggesting the possibility that tacrine and/or one or more of its metabolites may be retained {06} {55}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to other acridine derivatives, such as the topical antiseptics 9-aminoacridine (e.g., Akrinol, Monacrin), acriflavine (e.g., Panflavin), or proflavine {53}, may be hypersensitive to tacrine. {06}

Carcinogenicity

Since some members of its chemical class (acridines) are known to be animal carcinogens, tacrine may be carcinogenic. {03} {06}

Mutagenicity

Tacrine was mutagenic to bacteria in the Ames test {06}, but was not mutagenic in an in vitro mammalian mutation test. {06} Tacrine induced unscheduled DNA synthesis in rat and mouse hepatocytes in vitro {06}.

Pregnancy/Reproduction
Fertility—
Studies of effects of tacrine on fertility have not been performed. {06}

Pregnancy—
Studies have not been done in humans. {06}

Studies have not been done in animals. {06}

FDA Pregnancy Category C {06}.

Breast-feeding

Problems in humans have not been documented. It is not known whether tacrine is distributed into breast milk. {06} However, use of tacrine is not recommended in nursing mothers. {46}

Pediatrics

There are no adequate and well-controlled studies to determine the safety and efficacy of tacrine in any dementing illness occurring in pediatric patients. {55}


Geriatrics


Clinical trials of tacrine have included Alzheimer's disease patients 40 years of age and older {12} {13} {16} {19} {21} {26} {41} with no other significant disease {41} {42} {47}; information available on the effects of tacrine is based upon this population. Comparisons with younger age groups have not been performed. However, elderly patients are more likely to have age-related prostate problems, which may require caution in patients receiving tacrine, especially if urinary tract obstruction is present. {30}

Surgical

If possible, tacrine should be discontinued on a tapered schedule, under medical supervision, 3 days before any surgery involving general anesthesia. Possible interactions between tacrine and surgical adjuncts have not been fully characterized. {37} However, tacrine may prolong {29} {39} or exaggerate {06} the effects of neuromuscular blocking agents that are metabolized by plasma cholinesterase. {06} {29} {38} {39}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Interactions may occur when tacrine is given concurrently with other medications metabolized by cytochrome P450 enzymes, particularly the P450 1A2 isozyme, since that is the principal isozyme involved in tacrine metabolism {55}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticholinergics (see Appendix II ){06}{55}    (concurrent use may decrease the effects of either these medications {48} or tacrine {49})


Cholinomimetics (e.g., bethanecol) and cholinesterase inhibitors (e.g., neostigmine){06}{22}{55}    (concurrent use may increase the effects of either these medications or tacrine and increase the potential for toxicity {06})


» Cimetidine{06}{55}    (concurrent use increases peak tacrine plasma concentrations by about 54% and increases the area under the tacrine plasma concentration-time curve [AUC] by about 64%; the potential for toxicity may be increased)


» Neuromuscular blocking agents metabolized by plasma cholinesterase (e.g., succinylcholine, mivacurium){06}{29}{38}{39}    (tacrine inhibits cholinesterase {07} {11} {14} {19} {21} {22} {23} {28} {29} and may prolong {29} {39} or exaggerate {06} muscle relaxation)


» Nonsteroidal anti-inflammatory drugs (NSAIDs){06}{30}    (tacrine may increase gastric acid secretion {06}, which may contribute to gastrointestinal irritation; patient should be monitored for occult gastrointestinal bleeding {06})


» Smoking tobacco{06}{55}    (mean plasma concentration of tacrine is 67% lower in current smokers than in nonsmokers {06} {55}; the effectiveness of tacrine in smokers may be decreased {50})


» Theophylline{06}{22}{55}    (concurrent use increases mean plasma concentration and half-life of theophylline to approximately twice normal values {06}, increasing the potential for toxicity; theophylline plasma concentration should be monitored {06} {22}, and dosage reduced as indicated {06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


This medication should not be used when the following medical problems exist:
» Jaundice, tacrine treatment–associated, confirmed by elevated total bilirubin greater than 3 mg per dL (mg/dL), or history of{06}{55}    (condition may be exacerbated or reactivated)


» Known hypersensitivity to tacrine{06} or other acridine derivatives{06}{55}
Risk-benefit should be considered when the following medical problems exist
» Asthma, bronchial, active or latent{06}{30}    (asthma attack may be precipitated)


