Summary of Product Characteristics Updated 26-Aug-2016 | Sandoz Limited
PosologyRivastigmine oral solution should be administered twice a day, with morning and evening meals. The prescribed amount of solution should be withdrawn from the container using the oral dosing syringe supplied. Rivastigmine oral solution may be swallowed directly from the syringe. Rivastigmine oral solution and rivastigmine capsules may be interchanged at equal doses.
Initial dose1.5 mg twice a day.
Dose titrationThe 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 doseThe 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 therapyIf treatment is interrupted for more than three 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 impairmentNo dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment.However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic impairment have not been studied, however, rivastigmine oral solution may be used in this patient population provided close monitoring is exercised (see sections 4.4 and 5.2).
Paediatric populationThere is no relevant use of rivastigmine in the paediatric population in the treatment of Alzheimer's disease.
Special populationsPatients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be closely followed. Patients with severe hepatic impairment have not been studied. However, rivastigmine may be used in this patient population and close monitoring is necessary.Patients with body weight below 50 kg may experience more adverse reactions and may be more likely to discontinue due to adverse reactions.
PregnancyIn pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
Breast-feedingIn animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
FertilityNo adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see section 5.3). Effects of rivastigmine on human fertility are not known.
Summary of the safety profileThe most commonly reported adverse reactions (ADRs) 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.
Tabulated list of adverse reactionsAdverse reactions in Table 1 and Table 2 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.
|Infections and infestations Very rare||Urinary infection|
|Metabolism and nutrition disorders Very common Common Not known||Anorexia Decreased appetite Dehydration|
|Psychiatric disorders Common Common Common Common Uncommon Uncommon Very rare Not known||Agitation Confusion Anxiety Nightmares Insomnia Depression Hallucinations Aggression, restlessness|
|Nervous system disorders Very common Common Common Common Uncommon Rare Very rare||Dizziness Headache Somnolence Tremor Syncope Seizures Extrapyramidal symptoms (including worsening of Parkinson's disease)|
| Cardiac disorders
|Angina pectoris Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia) Sick sinus syndrome|
|Vascular disorders Very rare||Hypertension|
|Gastrointestinal disorders Very common Very common Very common Common Rare Very rare Very rare Not known||Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Gastric and duodenal ulcers Gastrointestinal haemorrhage Pancreatitis Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4).|
|Hepatobiliary disorders Uncommon Not known||Elevated liver function tests Hepatitis|
|Skin and subcutaneous tissue disorders Common Rare Not known||Hyperhydrosis Rash Pruritus, allergic dermatitis (disseminated)|
|General disorders and administration site conditions Common Common Uncommon||Fatigue and asthenia Malaise Fall|
|Investigations Common||Weight loss|
|Metabolism and nutrition disorders Common Common||Decreased appetite Dehydration|
|Psychiatric disorders Common Common Common Common Common Not known||Insomnia Anxiety Restlessness Hallucination, visual Depression Aggression|
|Nervous system disorders Very common Common Common Common Common Common Common Common Common Uncommon||Tremor Dizziness Somnolence Headache Parkinson's disease (worsening) Bradykinesia Dyskinesia Hypokinesia Cogwheel rigidity Dystonia|
|Cardiac disorders Common Uncommon Uncommon Not known||Bradycardia Arial fibrillation Atrioventricular block Sick sinus syndrome|
|Vascular disorders Common Uncommon||Hypertension Hypotension|
|Gastrointestinal disorders Very common Very common Common Common Common||Nausea Vomiting Diarrhoea Abdominal pain and dyspepsia Salivary hypersecretion|
|Hepatobiliary disorders Not known||Hepatitis|
|Skin and subcutaneous tissue disorders Common Not known||Hyperhydrosis Allergic dermatitis (disseminated)|
|General disorders and administration site conditions Very common Common Common Common||Fall Fatigue and asthenia Gait disturbance Parkinson gait|
|Pre-defined adverse events that may reflect worsening of parkinsonian symptoms in patients with dementia associated with Parkinson's disease||Rivastigmine n (%)||Placebo n (%)|
|Total patients studied Total patients with pre-defined AE(s)||362 (100) 99 (27.3)||179 (100) 28 (15.6)|
|Tremor Fall Parkinson's disease (worsening) Salivary hypersecretion Dyskinesia Parkinsonism Hypokinesia Movement disorder Bradykinesia Dystonia Gait abnormality Muscle rigidity Balance disorder Musculoskeletal stiffness Rigors Motor dysfunction||37 (10.2) 21 (5.8) 12 (3.3) 5 (1.4) 5 (1.4) 8 (2.2) 1 (0.3) 1 (0.3) 9 (2.5) 3 (0.8) 5 (1.4) 1 (0.3) 3 (0.8) 3 (0.8) 1 (0.3) 1 (0.3)||7 (3.9) 11 (6.1) 2 (1.1) 0 1 (0.6) 1 (0.6) 0 0 3 (1.7) 1 (0.6) 0 0 2 (1.1) 0 0 0|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product, Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).
