Selopral may be available in the countries listed below.
Metoprolol tartrate (a derivative of Metoprolol) is reported as an ingredient of Selopral in the following countries:
International Drug Name Search
Nicor may be available in the countries listed below.
Nicorandil is reported as an ingredient of Nicor in the following countries:
International Drug Name Search
Quadrax may be available in the countries listed below.
Ibuprofen is reported as an ingredient of Quadrax in the following countries:
International Drug Name Search
Amcopan may be available in the countries listed below.
Scopolamine butylbromide (a derivative of Scopolamine) is reported as an ingredient of Amcopan in the following countries:
International Drug Name Search
Vira-A is the trade name for vidarabine (also known as adenine arabinoside and Ara-A), an antiviral drug for the topical treatment of epithelial keratitis caused by Herpes simplex virus. The chemical name is 9H-Purin-6-amine, 9-β-D-arabinofuranosyl-, monohydrate. Each gram of the ophthalmic ointment contains 30 mg of vidarabine monohydrate equivalent to 28.11 mg of vidarabine in a sterile, inert, petrolatum base.
The empirical and structural formulas are:
Vira-A is rapidly deaminated to arabinosylhypoxanthine (Ara-Hx), the principal metabolite. Ara-Hx also possesses in vitro antiviral activity but this activity is less than that of Vira-A. Because of the low solubility of Vira-A, trace amounts of both Vira-A and Ara-Hx can be detected in the aqueous humor only if there is an epithelial defect in the cornea. If the cornea is normal, only trace amounts of Ara-Hx can be recovered from the aqueous humor.
Systemic absorption of Vira-A should not be expected to occur following ocular administration and swallowing lacrimal secretions. In laboratory animals, Vira-A is rapidly deaminated in the gastrointestinal tract to Ara-Hx.
In contrast to topical idoxuridine, Vira-A demonstrated less cellular toxicity in the regenerating corneal epithelium of the rabbit.
In controlled and uncontrolled clinical trials, an average of seven and nine days of continuous Vira-A Ophthalmic Ointment, 3%, therapy was required to achieve corneal re-epithelialization. In the controlled trials, 70 of 81 subjects (86%) re-epithelialized at the end of three weeks of therapy. In the uncontrolled trials, 101 of 142 subjects (71%) re-epithelialized at the end of three weeks. Seventy-five percent of the subjects in these uncontrolled trials had either not healed previously or had developed hypersensitivity to topical idoxuridine therapy.
Vidarabine is a purine nucleoside obtained from fermentation cultures of Streptomyces antibioticus. The antiviral mechanism of action has not been established. Vidarabine appears to interfere with the early steps of viral DNA synthesis.
Vidarabine has been shown to possess antiviral activity against the following viruses in vitro:
Herpes simplex types 1 and 2
Vaccinia
Varicella-Zoster
Except for Rhabdovirus and Oncornavirus, vidarabine does not display in vitro antiviral activity against other RNA or DNA viruses, including Adenovirus.
Susceptibility Tests - No universal, standardized, quantitative in vitro procedures have as yet been developed to estimate the susceptibility of viruses to antiviral agents.
Vira-A Ophthalmic Ointment, 3%, is indicated for the treatment of acute keratoconjunctivitis and recurrent epithelial keratitis due to Herpes simplex virus types l and 2. The clinical diagnosis of keratitis caused by Herpes simplex virus is usually established by the presence of typical dendritic or geographic lesions on slit-lamp examination. It is also effective in superficial keratitis caused by Herpes simplex virus which has not responded to topical idoxuridine or when toxic or hypersensitivity reactions due to idoxuridine have occurred. The effectiveness of Vira-A Ophthalmic Ointment, 3%, against stromal keratitis and uveitis due to Herpes simplex virus has not been established.
Vira-A Ophthalmic Ointment, 3%, is contraindicated in patients who develop hypersensitivity reactions to it.
