Tacrine Hydrochloride Capsules USP 40mg

Tacrine Hydrochloride Capsules USP 10mg
Tacrine Hydrochloride Capsules USP 20mg
Tacrine Hydrochloride Capsules USP 30mg
Tacrine Hydrochloride Capsules USP 40mg

DESCRIPTION

Tacrine hydrochloride (tacrine hydrochloride) is a reversible cholinesterase inhibitor, known chemically as 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate.

Tacrine hydrochloride is commonly referred to in the clinical and pharmacological literature as THA. It has an empirical formula of C13H14N2?HCl?H2O and a molecular weight of 252.74.

Tacrine hydrochloride is a white solid and is freely soluble in distilled water, 0.1N hydrochloric acid, acetate buffer (pH 4.0), phosphate buffer (pH 7.0 to 7.4), methanol, dimethylsulfoxide (DMSO), ethanol, and propylene glycol. The compound is sparingly soluble in linoleic acid and PEG 400.

COMPOSITION

a) Tacrine Hydrochloride Capsules USP 10mg
Each capsule contains:
Tacrine                                              10mg
(as Tacrine hydrochloride)
Excipients                                          q.s.  

b) Tacrine Hydrochloride Capsules USP 20mg
Each capsule contains:
Tacrine                                              20mg
(as Tacrine hydrochloride)
Excipients                                          q.s.     

c) Tacrine Hydrochloride Capsules USP 30mg
Each capsule contains:
Tacrine                                              30mg
(as Tacrine hydrochloride)
Excipients                                          q.s.     

d) Tacrine Hydrochloride Capsules USP 40mg
Each capsule contains:
Tacrine                                              40mg
(as Tacrine hydrochloride)
Excipients                                          q.s.       

Inactive ingredients are hydrous lactose, magnesium stearate, and microcrystalline cellulose. The hard gelatin capsules contain gelatin; silicon dioxide, sodium lauryl sulfate, and the dyes

Each 10-, 20-, 30-, and 40-mg Tacrine hydrochloride (tacrine) capsule for oral administration contains 12.75, 25.50, 38.25, and 51.00 mg of tacrine HCl, respectively.

INDICATIONS

Tacrine hydrochloride (tacrine hydrochloride capsules) is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

Evidence of Tacrine hydrochloride (tacrine) ‘s effectiveness in the treatment of dementia of the Alzheimer’s type derives from results of two adequate and well-controlled clinical investigations that compared tacrine and placebo on both a performance-based measure of cognition and a clinician’s global assessment of change.

DOSAGE AND ADMINISTRATION

The recommendations for dose titration are based on experience from clinical trials. The rate of dose escalation may be slowed if a patient is intolerant to the titration schedule recommended below. It is not advisable, however, to accelerate the dose incrementation plan.

Following initiation of therapy or any dosage increase, patients should be observed carefully for adverse effects. Tacrine hydrochloride (tacrine) should be taken between meals whenever possible; however, if minor GI upset occurs, Tacrine hydrochloride (tacrine) may be taken with meals to improve tolerability. Taking Tacrine hydrochloride (tacrine) with meals can be expected to reduce plasma levels approximately 30% to 40%.

Initiation of Treatment

The initial dose of Tacrine hydrochloride brand of tacrine hydrochloride is 40 mg/day (10 mg QID). This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment. It is important that the dose not be increased during this period because of the potential for delayed onset of transaminase elevations.

Dose Titration

Following 4 weeks of treatment at 40 mg/day (10 mg QID), the dose of Tacrine hydrochloride (tacrine) should then be increased to 80 mg/day (20 mg QID), providing there are no significant transaminase elevations and the patient is tolerating treatment. Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a QID schedule) at 4-week intervals on the basis of tolerance.

Dose Adjustment

Serum ALT/SGPT should be monitored every other week from at least week 4 to week 16 following initiation of treatment, after which monitoring may be decreased to every 3 months. For patients who develop ALT/SGPTelevations greater than two times, the upper limit of normal, the dose and monitoring regimen should be modified as described in Table 4.

A full monitoring and dose titration sequence must be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks.

Table 4. Recommended Dose and Monitoring Regimen Modification in Response to ALT/SGPT Elevations

Rechallenge

Patients who are required to discontinue Tacrine hydrochloride (tacrine) treatment because of ALT/SGPT elevations may be rechallenged once ALT/SGPT levels return to normal limits. Rechallenge of patients exposed to ALT/SGPT elevations less than 10 X ULN has not resulted in serious liver injury. However, because experience in the rechallenge of patients who had elevations greater than 10 X ULN is limited, the risks associated with the rechallenge of these patients are not well characterized. Careful, frequent (weekly) monitoring of serum ALT/SGPT should be undertaken when rechallenging such patients.

If rechallenged, patients should be given an initial dose of 40 mg/day (10 mg QID) and ALT/SGPT levels monitored weekly. If, after 6 weeks on 40 mg/day, the patient is tolerating the dosage with no unacceptable elevations in ALT/SGPT, the recommended dose-titration may be resumed. Weekly monitoring of the ALT/SGPT levels should continue for a total of 16 weeks after which monitoring may be decreased to monthly for 2 months and every 3 months thereafter.

SIDE EFFECTS

Common Adverse Events Leading to Discontinuation

In clinical trials, approximately 17% of the 2706 patients who received Tacrine hydrochloride (tacrine) and 5% of the 1886 patients who received placebo withdrew permanently because of adverse events. It should be noted that some of the placebo-treated patients were exposed to Tacrine hydrochloride (tacrine) prior to receiving placebo due to the variety of study designs used, including crossover studies. Transaminase elevations were the most common reason for withdrawals during Tacrine hydrochloride (tacrine) treatment (8% of all Tacrine hydrochloride (tacrine) -treated patients, or 212 of 456 patients withdrawn). The controlled clinical trial protocols required that any patient with an ALT/SGPT elevation > 3 X ULN be withdrawn, because of concern about potential hepatotoxicity. Apart from withdrawals due to transaminase elevations, 244 patients (9%) withdrew for adverse events while receiving Tacrine hydrochloride (tacrine).

Other adverse events that most frequently led to the withdrawal of tacrine-treated patients in clinical trials were nausea and/or vomiting (1.5%), agitation (0.9%), rash (0.7%), anorexia (0.7%), and confusion (0.5%). These adverse events also most frequently led to the withdrawal of placebo-treated patients, although at lower frequencies (0.1% to 0.2%).

Most Frequent Adverse Clinical Events Seen in Association With the Use of Tacrine

The events identified here are those that occurred at an absolute incidence of at least 5% of patients treated with Tacrine hydrochloride (tacrine) and at a rate at least 2-fold higher in patients treated with Tacrine hydrochloride (tacrine) than placebo.

The most common adverse events associated with the use of Tacrine hydrochloride (tacrine) were elevated transaminases, nausea and/or vomiting, diarrhoea, dyspepsia, myalgia, anorexia, and ataxia. Of these events, nausea and/or vomiting, diarrhoea, dyspepsia, and anorexia appeared to be dose-dependent.

Adverse Events Reported in Controlled Trials

The events cited in the tables below reflect experience gained under closely monitored conditions of clinical trials with a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behaviour, and the kinds of patients treated may differ.

Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with Alzheimer’s disease in placebo-controlled trials and who received the recommended regimen for dose introduction and titration of Tacrine hydrochloride (see DOSAGE AND ADMINISTRATION).

Table 3. Adverse Events Occurring in at Least 2% of Patients Receiving Tacrine hydrochloride (tacrine) at a Starting Dose of 40 mg/day with Titration in 40 mg/day Increments Every 6 Weeks in Controlled Clinical Trials [Number (%) of Patients]

Other Adverse Events Observed During All Clinical Trials

Tacrine hydrochloride (tacrine) has been administered to 2706 individuals during clinical trials. A total of 1471 patients were treated for at least 3 months, 1137 for at least 6 months, and 773 for at least 1 year. Any untoward reactions that occurred during these trials were recorded as adverse events by the clinical investigators using the terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary. These categories are used in the listing below. The frequencies represent the proportion of the 2706 individuals exposed to Tacrine hydrochloride (tacrine) who experienced that event while receiving Tacrine hydrochloride (tacrine). All adverse events are included except those already listed on the previous table and those COSTART terms too general to be informative. Events are further classified by body system categories and listed using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients, and rare adverse events are those occurring in less than 1/1000 patients. These adverse events are not necessarily related to Tacrine hydrochloride (tacrine) treatment. Only rare adverse events deemed to be potentially important are included.

Body As a Whole: Frequent: Chill, fever, malaise, peripheral oedema. Infrequent: Face oedema, dehydration, weight increase, cachexia, oedema (generalized), lipoma. Rare: Heat exhaustion, sepsis, cholinergic crisis, death.

Cardiovascular System: Frequent: Hypotension, hypertension. Infrequent: Heart failure, myocardial infarction, angina pectoris, cerebrovascular accident, transient ischemic attack, phlebitis, venous insufficiency, abdominal aortic aneurysm, atrial fibrillation or flutter, palpitation, tachycardia, bradycardia, pulmonary embolus, migraine, hypercholesterolemia. Rare: Heart arrest, premature atrial contractions, A-V block, bundle branch block.

Digestive System: Infrequent: Glossitis, gingivitis, mouth or throat dry, stomatitis, increased salivation, dysphagia, esophagitis, gastritis, gastroenteritis, GI haemorrhage, stomach ulcer, hiatal hernia, haemorrhoids, stools bloody, diverticulitis, faecal impaction, faecal incontinence, haemorrhage (rectum), cholelithiasis, cholecystitis, increased appetite. Rare: Duodenal ulcer, bowel obstruction.

Endocrine System: Infrequent: Diabetes. Rare: Hyperthyroid, hypothyroid.

Hemic and Lymphatic: Infrequent: Anemia, lymphadenopathy. 

Rare: Leukopenia, thrombocytopenia, hemolysis, pancytopenia.

Musculoskeletal: Frequent: Fracture, arthralgia, arthritis, hypertonia. Infrequent: Osteoporosis, tendinitis, bursitis, gout. 

Rare: Myopathy.

Nervous System: Frequent: Convulsions, vertigo, 

syncope, hyperkinesia, paresthesia. 

Infrequent: Dreaming abnormal, dysarthria, aphasia, amnesia, wandering, twitching, hypesthesia, delirium, paralysis, bradykinesia, movement disorder, cogwheel rigidity, paresis, neuritis, hemiplegia, Parkinson’s disease, neuropathy, extrapyramidal syndrome, reflexes decreased/absent. Rare: Tardive dyskinesia, dysesthesia, dystonia, encephalitis, coma, apraxia, oculogyric crisis, akathisia, oral-facial dyskinesia, Bell‘s palsy, exacerbation of Parkinson ‘s disease.

Psychobiologic Function: Frequent: Nervousness. 

Infrequent: Apathy, increased libido, paranoia, neurosis. Rare: Suicidal, psychosis, hysteria.

Respiratory System: Frequent: Pharyngitis, sinusitis, bronchitis, pneumonia, dyspnea. Infrequent: Epistaxis, chest congestion, asthma, hyperventilation, a lower respiratory infection. Rare: Hemoptysis, lung oedema, lung cancer, acute epiglottitis.

Skin and Appendages: Frequent: Sweating increased. Infrequent: Acne, alopecia, dermatitis, eczema, skin dry, herpes zoster, psoriasis, cellulitis, cyst, furunculosis, herpes simplex, hyperkeratosis, basal cell carcinoma, skin cancer. Rare: Desquamation, seborrhea, squamous cell carcinoma, ulcer (skin), skin necrosis, melanoma.

Urogenital System: 

Infrequent: Hematuria, renal stone, kidney infection, glycosuria, dysuria, polyuria, nocturia, pyuria, cystitis, urinary retention, urination urgency, vaginal haemorrhage, pruritus (genital), breast pain, impotence, prostate cancer. Rare: Bladder tumour, renal tumour, renal failure, urinary obstruction, breast cancer, epididymitis, carcinoma (ovary).

Special Senses: Frequent: Conjunctivitis. 

Infrequent: Cataract, eyes dry, eye pain, visual field defect, diplopia, amblyopia, glaucoma, hordeolum, deafness, earache, tinnitus, inner ear infection, otitis media, unusual taste. Rare: Vision loss, ptosis, blepharitis, labyrinthitis, inner ear disturbance.

Post introduction Reports

Voluntary reports of adverse events temporally associated with Tacrine hydrochloride (tacrine) that have been received since market introduction, that is not listed above, and that may have no causal relationship with the drug include the following: pancreatitis, perforated peptic ulcer, and falling.

DRUG INTERACTIONS

Possible metabolic basis for interactions. Tacrine is primarily eliminated by hepatic metabolism via cytochrome P450 drug-metabolizing enzymes. Drug-drug interactions may occur when Tacrine hydrochloride (tacrine) is given concurrently with agents such as theophylline that undergo extensive metabolism via cytochrome P450 IA2.

Theophylline. Coadministration of tacrine with theophylline increased theophylline elimination half-life and average plasma theophylline concentrations by approximately 2-fold. Therefore, monitoring of plasma theophylline concentrations and appropriate reduction of theophylline dose are recommended in patients receiving tacrine and theophylline concurrently. The effect of theophylline on tacrine pharmacokinetics has not been assessed.

Cimetidine. Cimetidine increased the Cmax and AUC of tacrine by approximately 54% and 64%, respectively.

Anticholinergics. Because of its mechanism of action, Tacrine hydrochloride (tacrine) has the potential to interfere with the activity of anticholinergic medications.

Cholinomimetics and Cholinesterase Inhibitors. A synergistic effect is expected when Tacrine hydrochloride (tacrine) is given concurrently with succinylcholine (see WARNINGS), cholinesterase inhibitors, or cholinergic agonists such as bethanechol.

Fluvoxamine. In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhoea following coadministration, consistent with the cholinergic effects of tacrine.

Other Interactions. Rate and extent of tacrine absorption were not influenced by the coadministration of an antacid containing magnesium and aluminium. Tacrine had no major effect on digoxin or diazepam pharmacokinetics or the anticoagulant activity of warfarin.