SymptomsMost cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment 24 hours after the overdose. Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary urination and/or defecation, lacrimation, hypotension and salivary hypersecretion. In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures and respiratory arrest with possible fatal outcome. Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, confusional state, hypertension, hallucinations and malaise.
ManagementAs 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.
Clinical studies in Alzheimer's dementiaThe 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 (Alzheimer's Disease Assessment Scale - Cognitive subscale, a performance based measure of cognition), the CIBIC-Plus (Clinician's Interview Based Impression of Change-Plus, a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (Progressive Deterioration Scale, 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 612 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.
|Patients with Clinically Significant Response (%)|
|Intent to Treat||Last Observation Carried Forward|
|Response Measure||Rivastigmine 6-12 mg N=473||Placebo N=472||Rivastigmine 6-12 mg N=379||Placebo N=444|
|ADAS-Cog: improvement of at least 4 points||21***||12||25***||12|
|PDS: improvement of at least 10%||26***||17||30***||18|
|At least 4 points improvement on ADAS-Cog with no worsening on CIBIC-Plus and PDS||10*||6||12**||6|
Clinical studies in dementia associated with Parkinson's diseaseThe 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).
|Dementia associated with Parkinson's Disease||ADAS-Cog Rivastigmine||ADAS-Cog Placebo||ADCS-CGIC Rivastigmine||ADCS-CGIC Placebo|
|ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD||(n=329) 23.8 ± 10.2 2.1 ± 8.2||(n=161) 24.3 ± 10.5 -0.7 ± 7.5||(n=329) n/a 3.8 ± 1.4||(n=165) n/a 4.3 ± 1.5|
|Adjusted treatment difference p-value versus placebo||2.881 <0.0011||n/a 0.0072|
|ITT - LOCF population Mean baseline ± SD Mean change at 24 weeks ± SD||(n=287) 24.0 ± 10.3 2.5 ± 8.4||(n=154) 24.5 ± 10.6 -0.8 ± 7.5||(n=289) n/a 3.7 ± 1.4||(n=158) n/a 4.3 ± 1.5|
|Adjusted treatment difference p-value versus placebo||3.541 <0.0011||n/a <0.0012|
|Dementia associated with Parkinson's Disease||ADAS-Cog Rivastigmine||ADAS-Cog Placebo||ADAS-Cog Rivastigmine||ADAS-Cog Placebo|
|Patients with visual hallucinations||Patients without visual hallucinations|
|ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD||(n=107) 25.4 ± 9.9 1.0 ± 9.2||(n=60) 27.4 ± 10.4 -2.1 ± 8.3||(n=220) 23.1 ± 10.4 2.6 ± 7.6||(n=101) 22.5 ± 10.1 0.1 ± 6.9|
|Adjusted treatment difference p-value versus placebo||4.271 0.0021||2.091 0.0151|
|Patients with moderate dementia (MMSE 10-17)||Patients with mild dementia (MMSE 18-24)|
|ITT + RDO population Mean baseline ± SD Mean change at 24 weeks ± SD||(n=87) 32.6 ± 10.4 2.6 ± 9.4||(n=44) 33.7 ± 10.3 -1.8 ± 7.2||(n=237) 20.6 ± 7.9 1.9 ± 7.7||(n=115) 20.7 ± 7.9 -0.2 ± 7.5|
|Adjusted treatment difference p-value versus placebo||4.731 0.0021||2.141 0.0101|
AbsorptionRivastigmine 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 oral solution with food delays absorption (tmax) by 74 min and lowers Cmax by 43% and increases AUC by approximately 9%.
DistributionProtein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.82.7 l/kg.
BiotransformationRivastigmine 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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.
EliminationUnchanged 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. A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% in patients with Alzheimer's disease (n=75 smokers and 549 non-smokers) following rivastigmine oral capsule doses of up to 12 mg/day.
Elderly populationWhile 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.
Hepatic impairmentThe 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.
Renal impairmentCmax 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.
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