Normally, corticosteroids alone are contraindicated in Herpes simplex virus infections of the eye. If Vira-A Ophthalmic Ointment, 3%, is administered concurrently with topical corticosteroid therapy, corticosteroid-induced ocular side effects must be considered. These include corticosteroid-induced glaucoma or cataract formation and progression of a bacterial or viral infection.
Vira-A is not effective against RNA virus or adenoviral ocular infections. It is also not effective against bacterial, fungal, or chlamydial infections of the cornea or nonviral trophic ulcers.
Although viral resistance to Vira-A has not been observed, this possibility may exist.
The diagnosis of keratoconjunctivitis due to Herpes simplex virus should be established clinically prior to prescribing Vira-A Ophthalmic Ointment, 3%.
Patients should be forewarned that Vira-A Ophthalmic Ointment, 3%, like any ophthalmic ointment, may produce a temporary visual haze.
Chronic parenteral (IM) studies of vidarabine have been conducted in mice and rats.
In the mouse study, there was a statistically significant increase in liver tumor incidence among the vidarabine-treated females. In the same study some vidarabine-treated male mice developed kidney neoplasia. No renal tumors were found in the vehicle-treated control mice or the vidarabine-treated female mice.
In the rat study, intestinal, testicular, and thyroid neoplasia occurred with greater frequency among the vidarabine-treated animals than in the vehicle-treated controls. The increases in thyroid adenoma incidence in the high-dose (50 mg/kg) males and the low-dose (30 mg/kg) females were statistically significant.
Hepatic megalocytosis, associated with vidarabine treatment, has been found in short and long-term rodent (rat and mouse) studies. It is not clear whether or not this represents a preneoplastic change.
The recommended frequency and duration of administration should not be exceeded (see DOSAGE AND ADMINISTRATION).
Results of in vitro experiments indicate that vidarabine can be incorporated into mammalian DNA and can induce mutation in mammalian cells (mouse L5178Y cell line). Thus far, in vivo studies have not been as conclusive, but there is some evidence (dominant lethal assay in mice) that vidarabine may be capable of producing mutagenic effects in male germ cells.
It has also been reported that vidarabine causes chromosome breaks and gaps when added to human leukocytes in vitro. While the significance of these effects in terms of mutagenicity is not fully understood, there is a well-known correlation between the ability of various agents to produce such effects and their ability to produce heritable genetic damage.
Vira-A parenterally is teratogenic in rats and rabbits. Ten percent Vira-A ointment applied to 10% of the body surface during organogenesis induced fetal abnormalities in rabbits. When 10% Vira-A ointment was applied to 2% to 3% of the body surface of rabbits, no fetal abnormalities were found. This dose greatly exceeds the total recommended ophthalmic dose in humans. The possibility of embryonic or fetal damage in pregnant women receiving Vira-A Ophthalmic Ointment, 3%, is remote. The topical ophthalmic dose is small, and the drug relatively insoluble. Its ocular penetration is very low. However, a safe dose for a human embryo or fetus has not been established. There are no adequate and well-controlled studies in pregnant women. Vira-A should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether Vira-A is secreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for Vira-A in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. However, breast milk excretion is unlikely because Vira-A is rapidly deaminated in the gastrointestinal tract.
The safety and effectiveness in pediatric patients below the age of 2 years have not been established.
Lacrimation, foreign body sensation, conjunctival injection, burning, irritation, superficial punctate keratitis, pain, photophobia, punctal occlusion, and sensitivity have been reported with Vira-A Ophthalmic Ointment, 3%. The following have also been reported but appear disease-related: uveitis, stromal edema, secondary glaucoma, trophic defects, corneal vascularization, and hyphema.
Acute massive overdosage by oral ingestion of the ophthalmic ointment has not occurred. However, the rapid deamination to arabinosylhypoxanthine should preclude any difficulty. The oral LD50 for vidarabine is greater than 5020 mg/kg in mice and rats. No untoward effects should result from ingestion of the entire contents of the tube.
