Symptoms
Signs and symptoms of significant overdosing of Гальнора СР are predicted to be similar to those of overdosing of other cholinomimetics. These effects generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. In addition to muscle weakness or fasciculations, some or all of the signs of a cholinergic crisis may develop: severe nausea, vomiting, gastro-intestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions. Increasing muscle weakness together with tracheal hypersecretions and bronchospasm, may lead to vital airway compromise.
There have been post-marketing reports of Torsade de Pointes, QT prolongation, bradycardia, ventricular tachycardia and brief loss of consciousness in association with an inadvertent overdoses of Гальнора СР. In one case where the dose was known, eight 4 mg tablets (32 mg total) were ingested on a single day.
Two additional cases of accidental ingestion of 32 mg (nausea, vomiting, and dry mouth; nausea, vomiting, and substernal chest pain) and one of 40 mg (vomiting) resulted in brief hospitalisations for observation with full recovery. One patient, who was prescribed 24 mg/day and had a history of hallucinations over the previous two years, mistakenly received 24 mg twice daily for 34 days and developed hallucinations requiring hospitalisation. Another patient, who was prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg (40 ml) and experienced sweating, vomiting, bradycardia, and near-syncope one hour later, which necessitated hospital treatment. His symptoms resolved within 24 hours.
Treatment
As in any case of overdose, general supportive measures should be used. In severe cases, anticholinergics such as atropine can be used as a general antidote for cholinomimetics. An initial dose of 0.5 to 1.0 mg intravenously is recommended, with subsequent doses based on the clinical response.
Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.
Because no data are available on the use of Гальнора СР in patients with severe hepatic impairment (Child-Pugh score greater than 9) and creatinine clearance less than 9 ml/min, Гальнора СР is contraindicated in these populations. Гальнора СР is contraindicated in patients who have both significant renal and hepatic dysfunction.
Not applicable.
The table below reflects data obtained with Гальнора СР in eight placebo-controlled, double-blind clinical trials (N=6,502), five open-label clinical trials (N=1,454), and from post marketing spontaneous reports. The most commonly reported adverse reactions were nausea (21%) and vomiting (11%). They occurred mainly during titration periods, lasted less than a week in most cases and the majority of patients had one episode. Prescription of anti-emetics and ensuring adequate fluid intake may be useful in these instances.
Frequency estimate: 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) and very rare (< 1/10,000).
| System Organ Class | Adverse Reaction Frequency | |||
| Very Common | Common | Uncommon | Rare | |
| Immune system disorders | Hypersensitivity | |||
| Metabolism and nutrition disorders | Decreased appetite | Dehydration | ||
| Psychiatric disorders | Hallucination Depression | Hallucination visual Hallucination auditory | ||
| Nervous system disorders | Syncope Dizziness Tremor Headache Somnolence Lethargy | Paraesthesia Dysgeusia Hypersomnia Seizures* | ||
| Eye disorders | Vision blurred | |||
| Ear and labyrinth disorders | Tinnitus | |||
| Cardiac disorders | Bradycardia | Supraventricular extrasystoles Atrioventricular block first degree Sinus bradycardia Palpitations | ||
| Vascular disorders | Hypertension | Hypotension Flushing | ||
| Gastrointestinal disorders | Vomiting Nausea | Abdominal pain Abdominal pain upper Diarrhoea Dyspepsia Abdominal discomfort | Retching | |
| Hepatobiliary disorders | Hepatitis | |||
| Skin and subcutaneous tissue disorders | Hyperhydrosis | Stevens-Johnson Syndrome; Acute generalized exanthematous pustulosis; Erythema multiforme | ||
| Musculoskeletal and connective tissue disorders | Muscle spasms | Muscular weakness | ||
| General disorders and administration site conditions | Fatigue Asthenia Malaise | |||
| Investigations | Weight decreased | Hepatic enzyme increased | ||
| Injury, poisoning and procedural complications | Fall; Laceration | |||
* Class-related effects reported with acetylcholinesterase-inhibitor antidementia drugs include convulsions/seizures
Reporting of suspected adverse reactions
Reporting 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 at www.mhra.gov.uk/yellowcard
Nonclinical data suggest no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproduction toxicity studies showed a slight delay in development in rats and rabbits, at doses that are below the threshold of toxicity in the pregnant females.