WARNINGS

Anaesthesia

Tacrine hydrochloride (tacrine), as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Cardiovascular Conditions

Because of its pharmacological action, Tacrine hydrochloride (tacrine) may have vagotonic effects on the sinoatrial and atrioventricular nodes possibly leading to bradycardia and/or heart block. These effects may be particularly harmful to patients with conduction abnormalities, bradyarrhythmias, or a sick sinus syndrome, but may also occur in patients without known preexisting cardiac disease.

Gastrointestinal Disease and Dysfunction

Tacrine hydrochloride (tacrine) is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients are at increased risk for developing ulcers. Those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) should be monitored closely for symptoms of active or occult gastrointestinal disease.

Tacrine hydrochloride (tacrine), also as a predictable consequence of its pharmacological properties, can cause nausea, vomiting, and loose stools at recommended doses.

Liver Injury

Tacrine hydrochloride (tacrine) should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and gamma-glutamyl transpeptidase (GGT) levels (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

The use of tacrine in patients without a prior history of liver disease is commonly associated with serum aminotransferase elevations, some to levels ordinarily considered to indicate clinically important hepatic injury (see Table 2).

Experience gained in more than 12,000 patients who received tacrine in clinical studies and the treatment IND program indicates that if tacrine is promptly withdrawn following the detection of these elevations, clinically evident signs and symptoms of liver injury are rare.

Long-term follow up of patients who experience transaminase elevations, however, is limited and it is impossible, therefore, to exclude, with certainty, the possibility of chronic sequelae.

Controlled Clinical Trials, Treatment IND and Post Marketing Experience

Experience with tacrine in controlled trials and in a large, less closely monitored experience (a treatment IND) is summarized below:

Clinically evident liver toxicity: One of more than 12,000 patients exposed to tacrine in clinical studies and the treatment IND program had documented elevated bilirubin (5.3 X Upper Limit of Normal, ULN) and jaundice with transaminase levels (AST/SGOT) nearly 20 X ULN.

Rare cases of liver toxicity associated with jaundice, raised serum bilirubin, pyrexia, hepatitis and liver failure have been reported in post-marketing experience. Most of these cases have been reversible but some deaths have occurred. Since there were multiple pathologies including infection, gallstones and carcinoma it was not possible to clearly establish the relationship to Tacrine hydrochloride (tacrine) treatment.

Blood chemistry signs of liver injury: Experience from the 30-week clinical study (described earlier) provides a representative estimate of the frequency of ALT/SGPT elevations expected for patients whose transaminase levels are monitored weekly and who receive Tacrine hydrochloride (tacrine) according to the recommended regimen for dose introduction and titration (Table 2). A dosing regimen employing a more rapid escalation of the daily dose of tacrine may be associated with more serious clinical events (see Monitoring of Liver Function and the Management of the patient who develops transaminase elevations).

Table 2. Cumulative Incidence of ALT/SGPT Elevations Based on Maximum Values with Weekly Monitoring During the 30-Week Study [Number and (%) of Patients]

Experience in 2446 patients who participated in all clinical trials, including the 30-week study, indicates approximately 50% of patients treated with Tacrine hydrochloride (tacrine) can be expected to have at least 1 ALT/SGPT level above ULN; approximately 25% of patients are likely to develop elevations > 3 X ULN, and about 7% of patients may develop elevations > 10 X ULN. Data collected from the treatment IND program were consistent with those obtained during clinical studies, and showed 3% of 5665 patients experiencing an ALT/SGPT elevation > 10 X ULN.

In clinical trials where transaminases were monitored weekly, the median time to onset of the first ALT/SGPT elevation above ULN was approximately 6 weeks, with maximum ALT/SGPT occurring 1 week later, even in instances when Tacrine hydrochloride (tacrine) treatment was stopped. Under the conditions of forced slow upwards dose titration (increases of 40 mg a day every 6 weeks) employed in clinical studies, 95% of transaminase elevations > 3 X ULN occurred within the first 18 weeks of Tacrine hydrochloride (tacrine) therapy, and 99% of the 10-fold elevations occurred by the 12th week and on not more than 80 mg; note, however, that for most patients ALT was monitored weekly and Tacrine hydrochloride (tacrine) was stopped when liver enzymes exceeded 3 X ULN. A total of 276 patients were monitored for ALT/SGPT levels every other week in two double-blind clinical studies, an open-label study, and amended treatment IND. The incidence, severity, time to onset, peak and recovery of ALT/SGPT levels were similar to weekly monitoring. With less frequent monitoring than every other week or the less stringent discontinuation criteria recommended below (see DOSAGE AND ADMINISTRATION), it is possible that marked elevations might be more common. It must also be appreciated that experience with prolonged exposure to the high dose (160 mg/day) is limited. In all cases, transaminase levels returned to within normal limits upon discontinuation of Tacrine hydrochloride (tacrine) treatment or following dosage reduction, usually within 4 to 6 weeks.

This relatively benign experience may be the consequence of careful laboratory monitoring that facilitated the discontinuation of patients early on after the onset of their transaminase elevations. Consequently, frequent monitoring of serum transaminase levels is recommended (see DOSAGE AND ADMINISTRATION, WARNINGS: Liver Injury: Monitoring of Liver Function and the Management of the Patient Who Develops Transaminase Elevations and PRECAUTIONS: Laboratory Tests).

Liver biopsy experience: Liver biopsy results in 7 patients who received tacrine (1 in a Parke-Davis sponsored study and 6 in studies reported in the literature) revealed hepatocellular necrosis in 6 patients and granulomatous changes in the seventh. In all cases, liver function tests returned to normal with no evidence of persisting hepatic dysfunction.

Experience with the rechallenge of patients with transaminase elevations following recovery: Two hundred and twelve patients among the 866 patients assigned to tacrine in the 12 and 30-week studies were withdrawn because they developed transaminase elevations > 3 X ULN. One hundred and forty-five of these patients were subsequently rechallenged with weekly monitoring of ALT/SGPT. During their initial exposure to tacrine, 20 of these 145 had experienced initial elevations > 10 times ULN, while the remainder had experienced elevations between 3 and 10 X ULN.

Upon rechallenge with an initial dose of 40 mg/day, only 48 (33%) of the 145 patients developed transaminase elevations greater than 3 X ULN. Of these patients, 44 had elevations that were between 3 and 10 X ULN and 4 had elevations that were > 10 X ULN.

The mean time to onset of elevations occurred earlier on rechallenge than on initial exposure (22 versus 48 days). Of the 145 patients rechallenged, 127 (88%) were able to continue Tacrine hydrochloride (tacrine) treatment, and 91 of these 127 patients titrated to doses higher than those associated with the initial transaminase elevation.

Predictors of the risk of transaminase elevations: The incidence of transaminase elevations is higher among females. There are no other known predictors of the risk of hepatocellular injury.

Monitoring of Liver Function and the Management of the patient who develops transaminase elevations. (See also DOSAGE AND ADMINISTRATION and PRECAUTIONS: Laboratory Tests.)

Blood chemistries: Serum transaminase levels (specifically ALT/SGPT) should be monitored every other week from at least week 4 to week 16 following initiation of treatment, after which monitoring may be decreased to every 3 months. For patients who develop ALT/SGPT elevations greater than two times, the upper limit of normal, the dose and monitoring regimen should be modified as described in Table 4 (see DOSAGE AND ADMINISTRATION).