» Cardiovascular conditions, such as:
Bradycardia{30}{55}
Hypotension{30}{55}
Sick sinus syndrome{06}{55}    (vagotonic effect on heart may exacerbate pre-existing conditions {06})


» Epilepsy or history of seizures{55} or
» Head injury with loss of consciousness{51} or
» Increased intracranial pressure, pre-existing{43} or
» Intracranial lesions{43} or
» Metabolic disorders{01} , unstable{51}    (seizures may occur)


» Gastrointestinal obstruction{30} or
» Urinary tract obstruction{30}{55}    (increased activity of gastrointestinal tract or urinary bladder may be harmful)


» Hepatic function impairment, current or history of{06}{55}    (condition may be exacerbated or reactivated)


» Parkinson's disease{30}{31}    (increased cholinergic activity in the central nervous system may exacerbate condition {30} {31})


» Peptic ulcer, active or history of{06}{30}{55}    (increased gastric acid secretion may exacerbate or reactivate condition {06} {30})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cognitive function{42}{47}    (periodic objective assessment of cognitive status is recommended to determine effectiveness of tacrine treatment)


» Alanine aminotransferase (ALT [SGPT]) serum values{06}    (monitoring every other week {54} is required from at least week 4 to week 16 following initiation of therapy and following reinstitution of tacrine after a suspension of therapy of more than 4 weeks. {54} Testing frequency may then be reduced to once every 3 months {54} in the absence of ALT [SGPT] serum value elevations. However, weekly testing should be performed if ALT [SGPT] serum values are greater than twice the upper limit of normal [ULN] {06} {54}. For serum values up to three times the ULN, recommended dosage titration may be continued {06} {54}; for serum values greater than three, and up to five times the ULN, the dosage should be reduced by 40 mg per day {06} {54}; dosage titration {06} {54} and monitoring every other week {54} may be resumed when ALT [SGPT] serum values return to within normal limits; for serum values greater than five times the ULN, tacrine should be discontinued {06} {54} and the patient should be monitored closely for signs and symptoms of hepatitis {54}; rechallenge may be considered when ALT [SGPT] serum values return to within normal limits {06} {54})


Note: Experience rechallenging patients who have had ALT (SGPT) serum values greater than 10 times the ULN is limited; risk versus demonstrated benefit should be considered. {06} {54} Patients who have experienced tacrine treatment–related jaundice confirmed by elevated total bilirubin greater than 3 mg per dL (mg/dL) {06} {54} and patients exhibiting clinical signs of hypersensitivity, such as rash or fever, in association with ALT (SGPT) serum value elevations {54} should permanently discontinue the use of tacrine and should not be rechallenged {06} {54}.




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Ataxia{06}{22} (clumsiness or unsteadiness)
    
gastrointestinal toxicity, specifically anorexia{06}{15}{16}{26} (loss of appetite), diarrhea{06}{07}{10}{11}{13}{16}{19}{21}{22}{23}{26}
nausea{06}{07}{09}{10}{11}{12}{13}{15}{16}{19}{21}{22}{23}{26}
or vomiting{06}{07}{09}{10}{11}{12}{13}{15}{16}{19}{21}{22}{23}{26}
    
hepatotoxicity (50%){06}{07}{09}{15}{17}{22} (change in stool color [rare]{06}; fever [infrequent]{06}{34}; yellow eyes or skin [rare]{06}{07}{15}{34})

Note: Approximately 50% of all patients started on tacrine will develop elevated transaminase serum values {06} {07} {09} {15} {19} {21} {22} {40}, usually within 12 weeks {06} {07} {21} {22} {40} of initiation of therapy. Approximately 25% of all patients started on tacrine will develop transaminase serum values greater than three times the upper limit of normal (ULN) {06} {07} {16} {19} {21} {22} {40}, and about 7% will develop elevations greater than 10 times the ULN {55}. Females are at greater risk than males for developing transaminase elevation. {06} {07} {08} {15} {17} {19} {40} Rarely, clinical signs of hepatotoxicity emerge, such as jaundice {06} {07} {11} {15} {34} and fever {34}. Liver biopsies in these patients have revealed granulomatous changes {06} {07} {12} {22} and hepatocellular necrosis {06} {07} {08} {12} {13} {22} {34}. In cases of hepatotoxicity reported to date, liver function tests have returned to normal {06} {07} {08} {09} {12} {13} {15} {16} {17} {19} {21} {23} {40}, usually within 6 weeks of dosage reduction or discontinuation of tacrine. {06} {07} {12} {13} {15} {19} {21} {22}
Anorexia, diarrhea, nausea, and vomiting appear to be dose-related {55}.


