Cognex

Cognex® (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.
The molecular formula of tacrine hydrochloride is:
 



 
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.
 
Each capsule of Cognex® contains tacrine as the hydrochloride. Inactive ingredients are hydrous lactose, magnesium stearate, and microcrystalline cellulose. The hard gelatin capsules contain gelatin, NF; silicon dioxide, NF; sodium lauryl sulfate, NF; and the following dyes: 10 mg: D&C Yellow #10, FD&C Green #3, titanium dioxide; 20 mg: D&C Yellow #10, FD&C Blue #1, titanium dioxide; 30 mg: D&C Yellow #10, FD&C Blue #1, FD&C Red #40, titanium dioxide; 40 mg: D&C Yellow #10, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide.
 
Each 10-, 20-, 30-, and 40-mg Cognex® capsule for oral administration contains 12.75, 25.50, 38.25, and 51.00 mg of tacrine HCl, respectively.

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.

The conclusion that Cognex® is an effective treatment for Alzheimer's Disease derives from two adequate and well controlled clinical investigations that evaluated tacrine's effects in patients with probable Alzheimer's disease of mild to moderate severity (NINCDS criteria, Mini-Mental State Examination (MMSE) of Folstein, Folstein and McHugh scores of 10 to 26).
 
 
In each study, outcomes during treatment with tacrine and placebo were assessed on two primary measures: (1) the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog) of Rosen, Mohs, and Davis and (2) a clinician's rated clinical global impression of change.

In one study of 12 weeks duration, patients were randomized to sequences that provided a comparison between placebo, 20, 40, and 80 mg/day by study's end. Statistically significant drug-placebo differences were detected on both primary outcome measures for the group titrated to 80 mg/day. Estimates of the size of the treatment effect varied between 2 and 4 ADAS cog units. The imprecision in these estimates reflects the fact that different analyses, conducted in attempts to account for the effects of the failure of a substantial fraction of the patients randomized to complete the full 12 weeks of the study, yielded different results.
 
The placebo-80 mg/day comparison also achieved statistical significance on the clinician's global impression of change (CGIC) with a 0.3 to 0.4 unit mean difference. The following diagram illustrates the percentages of patients falling into each global category at trial's end for the patients given placebo or 80 mg/day.
 



 
FIGURE 1. Percent of Patients in Each of the Seven Outcome Categories on the Clinician-Rated CGIC for Patients Completing 12 Weeks of Treatment (83% of patients randomized to placebo completed 12 weeks of treatment and are represented above; 56% of those randomized to the 80 mg/day Cognex® sequence completed 12 weeks)

The second study was 30 weeks long. Six hundred sixty-three patients were randomized to 4 treatment sequences (placebo and 3 drug groups) that called for the daily dose of tacrine to be increased at 6-week intervals, starting with a 40-mg/day dose. By study's end, a comparison between placebo, 80, 120, and 160 mg/day was possible. Patients in the 160 mg group received this dose for the final 12 weeks; the 120 mg group received that dose for 18 weeks.
 
The study showed statistically significant drug-placebo differences for the 80 and 120 mg/day groups at 18 weeks and for the 120 and 160 mg/day groups at 30 weeks on both a performance-based test of cognitive function (the ADAS cog) and a clinician's assessment of global change (Clinician Interview Based Impression: CIBI). Because many patients failed to complete 30 weeks on treatment, analyses that used each patient's last on-study value or retrieved patients' (see below) 30-week value, even if they were no longer in the study ("intent-to-treat'' analysis) were also carried out. All analyses confirmed the effectiveness of tacrine, although the estimated mean treatment effect was different in each analysis.

Cognex® (tacrine hydrochloride capsules) is indicated for the treatment of mild to moderate dementia of the Alzheimer's type.
 
Evidence of Cognex®'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. (See CLINICAL PHARMACOLOGY Section: Clinical Trial Data).

Cognex® is contraindicated in patients with known hypersensitivity to tacrine or acridine derivatives.
 
Cognex® is contraindicated in patients previously treated with Cognex® 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.

