Exelon

Rivastigmine hydrogen tartrate.

Each 1-, 3- and 6-mg capsule also contains the following inactive ingredients: Gelatin, red iron oxide (E172), yellow iron oxide (E172), magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, printing ink based on red iron oxide (E172), colloidal anhydrous silica and titanium dioxide (E171).
Each 1.5-mg capsule also contains the following inactive ingredients: Gelatin, yellow iron oxide (E172), magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, printing ink based on red iron oxide (E172), colloidal anhydrous silica and titanium dioxide (E171).
Each 4.5-mg capsule also contains the following inactive ingredients: Gelatin, red iron oxide (E172), yellow iron oxide (E172), magnesium stearate, methylhydroxypropylcellulose, microcrystalline cellulose, printing ink based on titanium dioxide (E171), colloidal anhydrous silica and titanium dioxide (E171).

Brain-selective cholinesterase inhibitor.
Pharmacology: Pathological changes in Alzheimer's disease involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are known to be involved in attention, learning and memory and other cognitive processes. Rivastigmine, a brain-selective acetylcholinesterase inhibitor of the carbamate type, is thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Data from animal studies indicate that rivastigmine selectively increases the availability of acetylcholine in the cortex and hippocampus. Thus, Exelon may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer's disease. In addition, there is some evidence that cholinesterase inhibition could slow the formation of amyloidogenic β-amyloid-precursor protein (APP) fragments, and thus of amyloid plaques, which are one of the main pathological features of Alzheimer's disease.
Rivastigmine interacts with its target enzyme by forming a covalently bound complex that temporarily inactivates the enzyme. In man, an oral 3-mg dose decreases acetylcholinesterase activity in CSF by approximately 40% within the first 1.5 hrs after administration. Activity of the enzyme returns to baseline levels about 9 hrs after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of acetylcholinesterase in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested.
Clinical Studies: The efficacy of Exelon in the treatment of Alzheimer's disease has been demonstrated in placebo-controlled studies. Results from 2 pivotal 26-week multicentre studies comparing 1-4 mg/day and 6-12 mg/day with placebo, as well as pooled analysis of phase III studies have established that Exelon produces significant improvement in the major domains of cognition, global functioning and activities of daily living, and in disease severity. Both the low and high dose ranges showed benefit for cognition, global functioning and disease severity; in addition, the higher dose range produced benefit in activities of daily living.
The following key outcome measures were used in these studies: Alzheimer's Disease Assessment Scale (ADAS-Cog): A performance-based test system that measures cognitive areas relevant for patients with Alzheimer's disease eg, attention, learning, memory and language.
Clinician Interview-Based Impression of Change-Plus (CIBIC-Plus): A clinician-rated assessment of the patient's global change in the domains of cognition, behavior and functioning, incorporating separate patient and caregiver inputs.
Progressive Deterioration Scale (PDS): A caregiver-rated evaluation of the patient's ability to perform activities of daily living eg, toileting, washing, eating and helping with household chores and shopping.
Study results have indicated that onset of efficacy is generally as early as week 12 and is maintained at the end of 6 months of treatment. Patients treated with 6-12 mg experienced improvement in cognition, activities of daily living and global functioning, while placebo patients showed deterioration. The effects of Exelon on these measures (eg, ADAS-Cog difference from placebo 5 points at week 26) indicate a delay in the rate of deterioration of at least 6 months.
Analyses performed to detect those subtests and symptoms of the ADAS-Cog and CIBIC-Plus, respectively, which improved in patients treated with Exelon indicated that ADAS-Cog subtests (ideational praxis, orientation, test instructions, word recall, language ability and word recognition) were significantly improved at week 26 with Exelon 6-12 mg.
Pharmacokinetics: Absorption: Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hr. As a consequence of the drug's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3-mg dose is about 36%. Administration of rivastigmine with food delays absorption (t_max) by 90 min and lowers C_max and increases AUC by approximately 30%.
Distribution: Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brain barrier and has an apparent volume of distribution in the range of 1.8-2.7 L/kg.
Metabolism: Rivastigmine is rapidly and extensively metabolized (half-life in plasma approximately 1 hr), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies, the major cytochrome P-450 isoenzymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions relating to cytochrome P-450 have been observed in humans (see Interactions).
Excretion: Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of ¹⁴C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hrs. Less than 1% of the administered dose is excreted in the feces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.
Elderly Subjects: While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients between 50 and 92 years showed no change in bioavailability with age.

Treatment of patients with mild to moderately severe dementia of the Alzheimer type, also termed probable Alzheimer's disease or Alzheimer's disease.
Treatment of patients with mild to moderately severe dementia associated with Parkinson's disease.