Incidence less frequent
    
Cardiovascular effects, specifically bradycardia{06}{07}{10}{11}{12}{33} (slow heartbeat), hypertension{06} (high blood pressure), hypotension{06} (low blood pressure), or palpitation{06}{13} (fast or pounding heartbeat)
    
skin rash{06}{13}{16}{21}{23}
    
syncope{06} (fainting)

Incidence rare
    
Asthma{06} (cough; tightness in chest; trouble in breathing; wheezing)
    
convulsions{06} (seizures)—associated with cholinergic effects, particularly diarrhea{47}
    
mood or mental changes, specifically aggression{16} , irritability{16} , or nervousness{06}
    
parkinsonian extrapyramidal effects{06}{50}{52} (stiffness of arms or legs; slow movement; trembling and shaking of hands and fingers)
    
tachycardia{06}{07} (fast heartbeat)
    
urinary obstruction{06} (trouble in urinating)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dizziness{06}{07}{13}
    
gastrointestinal effects, specifically abdominal pain or cramping{06}{07}{09}{11}{13}{19}{21}{23}{33} , or dyspepsia{06}{16}{21} (indigestion)
    
headache{07}{12}{15}{16}{19}{22}
    
myalgia{06}{11}{22} (muscle pain)

Note: Dyspepsia appears to be dose-related {55}.


Incidence less frequent
    
Belching{10}{23}
    
flushing of skin{06}{16}
    
hyperventilation{06} (fast breathing)
    
insomnia{06}{07} (trouble in sleeping)
    
lacrimation, increased{11} (watering of eyes)
    
malaise{06}{15} (general feeling of discomfort or illness)
    
peripheral edema{06}{11} (swelling of feet or lower legs)
    
polyuria{06}{10}{13} (frequent urination or increased volume of urine)
    
rhinitis{06} (runny nose)
    
salivation, increased{06}{13} (watering of mouth)
    
sweating, increased{06}{07}{10}{13}{21}{23}





Overdose
For specific information on the agents used in the management of tacrine overdose, see:
   • Atropine sulfate in Anticholinergics/Antispasmodics (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Cardiovascular effects, specifically bradycardia{06} (slow heartbeat), hypotension{06} (low blood pressure), or shock{06} (fast weak pulse; irregular breathing; large pupils)
    
convulsions{06} (seizures)
    
muscular weakness, increasing —may lead to death if respiratory muscles are involved{06}
    
nausea, severe{06}
    
salivation, excessive{06} (watering of mouth)
    
sweating, excessive{06}
    
vomiting, severe{06}


Treatment of overdose
Specific treatment—


In adults: Administering intravenous atropine sulfate, initial dose of 1 to 2 mg, with subsequent doses based on clinical response. {06}


In children: Administering intramuscular or intravenous atropine sulfate, initial dose of 0.05 mg per kg of body weight (mg/kg), with subsequent doses administered every 10 to 30 minutes until muscarinic signs and symptoms subside; if symptoms reappear, dose may be repeated. {55}

Supportive care—Providing supportive therapy. {06} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tacrine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to tacrine or other acridine derivatives {06}
Other medications, especially cimetidine, neuromuscular blocking agents, NSAIDs, smoking tobacco, and theophylline
Other medical problems, especially asthma, cardiovascular conditions (such as bradycardia, hypotension, or sick sinus syndrome), epilepsy or history of seizures, gastrointestinal or urinary tract obstruction, head injury with loss of consciousness, hepatic function impairment, increased intracranial pressure, intracranial lesions, Parkinson's disease, peptic ulcer, and unstable metabolic disorders

Proper use of this medication
» Not taking more medication than the amount prescribed because of increased risk of adverse effects {06}

Taking tacrine on empty stomach if tolerated {06}

Taking doses at regular intervals for maximum efficacy {06}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if within 2 hours of time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of complying with monitoring schedule and keeping appointments with physician and/or laboratory

Informing physician when new symptoms arise or when previously noted symptoms increase in severity {06}