Overdosage by ocular instillation is unlikely because any excess should be quickly expelled from the conjunctival sac.
Administer approximately one-half inch of Vira-A Ophthalmic Ointment, 3%, into the lower conjunctival sac five times daily at three-hour intervals.
If there are no signs of improvement after 7 days, or complete re-epithelialization has not occurred by 21 days, other forms of therapy should be considered. Some severe cases may require longer treatment.
Too frequent administration should be avoided.
After re-epithelialization has occurred, treatment for an additional 7 days at a reduced dosage (such as twice daily) is recommended in order to prevent recurrence.
The following topical antibiotics: gentamicin, erythromycin, chloramphenicol; or topical steroids: prednisolone or dexamethasone have been administered concurrently with Vira-A Ophthalmic Ointment, 3%.
NDC 61570-367-71
Vira-A Ophthalmic Ointment, 3%, is supplied sterile in ophthalmic ointment tubes of 3.5 g. The base is a 60:40 mixture of solid and liquid petrolatum.
Store at room temperature 15°–30°C (59°F–86°F).
Rx only.
Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured by: Parkedale Pharmaceuticals, Inc., Rochester, MI 48307
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Generic Name: ibuprofen lysine (Intravenous route)
eye-bue-PROE-fen LYE-seen
In the U.S.
Available Dosage Forms:
Therapeutic Class: Analgesic
Pharmacologic Class: Ibuprofen
Chemical Class: Ibuprofen
Ibuprofen lysine is used to treat patent ductus arteriosus (PDA) in premature infants (babies born too early) who weigh between 1.1 and 3.3 pounds. PDA is a heart problem where a blood vessel, the ductus arteriosus, fails to close normally after birth. This blood vessel is only used before birth, and is no longer needed after the baby is born. Ibuprofen lysine works by causing the PDA to constrict, and this closes the blood vessel .
This medicine is available only with your doctor's prescription .
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of ibuprofen lysine in premature babies .
| Pregnancy Category | Explanation | |
|---|---|---|
| 1st Trimester | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
| 2nd Trimester | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
| 3rd Trimester | D | Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
Ibuprofen lysine may change how the body reacts during an infection. Tell your baby's doctor if you notice any fever, chills, or other unusual behavior in your baby while this medicine is being used .
This medicine may affect the action of platelets, which are necessary for clotting the blood. This may increase the chance of bleeding for your baby. Call your baby's doctor right away if you notice any unusual bleeding or bruising, any dark-colored urine or stools, or other signs of bleeding in your baby .
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Neoprofen Intravenous side effects (in more detail)
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Rivastigmine Sandoz 4.5 mg hard capsules
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg.
For a full list of excipients, see section 6.1.
Hard capsule
Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint “RIV 4.5 mg” on the body.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.
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 of treatment at that dose level.
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.
Re-initiation of therapy
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.
Renal and hepatic impairment
Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see section 5.2).
Patients with severe liver impairment have not been studied (see section 4.3).
Children
Rivastigmine is not recommended for use in children.
The use of this medicinal product is contraindicated in patients with
- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation,
- severe liver impairment, as it has not been studied in this population.
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse reactions occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.
The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse reactions.
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.
In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.
No pharmacokinetic interaction was observed between rivastigmine 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 rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.
The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (
Table 1
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The following additional adverse reactions have been observed with rivastigmine transdermal patches: anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with rivastigmine.
Table 2
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Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.
Table 3
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Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg 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 rivastigmine 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 reactions should be given as necessary.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) 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 AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.
Clinical studies in Alzheimer's dementia
The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.
Table 4
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*p<0.05, **p<0.01, ***p<0.001
Clinical studies in dementia associated with Parkinson's disease
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change).
Table 5
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1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).
Table 6
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1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine'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%±13%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.
Distribution
Protein binding of rivastigmine is 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. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.
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 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.
Subjects with hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal impairment
Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment.
Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.
Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals.
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
Not applicable.
5 years
Do not store above 30°C.