Exelon should be administered twice a day, with morning and evening meals.
Initial Dose: 1.5 mg twice a day. Patients known to be particularly sensitive to the effects of cholinergic drugs should be started at a dose of 1 mg twice a day.
Dose Titration: The recommended starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of 2 weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of 2 weeks of treatment at that dose level.
If adverse effects (eg, nausea, vomiting, abdominal pain or loss of appetite) or weight decrease are observed during treatment, these may respond to omitting one or more doses. If adverse effects persist, the daily dose should be reduced to the previous well-tolerated dose.
Maintenance Dose: 1.5-6 mg twice a day. To achieve maximum therapeutic benefit, patients should be maintained on their highest well-tolerated dose.
Recommended Maximum Daily Dose: 6 mg twice a day.
Patients with Renal or Hepatic Impairment: No dose adjustment is necessary in patients with renal or hepatic impairment.

Symptoms: Most cases of accidental overdosage have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued Exelon treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhea. In the majority of these events, no therapeutic intervention was required. Ingestion of 46 mg has occurred in one case; following conservative management, the patient fully recovered within 24 hrs.
Treatment: As rivastigmine has a plasma half-life of about 1 hr and a duration of acetylcholinesterase inhibition of about 9 hrs, it is recommended that in cases of asymptomatic overdose, no further dose of Exelon should be administered for the next 24 hrs. In overdosage accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse events should be given as necessary.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg IV atropine sulfate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

Patients with known hypersensitivity to rivastigmine, other carbamate derivatives or other components of Exelon (see Description).

Exelon is not associated with adverse cardiovascular effects. However, as with other cholinomimetics, care must be taken when using Exelon in patients with sick-sinus syndrome or severe cardiac arrhythmias.
Cholinergic stimulation may cause increased gastric acid secretion. Although data from clinical studies have not shown any significant increase in symptoms suggestive of ulcerative conditions, care should be exercised in treating patients predisposed to such diseases.
Patients treated with Exelon have not experienced new or exacerbation of preexisting respiratory signs or symptoms, including patients with history of, or with current respiratory disease. However, like other cholinomimetics, Exelon should be used with caution in these patients. No experience is available in treating patients with acute bronchial asthma.
Cholinomimetics may exacerbate urinary obstruction and seizures. Although this has not been observed with Exelon, caution is recommended in such cases.
Use in Pregnancy & Lactation: In animal studies, rivastigmine was not teratogenic. However, the safety of Exelon in human pregnancy has not been established and it should only be given to pregnant women if the potential benefit outweighs the potential risk to the fetus.
It is not known if Exelon is excreted in human milk, hence patients on Exelon should not breastfeed.

In animal studies, rivastigmine was not teratogenic. However, the safety of Exelon in human pregnancy has not been established and it should only be given to pregnant women if the potential benefit outweighs the potential risk to the fetus.
It is not known if Exelon is excreted in human milk, hence patients on Exelon should not breastfeed.

In general, adverse events are mild to moderate and usually resolve without therapeutic intervention. The incidence and severity of adverse events are generally increased with higher doses.
The following table lists the adverse events that occurred during all phase II and III therapeutic trials in Europe, North America, South Africa, Australia and Japan. It includes all adverse events reported with an incidence of ≥5%, irrespective of causal relationship to Exelon. (See table.)

Click on icon to see table/diagram/image

In addition, the incidence of the following adverse events was at least 2% higher among patients given Exelon than those given placebo: Increased sweating, malaise, weight loss, tremor.
Female patients were found to be more susceptible to nausea, vomiting, loss of appetite and weight loss.
As treatment with Exelon is not associated with alterations in any laboratory tests, including liver function tests, or the ECG, no specific monitoring of these measures is required.

Rivastigmine is metabolized mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P-450 isoenzymes. Thus, no pharmacokinetic interactions are anticipated with other drugs metabolized by these enzymes.
No pharmacokinetic interaction was observed between Exelon and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of Exelon. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and Exelon.
In patients with Alzheimer's disease, concomitant administration of Exelon with commonly prescribed medications eg, antacids, antiemetics, antidiabetics, centrally acting antihypertensives (β-blockers, calcium-channel blockers, inotropic drugs, antianginals), nonsteroidal anti-inflammatory drugs, estrogens, analgesics, benzodiazepines and antihistamines, was not associated with an alteration in the kinetics of Exelon or an increased risk of clinically relevant untoward effects.
In view of its pharmacodynamic effects, Exelon should not be given concomitantly with other cholinomimetic drugs and might interfere with the activity of anticholinergic medications.
As a cholinesterase inhibitor, Exelon may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia.

Neurodegenerative Disease Drugs

N06DA03 - rivastigmine ; Belongs to the class of anticholinesterases. Used in the management of dementia.

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