Caution if any kind of surgery or emergency treatment is required; informing physician or dentist in charge that tacrine is being taken {06}

Caution if dizziness, clumsiness, or unsteadiness occurs

» Not decreasing dose or discontinuing treatment without consulting physician because of possible decline in cognitive function and behavioral disturbances {06}

» Suspected overdose: Getting emergency help at once


Side/adverse effects
Ataxia; gastrointestinal toxicity, specifically anorexia, diarrhea, nausea, or vomiting; hepatotoxicity; cardiovascular effects, specifically bradycardia, hypertension, hypotension, or palpitation; skin rash; syncope; asthma; convulsions; mood or mental changes, specifically aggression, irritability, or nervousness; parkinsonian extrapyramidal effects; tachycardia; urinary obstruction


General Dosing Information
Tacrine should be taken on an empty stomach {06} (either 1 hour before meals or 2 hours after meals) for more complete absorption {06} {22}. However, if stomach upset occurs, tacrine may be taken with food {06}; if taken with food, tacrine plasma concentrations will be decreased by approximately 30 to 40% {55}.

Tacrine should be taken at regular intervals for best effect. {06}

The rate of dosage escalation may be slowed in patients who are having difficulty tolerating the recommended dosage escalation schedule. However, dosage escalation should not be accelerated, or the incidence of serious adverse effects may be increased. {06}

The first dosage increase should not be made earlier than 6 weeks after initiation of tacrine therapy because of the possibility of delayed transaminase elevation. {06}

The patient should be carefully observed for side effects following initiation of therapy and following every dosage increase. {06}

Abrupt discontinuation of tacrine {06} {26} or a decrease of 80 mg or greater in daily tacrine dose {06} has caused decreased cognitive function {06} {26} {55} and behavioral disturbances. {06} {55}


Oral Dosage Forms

Note: The available dosage form contains tacrine hydrochloride, but dosage and strength are expressed in terms of the base. {06}

TACRINE CAPSULES

Usual adult dose
Alzheimer's dementia
Oral, initially 10 mg (base) four times a day. After at least four weeks, if there are no significant transaminase elevations and the patient is tolerating treatment, the dose may be increased to 20 mg four times a day. Further increases to 30 mg four times a day, and then to 40 mg four times a day may be instituted at intervals of at least four weeks, based on patient tolerance. {06}

If elevations of serum transaminase occur, tacrine dosage should be modified. Recommended modifications are:

Transaminase
serum value
(times upper limit
of normal [ULN])
Treatment regimen
modification
£ 2
No modification.
> 2 to £ 3
Continue recommended dose titrations. Monitor transaminase serum values weekly until within normal limits.
> 3 to £ 5
Reduce the daily dose of tacrine by 40 mg per day. Monitor transaminase serum values weekly, and resume dose titration when values return to within normal limits.
> 5
Stop tacrine treatment. Monitor transaminase serum values until within normal limits. Consider rechallenge with tacrine.
> 10
Rechallenge experience is limited with these patients. Risk versus demonstrated benefit should be considered.


Note: For rechallenge: Dose titration schedule is the same as that for new patients. {06} {54} However, ALT (SGPT) serum values should be monitored weekly for the first sixteen weeks following re-initiation of tacrine therapy {55}. If unacceptable elevations in ALT (SGPT) serum values do not recur, monitoring frequency may be decreased to monthly for two months and every three months thereafter. {54} {55}
Patients who have experienced tacrine treatment–related jaundice confirmed by elevated total bilirubin greater than 3 mg per dL (mg/dL) {06} {54} and patients exhibiting clinical signs of hypersensitivity, such as rash or fever, in association with ALT (SGPT) serum value elevations {54} should permanently discontinue use of tacrine and should not be rechallenged. {06} {54}



Usual adult prescribing limits
160 mg a day. {06}

Usual pediatric dose
Safety and efficacy have not been established. {06}

Usual geriatric dose
See Usual adult dose. {06}

Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Cognex (hydrous lactose) (magnesium stearate) (microcrystalline cellulose) (gelatin) (silicon dioxide) (sodium lauryl sulfate) (D&C Yellow #10) (FD&C Green #3) (titanium dioxide)]


20 mg (base) (Rx) [Cognex (hydrous lactose) (magnesium stearate) (microcrystalline cellulose) (gelatin) (silicon dioxide) (sodium lauryl sulfate) (D&C Yellow #10) (FD&C Blue #1) (titanium dioxide)]