Гальнора СР is indicated for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer type.
Pharmacotherapeutic group: Antidementia drugs; ATC-code: N06DA04.
Mechanism of action
Гальнора СР, a tertiary alkaloid is a selective, competitive and reversible inhibitor of acetylcholinesterase. In addition, Гальнора СР enhances the intrinsic action of acetylcholine on nicotinic receptors, probably through binding to an allosteric site of the receptor. As a consequence, an increased activity in the cholinergic system associated with improved cognitive function can be achieved in patients with dementia of the Alzheimer type.
Clinical studies
The dosages of Гальнора СР effective in placebo-controlled clinical trials with a duration of 5 to 6 months were 16, 24 and 32 mg/day. Of these doses 16 and 24 mg/day were determined to have the best benefit/risk relationship and are the recommended maintenance doses. The efficacy of Гальнора СР has been shown using outcome measures which evaluate the three major symptom complexes of the disease and a global scale: the ADAS-Cog (a performance based measure of cognition), DAD and ADCS-ADL-Inventory (measurements of basic and instrumental Activities of Daily Living), the Neuropsychiatric Inventory (a scale that measures behavioural disturbances) and the CIBIC-plus (a global assessment by an independent physician based on a clinical interview with the patient and caregiver).
Composite responder analysis based on at least 4 points improvement in ADAS-Cog/11 compared to baseline and CIBIC-plus unchanged + improved (1-4), and DAD/ADL score unchanged + improved. See Table below.
| Treatment | At least 4 points improvement from baseline in ADAS-Cog/11 and CIBIC-plus Unchanged+Improved | |||||||
| Change in DAD >0 GAL-USA-1 and GAL-INT-1 (Month 6) | Change in ADCS/ADL-Inventory >0 GAL-USA-10 (Month 5) | |||||||
| N | n (%) of responder | Comparison with placebo | N | n (%) of responder | Comparison with placebo | |||
| Diff (95%CI) | p-value†| Diff (95%CI) | p-value†| |||||
| Classical ITT | ||||||||
| Placebo | 422 | 21 (5.0) | - | = | 273 | 18 ( 6.6) | - | - |
| Gal 16 mg/day | - | - | - | - | 266 | 39 (14.7) | 8.1 (3, 13) | 0.003 |
| Gal 24 mg/day | 424 | 60 (14.2) | 9.2 (5, 13) | <0.001 | 262 | 40 (15.3) | 8.7 (3, 14) | 0.002 |
| Traditional LOCF* |
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| Placebo | 412 | 23 (5.6) | - | - | 261 | 17 (6.5) | - | - |
| Gal 16 mg/day | - | - | - | - | 253 | 36 (14.2) | 7.7 (2, 13) | 0.005 |
| Gal 24 mg/day | 399 | 58 (14.5) | 8.9 (5, 13) | <0.001 | 253 | 40 (15.8) | 9.3 (4, 15) | 0.001 |
| #ITT: Intent To Treat †CMH test of difference from placebo. * LOCF: Last Observation Carried Forward. | ||||||||
Vascular dementia or Alzheimer's disease with cerebrovascular disease
The results of a 26-week double-blind placebo-controlled trial, in which patients with vascular dementia and patients with Alzheimer's disease and concomitant cerebrovascular disease (“mixed dementiaâ€) were included, indicate that the symptomatic effect of Гальнора СР is maintained in patients with Alzheimer's disease and concomitant cerebrovascular disease. In a post-hoc subgroup analysis, no statistically significant effect was observed in the subgroup of patients with vascular dementia alone.