A full monitoring sequence should be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks.

If ALT/SGPT elevations occur, the frequency of monitoring and the dose of Tacrine hydrochloride (tacrine) should be modified according to the table shown below in DOSAGE AND ADMINISTRATION.

Rechallenge: Patients with clinical jaundice confirmed by a significant elevation in total bilirubin ( > 3 mg/dL) and/or those exhibiting clinical signs and/or symptoms of hypersensitivity (e.g. rash or fever) in association with ALT/SGPT elevations should immediately and permanently discontinue Tacrine hydrochloride (tacrine) and not be rechallenged. Other patients who are required to discontinue Tacrine hydrochloride (tacrine) treatment because of ALT/SGPT elevations may be rechallenged once ALT/SGPT levels return to within normal limits. (See DOSAGE AND ADMINISTRATION.)

Rechallenge of patients with ALT/SGPT elevations less than 10 X ULN has not resulted in serious liver injury. However, because experience in the rechallenge of patients who had elevations greater than 10 X ULN is limited, the risks associated with the rechallenge of these patients are not well characterized. Careful, frequent (weekly) mon-touring of serum ALT/SGPT should be undertaken when rechallenging such patients.

If rechallenged, patients should be given an initial dose of 40 mg/day (10 mg QID) and ALT/SGPT levels monitored weekly. If, after 6 weeks on 40 mg/day, the patient is tolerating the dosage with no unacceptable elevations in ALT/SGPT, recommended dose-titration may be resumed. Weekly monitoring of the ALT/SGPT levels should continue for a total of 16 weeks after which monitoring may be decreased to monthly for 2 months and every 3 months thereafter.

Liver biopsy: Liver biopsy is not indicated in cases of uncomplicated transaminase elevation.

Genitourinary

Cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions; seizure activity may, however, also be a manifestation of Alzheimer’s disease.

Sudden worsening of the degree of cognitive impairment: Worsening of cognitive function has been reported following abrupt discontinuation of Tacrine hydrochloride (tacrine) or after a large reduction in total daily dose (80 mg/day or more).

Pulmonary Conditions

Because of its cholinomimetic action, Tacrine hydrochloride (tacrine)  should be prescribed with care to patients with a history of asthma.

PRECAUTIONS

General

Liver Injury: see WARNINGS.

Haematology

An absolute neutrophil count (ANC) less than 500/?L occurred in 4 patients who received Tacrine hydrochloride (tacrine) during the course of clinical trials. Three of the 4 patients had concurrent medical conditions commonly associated with a low ANC; 2 of these patients remained on Tacrine hydrochloride (tacrine). The fourth patient, who had a history of hypersensitivity (penicillin allergy), withdrew from the study as a result of a rash and also developed an ANC < 500/?L, which returned to normal; this patient was not rechallenged and, therefore, the role played by Tacrine hydrochloride (tacrine) in this reaction is unknown.

Six patients had an absolute neutrophil count 1500/? L, associated with an elevation of ALT/SGPT.

The total clinical experience in more than 12,000 patients does not indicate a clear association between Tacrine hydrochloride (tacrine) treatment and serious white blood cell abnormalities.

Laboratory Tests (see WARNINGS: Liver Injury and DOSAGE AND ADMINISTRATION)

Serum transaminase levels (specifically ALT/SGPT) should be monitored in patients given Tacrine hydrochloride (tacrine) (see WARNINGS: Liver Injury).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tacrine was mutagenic to bacteria in the Ames test. Unscheduled DNA synthesis was induced in rat and mouse hepatocytes in vitro. Results of cytogenetic (chromosomal aberration) studies were equivocal. Tacrine was not mutagenic in an in vitro mammalian mutation test. Overall, the results of these tests, along with the fact that tacrine belongs to a chemical class (acridines) containing some members which are animal carcinogens, suggest that tacrine may be carcinogenic.

Studies of the effects of tacrine on fertility have not been performed.

Pregnancy

Category C: Animal reproduction studies have not been conducted with tacrine. It is also not known whether Tacrine hydrochloride (tacrine) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Nursing Mothers

It is not known whether this drug is excreted in human milk.

Pediatric Use

There are no adequate and well-controlled trials to document the safety and efficacy of tacrine in any dementing illness occurring in pediatric patients.

OVERDOSE

As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing 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 Tacrine hydrochloride (tacrine) overdosage. Intravenous atropine sulfate titrated to effect is recommended: in adults, the initial dose of 1.0 to 2.0 mg IV with subsequent doses based on clinical response. In children, the usual IM or IV dose is 0.05 mg/kg, repeated every 10-30 minutes until muscarinic signs and symptoms subside and repeated if they reappear. Atypical increases in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate.

It is not known whether Tacrine hydrochloride (tacrine) or its metabolites can be eliminated by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

The estimated median lethal dose of tacrine following a single oral dose in rats is 40 mg/kg, or approximately 12 times the maximum recommended human dose of 160 mg/day. Dose-related signs of cholinergic stimulation were observed in animals and included vomiting, diarrhoea, salivation, lacrimation, ataxia, convulsions, tremor, and stereotypic head and body movements.

CONTRAINDICATIONS

Tacrine hydrochloride (tacrine) is contraindicated in patients with known hypersensitivity to tacrine or acridine derivatives.

Tacrine hydrochloride (tacrine) is contraindicated in patients previously treated with Tacrine hydrochloride (tacrine) who developed treatment-associated jaundice; a serum bilirubin > 3 mg/dL; and/or those exhibiting clinical signs or symptoms of hypersensitivity (eg, rash or fever) in association with ALT/SGPT elevations.

CLINICAL PHARMACOLOGY

Although widespread degeneration of multiple CNS neuronal systems eventually occurs, early pathological changes in Alzheimer’s Disease involve, in a relatively selective manner, cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. The resulting deficiency of cortical acetylcholine is believed to account for some of the clinical manifestations of mild to moderate dementia. Tacrine, an orally bioavailable, centrally active, reversible cholinesterase inhibitor, presumably acts by elevating acetylcholine concentrations in the cerebral cortex by slowing the degradation of acetylcholine released by still intact cholinergic neurons. If this theoretical mechanism of action is correct, tacrine’s effects may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process.

Clinical Pharmacokinetics (Absorption, Distribution, Metabolism, and Elimination)

Absorption: Tacrine hydrochloride (tacrine) is rapidly absorbed after oral administration; maximal plasma concentrations occur within 1 to 2 hours. The rate and extent of tacrine absorption allowing administration of tacrine capsules and solution are virtually indistinguishable. The absolute bioavailability of tacrine is approximately 17 (SD?13) %. Food reduces f tacrine bioavailability by approximately 30-40%; however, there is no food effect if tacrine is administered at least an hour before meals. The effect of achlorhydria on the absorption of tacrine is unknown.

Distribution: Mean volume of distribution of tacrine is approximately 349 (SD ?193) L. Tacrine is about 55% bound to plasma proteins. The extent and degree of tacrine’s distribution within various body compartments have not been systematically studied. However, 336 hours after the administration of a single radiolabeled dose, approximately 25% of the radiolabel was not recovered in a mass balance study, suggesting the possibility that tacrine and/or one or more of its metabolites may be retained.