30 mg (base) (Rx) [Cognex (hydrous lactose) (magnesium stearate) (microcrystalline cellulose) (gelatin) (silicon dioxide) (sodium lauryl sulfate) (D&C Yellow #10) (FD&C Blue #1) (FD&C Red #40) (titanium dioxide)]


40 mg (base) (Rx) [Cognex (hydrous lactose) (magnesium stearate) (microcrystalline cellulose) (gelatin) (silicon dioxide) (sodium lauryl sulfate) (D&C Yellow #10) (FD&C Blue #1) (FD&C Red #40) (D&C Red #28) (titanium dioxide)]

Canada—
Not commercially available. {35}

Note: Tacrine may be available from the manufacturer through a compassionate use program. {46}


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, away from moisture {46}, unless otherwise specified by manufacturer. {06}

Preparation of dosage form:
For patients who cannot take oral solids—Tacrine capsules may be dissolved in any aqueous solution. However, orange juice will best mask the bitter taste of the medication. The capsule should be placed in the liquid intact to avoid loss of medication through spillage. Some excipients may remain undissolved. Prepare each dose as needed; do not store solution for later use. {27} {46}

Auxiliary labeling:
   • Take on empty stomach.
   • May cause dizziness.
   • Take exactly as directed.



Revised: 11/19/1998



References
  1. Parker WA. Epilepsy. In: Herfindal ET, Gourley DR, Hart LL, editors. Clinical pharmacy and therapeutics. 4th ed. Baltimore: Williams and Wilkins; 1988. p. 571.
  1. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc; 1994. p. 287.
  1. Wingard LB, Brody TM, Larner J, Schwartz A. Human pharmacology: molecular-to-clinical. St Louis: Mosby-Year Book; 1991. p. 763
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press; 1993. p. 1121.
  1. Puri SK, Hsu R, Ho I, Lassman HB. Single-dose safety, tolerance, and pharmacokinetics of HP 029 in elderly men: a potential Alzheimer agent. Cur Ther Res 1988 Nov; 44(5): 766-80.
  1. Cognex package insert (Parke-Davis—US), Rev 5/93.
  1. Schneider LS. Clinical pharmacology of aminoacridines in Alzheimer's disease. Neurology 1993 Aug; 43 Suppl 4: S64-S79.
  1. Gauthier S, Gauthier L. Status of THA as therapy for Alzheimer's disease. In: Becker R, Giacobini E, editors. Cholinergic basis for Alzheimer therapy. Cambridge: Birkhäuser Boston; 1991. p. 224-30.
  1. Nybäck H, Ahlin A, Gustafson L, Minthon L. Swedish experiences of THA therapy in Alzheimer's disease. In: Becker R, Giacobini E, editors. Cholinergic basis for Alzheimer therapy. Cambridge: Birkhäuser Boston; 1991. p. 216-23.
  1. Volger BW. Alternatives in the treatment of memory loss in Alzheimer's disease: focus on tacrine. Mich Drug Lett 1991 Feb; 10(2).
  1. Chatellier G, Lacomblez L, Derouesne C. Tetrahydroaminoacridine in Alzheimer's disease: a review of its safety and its effectiveness. Dementia 1991; 2(4): 200-6.
  1. Chatellier G, Lacomblez L, on behalf of Groupe Français d'Etude de la Tetrahydroaminoacridine. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. Br Med J 1990 Feb; 300: 495-9.
  1. Gauthier S, Bouchard R, Lamontagne A, Bailey P, Bergman H, Ratner J, et al. Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease: results of a Canadian double-blind, crossover, multicenter study. N Engl J Med 1990 May; 322(18): 1272-6.
  1. Adem A, Mohammed AK, Winblad B. Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects. J Neural Transm [P-D Sect] 1990; 2: 113-28.
  1. O'Brien JT, Eagger S, Levy R. Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer's disease. Age Ageing 1991; 20: 129-31.
  1. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer's disease. Lancet 1991 Apr 27; 337: 989-92.
  1. Murray JR, Blakemore CB. Tacrine and lecithin in Alzheimer's disease [letter]. Br Med J 1990 Apr; 300: 939.
