EXELON^®

Rivastigmine.

Qualitative and Quantitative Composition

Exelon hard capsules contain 1.5, 3.0, 4.5 or 6.0 mg rivastigmine (as the hydrogen tartrate salt).

Pharmaceutical Form

Capsule.

Clinical Particulars

Therapeutic indications

Treatment of patients with mild to moderately severe Dementia of the Alzheimer type, also termed probable Alzheimer's Disease or Alzheimer's Disease.

Dosage and method of administration

Administration

Exelon should be administered twice a day, with morning and evening meals.

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two 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 two weeks' treatment at that dose level.

If adverse effects (e.g. 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 to 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

Re-initiation of therapy

The incidence and severity of adverse events are generally increased with higher doses.

If treatment is interrupted for longer than several days, treatment should be re-initiated with the lowest daily dose and titrated as described above.

Use in patients with renal or hepatic impairment

No dose adjustment is necessary in patients with renal or hepatic impairment.

Contraindications

The use of Exelon is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation (see List of excipients).

Exelon is contra-indicated in patients with severe liver impairment since it has not been studied in this population.

Special warnings and special precautions for use

As with other cholinomimetics, care must be taken when using Exelon in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see Adverse effects).

Cholinergic stimulation may cause increased gastric acid secretion and may exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such conditions.

Patients treated with Exelon have not experienced new, or exacerbation of pre-existing respiratory signs or symptoms, including patients with a 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.

Treatment should always be started at a dose of 1.5 mg twice daily and titrated to the patient's maintenance dose. If treatment is interrupted for longer than several days, treatment should be re-initiated with the lowest daily dose to reduce the possibility of adverse reactions (e.g. severe vomiting) (see Dosage and method of administration).

Interaction with other medicinal products and other forms of interaction

Rivastigmine is metabolised mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Thus, no pharmacokinetic interactions are anticipated with other drugs metabolised 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, such as antacids, antiemetics, antidiabetics, centrally acting antihypertensives, β-blockers, calcium channel blockers, inotropic drugs, antianginals, non-steroidal anti-inflammatory drugs, oestrogens, 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 anaesthesia.

Use during pregnancy and 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 for the foetus.

It is not known if Exelon is excreted into human milk, and patients on Exelon should therefore not breast-feed.

Effects on ability to drive and use machines

No impairment of motor function has been noted in patients treated with Exelon. However, the ability of Alzheimer patients to continue driving or operating complex machines should be routinely evaluated by the treating physician.

Adverse effects

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 table below 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% or higher, irrespective of causal relationship to Exelon.

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.

Rare cases of angina pectoris, gastric and duodenal ulcers, gastrointestinal haemorrhage, bradycardia, seizures, rashes, and syncope were observed.

Very rare cases of atrio-ventricular block have been reported.

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.

Overdose

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 diarrhoea. In the majority of these events, no therapeutic intervention was required. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg has occurred in one case; following conservative management the patient fully recovered within 24 hours.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of Exelon should be administered for the next 24 hours. In overdose 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 i.v. atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.

Pharmacological Properties

Pharmacodynamic properties

Pharmacotherapeutic group: brain-selective acetylcholinesterase inhibitor; ATC-code: N06DA03.

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 ß-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 3.0 mg dose decreases acetylcholinesterase activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours 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 two 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 such as 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, behaviour 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 such as 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 (e.g. 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 all ADAS-Cog subtests (ideational praxis, orientation, test instructions, word recall, language ability and word recognition) and all CIBIC-Plus items, except anxiety, were significantly improved at week 26 with Exelon 6-12 mg. Items which improved in at least 15% more Exelon than placebo patients completing treatment included word recall, functioning, agitation, tearfulness or crying, delusions, hallucinations, purposeless and inappropriate activities, and physical threats and/or violence.

Pharmacokinetic properties

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. 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 metabolised (half-life in plasma approximately 1 hour), 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 P450 isoenzymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions relating to cytochrome P450 have been observed in humans. (see Interaction with other medical products and other forms of interaction).

Elimination

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 hours. Less than 1% of the administered dose is excreted in the faeces. 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 aged between 50 and 92 years showed no change in bioavailability with age.

Preclinical safety data

Acute toxicity

The estimated oral LD₅₀ values in mice were 5.6 mg base/kg (males) and 13.8 mg base/kg (females). The estimated oral LD₅₀ values in rats were 8.1 mg base/kg (males) and 13.8 mg base/kg (females).

Repeated dose toxicity

Studies in rats, mice, dogs and monkeys (maximum doses 3.8, 6.3, 2.5 and 6.3 mg-base/kg/day, respectively) revealed evidence of cholinergic stimulation of the central and peripheral nervous systems. In-life tolerability to rivastigmine was variable between species, with the dog as the most sensitive species. No target organ toxicities or clinical pathology alterations were observed in any species, although gastro-intestinal effects were prominent in dogs.

Mutagenicity

Rivastigmine was not mutagenic in tests for gene mutation, primary DNA damage and chromosomal damage in vivo. In tests for chromosomal damage in vitro, a small increase in the number of cells carrying chromosomal aberrations occurred at very high concentrations. However, as there was no evidence of clastogenic activity in the more relevant in vivo chromosomal damage test, it is most likely that the in vitro findings were false positive observations.

Carcinogenicity

No evidence of carcinogenicity was found in studies conducted at dose levels up to 1.1 mg base/kg/day in rats and 1.6 mg base/kg/day in mice.

Reproductive toxicity

Oral studies in pregnant rats and rabbits with dose levels up to 2.3 mg base/kg/day gave no indication of teratogenic potential on the part of rivastigmine. Similarly, here was no evidence of adverse effects of rivastigmine on fertility, reproductive performance or in utero or postnatal growth and development in rats at given dose levels up to 1.1 mg base/kg/day.

Pharmaceutical Particulars

List of excipients

3.0 and 6.0 mg capsules

Gelatin; iron oxide, red (E 172); iron oxide, yellow (E 172); magnesium stearate; methylhydroxypropylcellulose; microcrystalline cellulose; printing ink, based on iron oxide, red (E 172); silica, colloidal anhydrous; titanium dioxide (E 171)

1.5 mg capsules

Gelatin; iron oxide, yellow (E 172); magnesium stearate; methylhydroxypropylcellulose; microcrystalline cellulose; printing ink, based on iron oxide, red (E 172); silica, colloidal anhydrous; titanium dioxide (E 171)

4.5 mg capsules

Gelatin; iron oxide, red (E 172); iron oxide, yellow (E 172); magnesium stearate; methylhydroxypropylcellulose; microcrystalline cellulose; printing ink, based on titanium dioxide (E 171); silica, colloidal anhydrous; titanium dioxide (E 171)

Incompatibilities

Not applicable

Shelf-life

5 years

Special precautions for storage

Store at below 30°C or 86°F.

Nature and content of container

Boxes of 28 or 56 capsules (Blister pack with 14 capsules; clear PVC tray with blue lidding foil). Each box contains 2 or 4 blister packs.

Instructions for use, handling and disposal (if appropriate)

Not applicable

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