Metabolism: Tacrine is extensively metabolized by the cytochrome P450 system to multiple metabolites, not all of which have been identified. The vast majority of radio-labelled species present in the plasma following a single dose of ¹⁴C radiolabeled tacrine are unidentified (ie, only 5% of the radioactivity in plasma has been identified [tacrine and 3-hydroxylated metabolites; 1-, 2-, and 4-hydroxytacrine]).

Studies utilizing human liver preparations demonstrated that cytochrome P450 IA2 is the principal isozyme involved in taurine metabolism. These findings are consistent with the observation that tacrine and/or one of its metabolites inhibits the metabolism of theophylline in humans (see PRECAUTIONS: Drug-Drug Interactions: theophylline). Results from a study utilizing quinidine to inhibit cytochrome P450 IID6 indicate that tacrine is not metabolized extensively by this enzyme system.

Following aromatic ring hydroxylation, tacrine ‘s metabolites undergo glucuronidation. Whether tacrine and/or its metabolites undergo biliary excretion or enterohepatic circulation is unknown.

Special Populations: Age: Based on pooled pharmacokinetic studies (n = 192), there is no clinically relevant influence of age (50 to 84 years) on tacrine clearance. Gender: Average tacrine plasma concentrations are approximately 50% higher in females than in males. This is not explained by differences in body surface area or elimination half-life. The difference is probably due to higher systemic availability after oral dosing and may reflect the known lower activity of cytochrome P450 IA2 in women. Race: The effect of race on tacrine clearance has not been studied. Smoking: Mean plasma taurine concentrations in current smokers are approximately one-third of the concentrations in nonsmokers. Cigarette smoking is known to induce cytochrome P450 IA2. Renal disease: Renal disease does not appear to affect the clearance of tacrine.Liver disease: Although studies in patients with liver disease have not been done, it is likely that functional hepatic impairment will reduce the clearance of tacrine and its metabolites.

Presystemic Clearance/Elimination/Excretion: Tacrine undergoes presystemic clearance (ie, first-pass metabolism). The extent of this first-pass metabolism depends upon the dose of tacrine administered. Because the enzyme system involved can be saturated at relatively low doses, a larger fraction of a high dose of tacrine will escape first t pass elimination than of a smaller dose. Thus, when a 40 mg daily dose is increased by 40 mg, the average plasma concentration will be increased by approximately 6 ng/mL. However, when a daily dose of 80 or 120 mg is increased by 40 mg, the increment in average plasma concentration is approximately 10 ng/mL.

Elimination of tacrine from the plasma, however, is not dose-dependent (ie, the half-life is independent of dose or plasma concentration). The elimination half-life is approximately 2 to 4 hours. Following initiation of therapy or a change in the daily dose, steady-state tacrine plasma concentration should be attained within 24 to 36 hours.

DOSAGE AND ADMINISTRATION

The recommendations for dose titration are based on experience from clinical trials. The rate of dose escalation may be slowed if a patient is intolerant to the titration schedule recommended below. It is not advisable, however, to accelerate the dose incrementation plan.

Following initiation of therapy or any dosage increase, patients should be observed carefully for adverse effects. Tacrine hydrochloride (tacrine) should be taken between meals whenever possible; however, if minor GI upset occurs, Tacrine hydrochloride (tacrine) may be taken with meals to improve tolerability. Taking Tacrine hydrochloride (tacrine) with meals can be expected to reduce plasma levels approximately 30% to 40%.

Initiation of Treatment

The initial dose of Tacrine hydrochloride brand of tacrine hydrochloride is 40 mg/day (10 mg QID). This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment. It is important that the dose not be increased during this period because of the potential for delayed onset of transaminase elevations.

Dose Titration

Following 4 weeks of treatment at 40 mg/day (10 mg QID), the dose of Tacrine hydrochloride (tacrine) should then be increased to 80 mg/day (20 mg QID), providing there are no significant transaminase elevations and the patient is tolerating treatment. Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a QID schedule) at 4-week intervals on the basis of tolerance.

Dose Adjustment

Serum ALT/SGPT should be monitored every other week from at least week 4 to week 16 following initiation of treatment, after which monitoring may be decreased to every 3 months. For patients who develop ALT/SGPTelevations greater than two times, the upper limit of normal, the dose and monitoring regimen should be modified as described in Table 4.

A full monitoring and dose titration sequence must be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks.

Table 4. Recommended Dose and Monitoring Regimen Modification in Response to ALT/SGPT Elevations

WARNINGS

Anaesthesia

Tacrine hydrochloride (tacrine), as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anaesthesia.

Cardiovascular Conditions

Because of its pharmacological action, Tacrine hydrochloride (tacrine) may have vagotonic effects on the sinoatrial and atrioventricular nodes possibly leading to bradycardia and/or heart block. These effects may be particularly harmful to patients with conduction abnormalities, bradyarrhythmias, or a sick sinus syndrome, but may also occur in patients without known preexisting cardiac disease.

Gastrointestinal Disease and Dysfunction

Tacrine hydrochloride (tacrine) is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients are at increased risk for developing ulcers. Those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs) should be monitored closely for symptoms of active or occult gastrointestinal disease.

Tacrine hydrochloride (tacrine), also as a predictable consequence of its pharmacological properties, can cause nausea, vomiting, and loose stools at recommended doses.

Liver Injury

Tacrine hydrochloride (tacrine) should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and gamma-glutamyl transpeptidase (GGT) levels (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

The use of tacrine in patients without a prior history of liver disease is commonly associated with serum aminotransferase elevations, some to levels ordinarily considered to indicate clinically important hepatic injury (see Table 2).

Experience gained in more than 12,000 patients who received tacrine in clinical studies and the treatment IND program indicates that if tacrine is promptly withdrawn following the detection of these elevations, clinically evident signs and symptoms of liver injury are rare.

Long-term follow up of patients who experience transaminase elevations, however, is limited and it is impossible, therefore, to exclude, with certainty, the possibility of chronic sequelae.

Controlled Clinical Trials, Treatment IND and Post Marketing Experience

Experience with tacrine in controlled trials and in a large, less closely monitored experience (a treatment IND) is summarized below:

Clinically evident liver toxicity: One of more than 12,000 patients exposed to tacrine in clinical studies and the treatment IND program had documented elevated bilirubin (5.3 X Upper Limit of Normal, ULN) and jaundice with transaminase levels (AST/SGOT) nearly 20 X ULN.

Rare cases of liver toxicity associated with jaundice, raised serum bilirubin, pyrexia, hepatitis and liver failure have been reported in post-marketing experience. Most of these cases have been reversible but some deaths have occurred. Since there were multiple pathologies including infection, gallstones and carcinoma it was not possible to clearly establish the relationship to Tacrine hydrochloride (tacrine) treatment.