  1. Growdon JH. Treatment for Alzheimer's disease? N Engl J Med 1992 Oct; 327(18): 1306-8.
  1. Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease. N Engl J Med 1992 Oct; 327(18): 1253-9.
  1. Ford JM, Truman CA, Wilcock GK, Roberts CJC. Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer's disease. Clin Pharmacol Ther 1993 Jun; 53(6): 691-5.
  1. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J, for the Tacrine Study Group. A controlled trial of tacrine in Alzheimer's disease. JAMA 1992 Nov 11; 268(18): 2523-9.
  1. Tacrine for Alzheimer's disease. Med Lett Drugs Ther 1993 Sep 17; 35(905): 87-8.
  1. Kumar V, Becker RE. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent for Alzheimer's disease. Int J Clin Pharmacol Ther Toxicol 1989; 27(10): 478-85.
  1. Hartvig P, Askmark H, Aquilonius SM, Wiklund L, Lindström B. Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine. Eur J Clin Pharmacol 1990; 38: 259-63.
  1. Drukarch B, Kits KS, Van der Meer EG, Lodder JC, Stoof JC. 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.
  1. Gauthier S, Bouchard R, Bacher Y, Bailey P, Bergman H, Carrier L, et al. Progress report on the Canadian multicentre trial of tetrahydroaminoacridine with lecithin in Alzheimer's disease. Can J Neurol Sci 1989; 16: 543-6.
  1. Personal communication, Drug Information Services, Parke-Davis Div of Warner-Lambert Co, 3/7/94.
  1. Adem A. Putative mechanisms of action of tacrine in Alzheimer's disease. Acta Neurol Scand 1992; 85 Suppl 139: 69-74.
  1. Freeman SE, Dawson RM. Tacrine: a pharmacological review. Prog Neurobiol 1991; 36: 257-77.
  1. Gennaro AR, editor. Remington's pharmaceutical sciences. 18th ed. Easton, PA: Mack Publishing Company; 1990. p. 893, 897.
  1. Ott BR, Lannon MC. Exacerbation of Parkinsonism by tacrine. Clin Neuropharmacol 1992; 15(4): 322-5.
  1. Forsyth DR, Wilcock GK, Morgan RA, Truman CA, Ford JM, Roberts CJC. Pharmacokinetics of tacrine hydrochloride in Alzheimer's disease. Clin Pharmacol Ther 1989 Dec; 46: 634-41.
  1. Cutler NR, Sedman AJ, Prior P, Underwood BA, Selen A, Balogh L, et al. Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease. Psychopharmacol Bull 1990; 26(2): 231-4.
  1. Hammel P, Larrey D, Bernuau J, Kalafat M, Fréneaux E, Babany G, et al. Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer's disease. J Clin Gastroenterol 1990; 12(3): 329-31.
  1. Personal communication, Medical Affairs Division, Parke-Davis, Canada, 3/7/94.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1998. p. 703.
  1. Personal communication, Drug Information Services, Parke-Davis Div of Warner-Lambert Co, 3/29/94.
  1. Personal communication, Drug Information Service, Burroughs Wellcome, 3/29/94.
  1. Mivacron package insert (Burroughs Wellcome—US), Rev 5/93, Rec 12/16/93.
  1. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's Disease. JAMA 1994 Apr 6; 271(13): 992-8.
  1. 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 Apr 6; 271(13): 985-91.
  1. Winkler MA. Tacrine for Alzheimer's Disease: Which patient, what dose? [editorial]. JAMA 1994 Apr 6; 271(13): 1023-4.
  1. Reviewers' consensus on monograph revision of 5/2/94.
  1. Guyton AC. Textbook of medical physiology. 8th ed. Philadelphia: W. B. Saunders; 1991. p. 673.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990. p. 124-6.
  1. Reviewer comment, 5/94.
  1. Panel comment, 5/94.
  1. Panel comment, 5/94.
  1. Panel comment, 5/94.
  1. Reviewer comment, 5/94.
  1. Reviewer comment, 5/94.
  1. Panel comment, 5/94.
  1. Budavar S, editor. The Merck index. An encyclopedia of chemicals, drugs, and biologicals. 11th ed. Rahway, NJ: Merck & Co., Inc.; 1989. p. 20, 67.
  1. Cognex package insert (Parke-Davis—US), Rev 4/95, Rec 8/2/95.
  1. Cognex package insert (Parke-Davis—US), Rev 10/97, Rec 9/98.
Hide
(web4)