In a second 26-week placebo-controlled trial in patients with probable vascular dementia, no clinical benefit of Гальнора СР treatment was demonstrated.
Гальнора СР is an alkalinic compound with one ionisation constant (pKa 8.2). It is slightly lipophilic and has a partition coefficient (Log P) between n-octanol/buffer solution (pH 12) of 1.09. The solubility in water (pH 6) is 31 mg/ml. Гальнора СР has three chiral centres, the S, R, S-form is the naturally occurring form. Гальнора СР is partially metabolised by various cytochromes, mainly CYP2D6 and CYP3A4. Some of the metabolites formed during the degradation of Гальнора СР have been shown to be active in vitro but are of no importance in vivo.
Absorption
The absorption is rapid, with a tmax of about 1 hour after both tablets and oral solution. The absolute bioavailability of Гальнора СР is high, 88.5 ± 5.4%. The presence of food delays the rate of absorption and reduces Cmax by about 25%, without affecting the extent of absorption (AUC).
Distribution
The mean volume of distribution is 175 L. Plasma protein binding is low, 18%.
Biotransformation
Up to 75% of Гальнора СР dosed is eliminated via metabolism. In vitro studies indicate that CYP2D6 is involved in the formation of O-desmethylГальнора СР and CYP3A4 is involved in the formation of N-oxide-Гальнора СР. The levels of excretion of total radioactivity in urine and faeces were not different between poor and extensive CYP2D6 metabolisers. In plasma from poor and extensive metabolisers, unchanged Гальнора СР and its glucuronide accounted for most of the sample radioactivity. None of the active metabolites of Гальнора СР (norГальнора СР, O-desmethylГальнора СР and O-desmethyl-norГальнора СР) could be detected in their unconjugated form in plasma from poor and extensive metabolisers after single dosing. NorГальнора СР was detectable in plasma from patients after multiple dosing, but did not represent more than 10% of the Гальнора СР levels. In vitro studies indicated that the inhibition potential of Гальнора СР with respect to the major forms of human cytochrome P450 is very low.
Elimination
Гальнора СР plasma concentration declines bi-exponentially, with a terminal half-life in the order of 7-8 h in healthy subjects. Typical oral clearance in the target population is about 200 ml/min with intersubject variability of 30% as derived from the population analysis. Seven days after a single oral dose of 4 mg ³H-Гальнора СР, 90-97% of the radioactivity is recovered in urine and 2.2 - 6.3% in faeces. After intravenous infusion and oral administration, 18-22% of the dose was excreted as unchanged Гальнора СР in the urine in 24 hours, with a renal clearance of 68.4 ± 22 ml/min, which represents 20-25% of the total plasma clearance.
Dose-linearity
After repeated oral dosing of 12 and 16 mg Гальнора СР twice daily as tablets, mean trough and peak plasma concentrations fluctuated between 29 - 97 ng/ml and 42 - 137 ng/ml. The pharmacokinetics of Гальнора СР are linear in the dose range of 4 - 16 mg twice daily. In patients taking 12 or 16 mg twice daily, no accumulation of Гальнора СР was observed between months 2 and 6.
Characteristics in patients with Alzheimer's disease
Data from clinical trials in patients indicate that the plasma concentrations of Гальнора СР in patients with Alzheimer's disease are 30-40% higher than in healthy young subjects. Based upon the population pharmacokinetic analysis, clearance in female subjects is 20% lower as compared to males. No major effects of age per se or race are found on the Гальнора СР clearance. The Гальнора СР clearance in poor metabolisers of CYP2D6 is about 25% lower than in extensive metabolisers, but no bimodality in the population is observed. Therefore, the metabolic status of the patient is not considered to be of clinical relevance in the overall population.