Blood chemistry signs of liver injury: Experience from the 30-week clinical study (described earlier) provides a representative estimate of the frequency of ALT/SGPT elevations expected for patients whose transaminase levels are monitored weekly and who receive Tacrine hydrochloride (tacrine) according to the recommended regimen for dose introduction and titration (Table 2). A dosing regimen employing a more rapid escalation of the daily dose of tacrine may be associated with more serious clinical events (see Monitoring of Liver Function and the Management of the patient who develops transaminase elevations).

Table 2. Cumulative Incidence of ALT/SGPT Elevations Based on Maximum Values with Weekly Monitoring During the 30-Week Study [Number and (%) of Patients]

Experience in 2446 patients who participated in all clinical trials, including the 30-week study, indicates approximately 50% of patients treated with Tacrine hydrochloride (tacrine) can be expected to have at least 1 ALT/SGPT level above ULN; approximately 25% of patients are likely to develop elevations > 3 X ULN, and about 7% of patients may develop elevations > 10 X ULN. Data collected from the treatment IND program were consistent with those obtained during clinical studies, and showed 3% of 5665 patients experiencing an ALT/SGPT elevation > 10 X ULN.

In clinical trials where transaminases were monitored weekly, the median time to onset of the first ALT/SGPT elevation above ULN was approximately 6 weeks, with maximum ALT/SGPT occurring 1 week later, even in instances when Tacrine hydrochloride (tacrine) treatment was stopped. Under the conditions of forced slow upwards dose titration (increases of 40 mg a day every 6 weeks) employed in clinical studies, 95% of transaminase elevations > 3 X ULN occurred within the first 18 weeks of Tacrine hydrochloride (tacrine) therapy, and 99% of the 10-fold elevations occurred by the 12th week and on not more than 80 mg; note, however, that for most patients ALT was monitored weekly and Tacrine hydrochloride (tacrine) was stopped when liver enzymes exceeded 3 X ULN. A total of 276 patients were monitored for ALT/SGPT levels every other week in two double-blind clinical studies, an open-label study, and amended treatment IND. The incidence, severity, time to onset, peak and recovery of ALT/SGPT levels were similar to weekly monitoring. With less frequent monitoring than every other week or the less stringent discontinuation criteria recommended below (see DOSAGE AND ADMINISTRATION), it is possible that marked elevations might be more common. It must also be appreciated that experience with prolonged exposure to the high dose (160 mg/day) is limited. In all cases, transaminase levels returned to within normal limits upon discontinuation of Tacrine hydrochloride (tacrine) treatment or following dosage reduction, usually within 4 to 6 weeks.

This relatively benign experience may be the consequence of careful laboratory monitoring that facilitated the discontinuation of patients early on after the onset of their transaminase elevations. Consequently, frequent monitoring of serum transaminase levels is recommended (see DOSAGE AND ADMINISTRATION, WARNINGS: Liver Injury: Monitoring of Liver Function and the Management of the Patient Who Develops Transaminase Elevations and PRECAUTIONS: Laboratory Tests).

Liver biopsy experience: Liver biopsy results in 7 patients who received tacrine (1 in a Parke-Davis sponsored study and 6 in studies reported in the literature) revealed hepatocellular necrosis in 6 patients and granulomatous changes in the seventh. In all cases, liver function tests returned to normal with no evidence of persisting hepatic dysfunction.

Experience with the rechallenge of patients with transaminase elevations following recovery: Two hundred and twelve patients among the 866 patients assigned to tacrine in the 12 and 30-week studies were withdrawn because they developed transaminase elevations > 3 X ULN. One hundred and forty-five of these patients were subsequently rechallenged with weekly monitoring of ALT/SGPT. During their initial exposure to tacrine, 20 of these 145 had experienced initial elevations > 10 times ULN, while the remainder had experienced elevations between 3 and 10 X ULN.

Upon rechallenge with an initial dose of 40 mg/day, only 48 (33%) of the 145 patients developed transaminase elevations greater than 3 X ULN. Of these patients, 44 had elevations that were between 3 and 10 X ULN and 4 had elevations that were > 10 X ULN.

The mean time to onset of elevations occurred earlier on rechallenge than on initial exposure (22 versus 48 days). Of the 145 patients rechallenged, 127 (88%) were able to continue Tacrine hydrochloride (tacrine) treatment, and 91 of these 127 patients titrated to doses higher than those associated with the initial transaminase elevation.

Predictors of the risk of transaminase elevations: The incidence of transaminase elevations is higher among females. There are no other known predictors of the risk of hepatocellular injury.

Monitoring of Liver Function and the Management of the patient who develops transaminase elevations. (See also DOSAGE AND ADMINISTRATION and PRECAUTIONS: Laboratory Tests.)

Blood chemistries: Serum transaminase levels (specifically ALT/SGPT) should be monitored every other week from at least week 4 to week 16 following initiation of treatment, after which monitoring may be decreased to every 3 months. For patients who develop ALT/SGPT elevations greater than two times, the upper limit of normal, the dose and monitoring regimen should be modified as described in Table 4 (see DOSAGE AND ADMINISTRATION).

A full monitoring sequence should be repeated in the event that a patient suspends treatment with tacrine for more than 4 weeks.

If ALT/SGPT elevations occur, the frequency of monitoring and the dose of Tacrine hydrochloride (tacrine) should be modified according to the table shown below in DOSAGE AND ADMINISTRATION.

Rechallenge: Patients with clinical jaundice confirmed by a significant elevation in total bilirubin ( > 3 mg/dL) and/or those exhibiting clinical signs and/or symptoms of hypersensitivity (e.g. rash or fever) in association with ALT/SGPT elevations should immediately and permanently discontinue Tacrine hydrochloride (tacrine) and not be rechallenged. Other patients who are required to discontinue Tacrine hydrochloride (tacrine) treatment because of ALT/SGPT elevations may be rechallenged once ALT/SGPT levels return to within normal limits. (See DOSAGE AND ADMINISTRATION.)

Rechallenge of patients with ALT/SGPT elevations less than 10 X ULN has not resulted in serious liver injury. However, because experience in the rechallenge of patients who had elevations greater than 10 X ULN is limited, the risks associated with the rechallenge of these patients are not well characterized. Careful, frequent (weekly) mon-touring of serum ALT/SGPT should be undertaken when rechallenging such patients.

If rechallenged, patients should be given an initial dose of 40 mg/day (10 mg QID) and ALT/SGPT levels monitored weekly. If, after 6 weeks on 40 mg/day, the patient is tolerating the dosage with no unacceptable elevations in ALT/SGPT, recommended dose-titration may be resumed. Weekly monitoring of the ALT/SGPT levels should continue for a total of 16 weeks after which monitoring may be decreased to monthly for 2 months and every 3 months thereafter.

Liver biopsy: Liver biopsy is not indicated in cases of uncomplicated transaminase elevation.

Genitourinary

Cholinomimetics may cause bladder outflow obstruction.

Neurological Conditions

Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions; seizure activity may, however, also be a manifestation of Alzheimer’s disease.

Sudden worsening of the degree of cognitive impairment: Worsening of cognitive function has been reported following abrupt discontinuation of Tacrine hydrochloride (tacrine) or after a large reduction in total daily dose (80 mg/day or more).

Pulmonary Conditions

Because of its cholinomimetic action, Tacrine hydrochloride (tacrine)  should be prescribed with care to patients with a history of asthma.