Cognex®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

Because of its pharmacological action, Cognex® 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.

Cognex® 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.
 
Cognex®, also as a predictable consequence of its pharmacological properties, can cause nausea, vomiting, and loose stools at recommended doses.

Cognex® 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 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.

Patients and caregivers should be advised that the effect of Cognex® (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 dose (eg, nausea, vomiting, loose stools, diarrhea, etc) and (2) those with a delayed onset (eg, rash, jaundice, changes in the color 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 Cognex® or a large reduction in total daily dose (80 mg/day or more) may cause a decline in cognitive function and behavioral 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.

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

Possible metabolic basis for interactions. Tacrine is primarily eliminated by hepatic metabolism via cytochrome P450 drug metabolizing enzymes. Drug-drug interactions may occur when Cognex® 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, Cognex® has the potential to interfere with the activity of anticholinergic medications.
 
Cholinomimetics and Cholinesterase Inhibitors. A synergistic effect is expected when Cognex® 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 diarrhea 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 aluminum. Tacrine had no major effect on digoxin or diazepam pharmacokinetics or the anticoagulant activity of warfarin.

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.

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

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

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

In clinical trials, approximately 17% of the 2706 patients who received Cognex® 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 Cognex® 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 Cognex® treatment  (8% of all Cognex®-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 Cognex®.
 
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%).

The events identified here are those that occurred at an absolute incidence of at least 5% of patients treated with Cognex®, and at a rate at least 2-fold higher in patients treated with Cognex® than placebo.
 
The most common adverse events associated with the use of Cognex® were elevated transaminases, nausea and/or vomiting, diarrhea, dyspepsia, myalgia, anorexia, and ataxia. Of these events, nausea and/or vomiting, diarrhea, dyspepsia, and anorexia appeared to be dose-dependent.

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 behavior, and the kinds of patients treated may differ.
 
Table 3 uls 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 Cognex ® (see DOSAGE AND ADMINISTRATION).
 

Cognex® 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 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 uling below. The frequencies represent the proportion of the 2706 individuals exposed to Cognex® who experienced that event while receiving Cognex®.  All adverse events are included except those already uled on the previous table and those COSTART terms too general to be informative. Events are further classified by body system categories and uled 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 Cognex® treatment. Only rare adverse events deemed to be potentially important are included.
 
Body As a Whole: Frequent: Chill, fever, malaise, peripheral edema. Infrequent: Face edema, dehydration, weight increase, cachexia, edema (generalized), lipoma. Rare: Heat exhaustion, sepsis, cholingeric 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 hemorrhage, stomach ulcer, hiatal hernia, hemorrhoids, stools bloody, diverticulitis, fecal impaction, fecal incontinence, hemorrhage (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, lower respiratory infection. Rare: Hemoptysis, lung edema, 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 hemorrhage, pruritus (genital), breast pain, impotence, prostate cancer. Rare: Bladder tumor, renal tumor, 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.

Voluntary reports of adverse events temporally associated with Cognex® that have been received since market introduction, that are not uled above, and that may have no causal relationship with the drug include the following: pancreatitis, perforated peptic ulcer, and falling.

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 Cognex® overdosage.  Intravenous atropine sulfate titrated to effect is recommended: in adults, 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 Cognex® 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, diarrhea, salivation, lacrimation, ataxia, convulsions, tremor, and stereotypic head and body movements.

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. Cognex® should be taken between meals whenever possible; however, if minor GI upset occurs, Cognex® may be taken with meals to improve tolerability. Taking Cognex® with meals can be expected to reduce plasma levels approximately 30% to 40%.

The initial dose of Cognex® 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.

Following 4 weeks of treatment at 40 mg/day (10 mg QID), the dose of Cognex® 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.

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/SGPT elevations 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.

Patients who are required to discontinue Cognex® 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.

Cognex® is supplied as capsules of tacrine hydrochloride containing 10, 20, 30, and 40 mg of tacrine. The capsule logo is "Cognex®” 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.