Special populations
Renal impairment
Elimination of Гальнора СР decreases with decreasing creatinine clearance as observed in a study with renally impaired subjects. Compared to Alzheimer patients, peak and trough plasma concentrations are not increased in patients with a creatinine clearance of >9 ml/min. Therefore, no increase in adverse events is expected and no dosage adjustments are needed.
Hepatic impairment
The pharmacokinetics of Гальнора СР in subjects with mild hepatic impairment (Child-Pugh score of 5-6) were comparable to those in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh score of 7-9), AUC and half-life of Гальнора СР were increased by about 30%.
Pharmacokinetic / pharmacodynamic relationship
No apparent correlation between average plasma concentrations and efficacy parameters (i.e. change in ADAS-Cog11 and CIBIC-plus at Month 6) were observed in the large Phase III trials with a dose-regimen of 12 and 16 mg twice daily.
Plasma concentrations in patients experiencing syncope were within the same range as in the other patients at the same dose.
The occurrence of nausea is shown to correlate with higher peak plasma concentrations.
Types of dementia
Гальнора СР is indicated for a patient with mild to moderately severe dementia of the Alzheimer type. The benefit of Гальнора СР in patients with other types of dementia or other types of memory impairment has not been demonstrated. In 2 clinical trials of two years duration in individuals with so called mild cognitive impairment (milder types of memory impairment not fulfilling the criteria of Alzheimer's dementia), Гальнора СР therapy failed to demonstrate any benefit either in slowing cognitive decline or reducing the clinical conversion to dementia. The mortality rate in the Гальнора СР group was significantly higher than in the placebo group, 14/1026 (1.4%) patients on Гальнора СР and 3 /1022 (0.3%) patients on placebo. The deaths were due to various causes. About half of the Гальнора СР deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death). The relevance of this finding for the treatment of patients with Alzheimer's dementia is unknown.
No increased mortality in the Гальнора СР group was observed in a long term, randomized, placebo controlled study in 2045 patients with mild to moderate Alzheimer´s disease. The mortality rate in the placebo group was significantly higher than in the Гальнора СР group. There were 56/1021 (5.5%) deaths in patients on placebo and 33/1024 (3.2%) deaths in patients on Гальнора СР (hazard ratio and 95% confidence intervals of 0.58 [0.37 , 0.89]; p=0.011).
A diagnosis of Alzheimer's dementia should be made according to current guidelines by an experienced physician. Therapy with Гальнора СР should occur under the supervision of a physician and should only be initiated if a caregiver is available who will regularly monitor medicinal product intake by the patient.
Serious skin reactions
Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving Гальнора СР. It is recommended that patients be informed about the signs of serious skin reactions, and that use of Гальнора СР be discontinued at the first appearance of skin rash.
Weight monitoring
Patients with Alzheimer's disease lose weight. Treatment with cholinesterase inhibitors, including Гальнора СР, has been associated with weight loss in these patients. During therapy, patient's weight should be monitored.
Conditions requiring caution
As with other cholinomimetics, Гальнора СР should be given with caution in the following conditions:
Cardiac disorders:
Because of their pharmacological action, cholinomimetics may have vagotonic effects on heart rate (e.g. bradycardia). The potential for this action may be particularly important to patients with 'sick sinus syndrome' or other supraventricular cardiac conduction disturbances or in those who use medicinal products that significantly reduce heart rate concomitantly, such as digoxin and beta blockers or for patients with an uncorrected electrolyte disturbance (e.g. hyperkalaemia, hypokalaemia).
Caution should therefore be exercised when administering Гальнора СР to patients with cardiovascular diseases, e.g. immediate post- myocardial infarction period, new-onset atrial fibrillation, second degree heart block or greater, unstable angina pectoris, or congestive heart failure, especially NYHA group III - IV.
In a pooled analysis of placebo-controlled studies in patients with Alzheimer dementia treated with Гальнора СР an increased incidence of certain cardiovascular adverse events were observed.