PRECAUTIONS

General

Liver Injury: see WARNINGS.

Haematology

An absolute neutrophil count (ANC) less than 500/?L occurred in 4 patients who received Tacrine hydrochloride (tacrine) during the course of clinical trials. Three of the 4 patients had concurrent medical conditions commonly associated with a low ANC; 2 of these patients remained on Tacrine hydrochloride (tacrine). The fourth patient, who had a history of hypersensitivity (penicillin allergy), withdrew from the study as a result of a rash and also developed an ANC < 500/?L, which returned to normal; this patient was not rechallenged and, therefore, the role played by Tacrine hydrochloride (tacrine) in this reaction is unknown.

Six patients had an absolute neutrophil count 1500/? L, associated with an elevation of ALT/SGPT.

The total clinical experience in more than 12,000 patients does not indicate a clear association between Tacrine hydrochloride (tacrine) treatment and serious white blood cell abnormalities.

Laboratory Tests (see WARNINGS: Liver Injury and DOSAGE AND ADMINISTRATION)

Serum transaminase levels (specifically ALT/SGPT) should be monitored in patients given Tacrine hydrochloride (tacrine) (see WARNINGS: Liver Injury).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tacrine was mutagenic to bacteria in the Ames test. Unscheduled DNA synthesis was induced in rat and mouse hepatocytes in vitro. Results of cytogenetic (chromosomal aberration) studies were equivocal. Tacrine was not mutagenic in an in-vitro mammalian mutation test. Overall, the results of these tests, along with the fact that tacrine belongs to a chemical class (acridines) containing some members which are animal carcinogens, suggest that tacrine may be carcinogenic.

Studies of the effects of tacrine on fertility have not been performed.

Pregnancy

Category C: Animal reproduction studies have not been conducted with tacrine. It is also not known whether Tacrine hydrochloride (tacrine) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Nursing Mothers

It is not known whether this drug is excreted in human milk.

Pediatric Use

There are no adequate and well-controlled trials to document the safety and efficacy of tacrine in any dementing illness occurring in pediatric patients.

OVERDOSE

As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing 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 Tacrine hydrochloride (tacrine) overdosage. Intravenous atropine sulfate titrated to effect is recommended: in adults, the initial dose of 1.0 to 2.0 mg IV with subsequent doses based on clinical response. In children, the usual IM or IV dose is 0.05 mg/kg, repeated every 10-30 minutes until muscarinic signs and symptoms subside and repeated if they reappear. Atypical increases in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate.

It is not known whether Tacrine hydrochloride (tacrine) or its metabolites can be eliminated by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).

The estimated median lethal dose of tacrine following a single oral dose in rats is 40 mg/kg, or approximately 12 times the maximum recommended human dose of 160 mg/day. Dose-related signs of cholinergic stimulation were observed in animals and included vomiting, diarrhoea, salivation, lacrimation, ataxia, convulsions, tremor, and stereotypic head and body movements.

CONTRAINDICATIONS

Tacrine hydrochloride (tacrine) is contraindicated in patients with known hypersensitivity to tacrine or acridine derivatives.

Tacrine hydrochloride (tacrine) is contraindicated in patients previously treated with Tacrine hydrochloride (tacrine) who developed treatment-associated jaundice; a serum bilirubin > 3 mg/dL; and/or those exhibiting clinical signs or symptoms of hypersensitivity (eg, rash or fever) in association with ALT/SGPT elevations.

DRUG INTERACTIONS

Possible metabolic basis for interactions. Tacrine is primarily eliminated by hepatic metabolism via cytochrome P450 drug-metabolizing enzymes. Drug-drug interactions may occur when Tacrine hydrochloride (tacrine) is given concurrently with agents such as theophylline that undergo extensive metabolism via cytochrome P450 IA2.

Theophylline. Coadministration of tacrine with theophylline increased theophylline elimination half-life and average plasma theophylline concentrations by approx-i mately 2-fold. Therefore, monitoring of plasma theophylline concentrations and appropriate reduction of theophylline dose are recommended in patients receiving tacrine and theophylline concurrently. The effect of theophylline on tacrine pharmacokinetics has not been assessed.

Cimetidine. Cimetidine increased the Cmax and AUC of tacrine by approximately 54% and 64%, respectively.

Anticholinergics. Because of its mechanism of action, Tacrine hydrochloride (tacrine) has the potential to interfere with the activity of anticholinergic medications.

Cholinomimetics and Cholinesterase Inhibitors. A synergistic effect is expected when Tacrine hydrochloride (tacrine) is given concurrently with succinylcholine (see WARNINGS), cholinesterase inhibitors, or cholinergic agonists such as bethanechol.

Fluvoxamine. In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhoea following coadministration, consistent with the cholinergic effects of tacrine.

Other Interactions. Rate and extent of tacrine absorption were not influenced by the coadministration of an antacid containing magnesium and aluminium. Tacrine had no major effect on digoxin or diazepam pharmacokinetics or the anticoagulant activity of warfarin.

SIDE EFFECTS

Common Adverse Events Leading to Discontinuation

In clinical trials, approximately 17% of the 2706 patients who received Tacrine hydrochloride (tacrine) and 5% of the 1886 patients who received placebo withdrew permanently because of adverse events. It should be noted that some of the placebo-treated patients were exposed to Tacrine hydrochloride (tacrine) prior to receiving placebo due to the variety of study designs used, including crossover studies. Transaminase elevations were the most common reason for withdrawals during Tacrine hydrochloride (tacrine) treatment (8% of all Tacrine hydrochloride (tacrine) -treated patients, or 212 of 456 patients withdrawn). The controlled clinical trial protocols required that any patient with an ALT/SGPT elevation > 3 X ULN be withdrawn, because of concern about potential hepatotoxicity. Apart from withdrawals due to transaminase elevations, 244 patients (9%) withdrew for adverse events while receiving Tacrine hydrochloride (tacrine).

Other adverse events that most frequently led to the withdrawal of tacrine-treated patients in clinical trials were nausea and/or vomiting (1.5%), agitation (0.9%), rash (0.7%), anorexia (0.7%), and confusion (0.5%). These adverse events also most frequently led to the withdrawal of placebo-treated patients, although at lower frequencies (0.1% to 0.2%).

Most Frequent Adverse Clinical Events Seen in Association With the Use of Tacrine

The events identified here are those that occurred at an absolute incidence of at least 5% of patients treated with Tacrine hydrochloride (tacrine) and at a rate at least 2-fold higher in patients treated with Tacrine hydrochloride (tacrine) than placebo.

The most common adverse events associated with the use of Tacrine hydrochloride (tacrine) were elevated transaminases, nausea and/or vomiting, diarrhoea, dyspepsia, myalgia, anorexia, and ataxia. Of these events, nausea and/or vomiting, diarrhoea, dyspepsia, and anorexia appeared to be dose-dependent.

Adverse Events Reported in Controlled Trials

The events cited in the tables below reflect experience gained under closely monitored conditions of clinical trials with a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behaviour, and the kinds of patients treated may differ.

Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with Alzheimer’s disease in placebo-controlled trials and who received the recommended regimen for dose introduction and titration of Tacrine hydrochloride (see DOSAGE AND ADMINISTRATION).

Table 3. Adverse Events Occurring in at Least 2% of Patients Receiving Tacrine hydrochloride (tacrine) at a Starting Dose of 40 mg/day with Titration in 40 mg/day Increments Every 6 Weeks in Controlled Clinical Trials [Number (%) of Patients]

Other Adverse Events Observed During All Clinical Trials

Tacrine hydrochloride (tacrine) has been administered to 2706 individuals during clinical trials. A total of 1471 patients were treated for at least 3 months, 1137 for at least 6 months, and 773 for at least 1 year. Any untoward reactions that occurred during these trials were recorded as adverse events by the clinical investigators using the terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary. These categories are used in the listing below. The frequencies represent the proportion of the 2706 individuals exposed to Tacrine hydrochloride (tacrine) who experienced that event while receiving Tacrine hydrochloride (tacrine). All adverse events are included except those already listed on the previous table and those COSTART terms too general to be informative. Events are further classified by body system categories and listed using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients, and rare adverse events are those occurring in less than 1/1000 patients. These adverse events are not necessarily related to Tacrine hydrochloride (tacrine) treatment. Only rare adverse events deemed to be potentially important are included.

Body As a Whole: Frequent: Chill, fever, malaise, peripheral oedema. Infrequent: Face oedema, dehydration, weight increase, cachexia, oedema (generalized), lipoma. Rare: Heat exhaustion, sepsis, cholinergic crisis, death.

Cardiovascular System: Frequent: Hypotension, hypertension. Infrequent: Heart-failure, myocardial infarction, angina pectoris, cerebrovascular accident, transient ischemic attack, phlebitis, venous insufficiency, abdominal aortic aneurysm, atrial fibrillation or flutter, palpitation, tachycardia, bradycardia, pulmonary embolus, migraine, hypercholesterolemia. Rare: Heart arrest, premature atrial contractions, A-V block, bundle branch block.

Digestive System: Infrequent: Glossitis, gingivitis, mouth or throat dry, stomatitis, increased salivation, dysphagia, esophagitis, gastritis, gastroenteritis, GI haemorrhage, stomach ulcer, hiatal hernia, haemorrhoids, stools bloody, diverticulitis, faecal impaction, faecal incontinence, haemorrhage (rectum), cholelithiasis, cholecystitis, increased appetite. Rare: Duodenal ulcer, bowel obstruction.

Endocrine System: Infrequent: Diabetes. Rare: Hyperthyroid, hypothyroid.

Hemic and Lymphatic: Infrequent: Anemia, lymphadenopathy. Rare: Leukopenia, thrombocytopenia, hemolysis, pancytopenia.

Musculoskeletal: Frequent: Fracture, arthralgia, arthritis, hypertonia. Infrequent: Osteoporosis, tendinitis, bursitis, gout. Rare: Myopathy.

Nervous System: Frequent: Convulsions, vertigo, syncope, hyperkinesia, paresthesia. Infrequent: Dreaming abnormal, dysarthria, aphasia, amnesia, wandering, twitching, hypesthesia, delirium, paralysis, bradykinesia, movement disorder, cogwheel rigidity, paresis, neuritis, hemiplegia, Parkinson’s disease, neuropathy, extrapyramidal syndrome, reflexes decreased/absent. Rare: Tardive dyskinesia, dysesthesia, dystonia, encephalitis, coma, apraxia, oculogyric crisis, akathisia, oral-facial dyskinesia, Bell‘s palsy, exacerbation of Parkinson ‘s disease.

Psychobiologic Function: Frequent: Nervousness. 

Infrequent: Apathy, increased libido, paranoia, neurosis. Rare: Suicidal, psychosis, hysteria.

Respiratory System: Frequent: Pharyngitis, sinusitis, bronchitis, pneumonia, dyspnea. Infrequent: Epistaxis, chest congestion, asthma, hyperventilation, a lower respiratory infection. Rare: Hemoptysis, lung oedema, lung cancer, acute epiglottitis.

Skin and Appendages: Frequent: Sweating increased. Infrequent: Acne, alopecia, dermatitis, eczema, skin dry, herpes zoster, psoriasis, cellulitis, cyst, furunculosis, herpes simplex, hyperkeratosis, basal cell carcinoma, skin cancer. Rare: Desquamation, seborrhea, squamous cell carcinoma, ulcer (skin), skin necrosis, melanoma.

Urogenital System: 

Infrequent: Hematuria, renal stone, kidney infection, glycosuria, dysuria, polyuria, nocturia, pyuria, cystitis, urinary retention, urination urgency, vaginal haemorrhage, pruritus (genital), breast pain, impotence, prostate cancer. Rare: Bladder tumour, renal tumour, renal failure, urinary obstruction, breast cancer, epididymitis, carcinoma (ovary).

Special Senses: Frequent: Conjunctivitis. 

Infrequent: Cataract, eyes dry, eye pain, visual field defect, diplopia, amblyopia, glaucoma, hordeolum, deafness, earache, tinnitus, inner ear infection, otitis media, unusual taste. Rare: Vision loss, ptosis, blepharitis, labyrinthitis, inner ear disturbance.

Post introduction Reports

Voluntary reports of adverse events temporally associated with Tacrine hydrochloride (tacrine) that have been received since market introduction, that is not listed above, and that may have no causal relationship with the drug include the following: pancreatitis, perforated peptic ulcer, and falling.

HOW SUPPLIED

Tacrine hydrochloride is supplied as capsules of tacrine hydrochloride containing 10, 20, 30, and 40 mg of tacrine. The capsule logo is “Tacrine hydrochloride (tacrine) ” with the strength (eg, 10, 20, 30, or 40) printed underneath

STORAGE
Store at 20-25?C (68-77?F); excursions permitted to 15-30?C (59-86?F) [See USP Controlled Room Temperature]. Protect from moisture.

PATIENT INFORMATION

Caregivers

Patients and caregivers should be advised that the effect of Tacrine hydrochloride (brand of tacrine hydrochloride) therapy is thought to depend upon its administration at regular intervals, as directed.

The caregiver should be advised about the possibility of adverse effects. Two types should be distinguished: (1) those occurring in close temporal association with the initiation of treatment or an increase in the dose (eg, nausea, vomiting, loose stools, diarrhoea, etc) and (2) those with delayed onset (eg, rash, jaundice, changes in the colour of stool-black, very dark or light [ie, acholic]).

Patients and caregivers should be encouraged to inform the physician about the emergence of new events or any increase in the severity of existing adverse clinical events. Caregivers should be advised that abrupt discontinuation of Tacrine hydrochloride (tacrine) or a large reduction in total daily dose (80 mg/day or more) may cause a decline in cognitive func-t ion and behavioural disturbances. Unsupervised increases in the dose of tacrine may also have serious consequences. Consequently, changes in dose should not be undertaken in the absence of direct instruction of a physician.

Manufactured in India by:
TAJ LIFE SCIENCES PVT. LTD.
Unit No. 214, Old Bake House,
Bake House Lane, Fort,
Mumbai-400001
at: Ahmedabad- Gujarat, INDIA.
Ho.NO. +91 8448 444 095
Toll Free Phone: (1800-222-434 / 1800-222-825)