Gastrointestinal disorders:
Patients at increased risk of developing peptic ulcers, e.g. those with a history of ulcer disease or those predisposed to these conditions, including those receiving concurrent non-steroidal anti-inflammatory drugs (NSAIDS),should be monitored for symptoms. The use of Гальнора СР is not recommended in patients with gastro-intestinal obstruction or recovering from gastro-intestinal surgery.
Nervous system disorders:
Seizures have been reported with Гальнора СР. Seizure activity may also be a manifestation of Alzheimer's disease. In rare cases an increase in cholinergic tone may worsen Parkinsonian symptoms. In a pooled analysis of placebo-controlled studies in patients with Alzheimer's dementia treated with Гальнора СР cerebrovascular events were uncommonly observed. This should be considered when administering Гальнора СР to patients with cerebrovascular disease.
Respiratory, thoracic and mediastinal disorders:
Cholinomimetics should be prescribed with care for patients with a history of severe asthma or obstructive pulmonary disease or active pulmonary infections (e.g. pneumonia).
Renal and urinary disorders:
The use of Гальнора СР is not recommended in patients with urinary outflow obstruction or recovering from bladder surgery.
Surgical and medical procedures: Гальнора СР, as a cholinomimetic is likely to exaggerate succinylcholinetype muscle relaxation during anaesthesia, especially in cases of pseudocholinesterase deficiency.
Excipient of Гальнора СР 4 mg/ml oral solution:
This product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Methyl-/Propyl-para-hydroxybenzoate may cause allergic reactions (possibly delayed).
Гальнора СР has minor to moderate influence on the ability to drive and use machines. Symptoms include dizziness and somnolence, especially during the first weeks after initiation of treatment.
Posology
Adults/Elderly
Before start of treatment
The diagnosis of probable Alzheimer type of dementia should be adequately confirmed according to current clinical guidelines.
Starting dose
The recommended starting dose is 8 mg/day (4 mg twice a day) for four weeks.
Maintenance dose
- The tolerance and dosing of Гальнора СР should be reassessed on a regular basis, preferably within three months after start of treatment. Thereafter, the clinical benefit of Гальнора СР and the patient's tolerance of treatment should be reassessed on a regular basis according to current clinical guidelines. Maintenance treatment can be continued for as long as therapeutic benefit is favourable and the patient tolerates treatment with Гальнора СР. Discontinuation of Гальнора СР should be considered when evidence of a therapeutic effect is no longer present or if the patient does not tolerate treatment.
The initial maintenance dose is 16 mg/day (8 mg twice a day) and patients should be maintained on 16 mg/day for at least 4 weeks.
An increase to the maintenance dose of 24 mg/day (12 mg twice a day) should be considered on an individual basis after appropriate assessment including evaluation of clinical benefit and tolerability.
- In individual patients not showing an increased response or not tolerating 24 mg/day, a dose reduction to 16 mg/day should be considered.
Treatment withdrawal
- There is no rebound effect after abrupt discontinuation of treatment (e.g. in preparation for surgery).
Renal impairment
Гальнора СР plasma concentrations may be increased in patients with moderate to severe renal impairment.
For patients with a creatinine clearance >9 ml/min, no dosage adjustment is required.
The use of Гальнора СР is contraindicated in patients with creatinine clearance less than 9 ml/min.
Hepatic impairment
Гальнора СР plasma concentrations may be increased in patients with moderate to severe hepatic impairment.
In patients with moderately impaired hepatic function (Child-Pugh score 7-9), based on pharmacokinetic modelling, it is recommended that dosing should begin with 4 mg once daily, preferably taken in the morning, for at least one week. Thereafter, patients should proceed with 4 mg twice daily. for at least 4 weeks. In these patients, daily doses should not exceed 8 mg twice daily.
In patients with severe hepatic impairment (Child-Pugh score greater than 9), the use of Гальнора СР is contraindicated. No dosage adjustment is required for patients with mild hepatic impairment.
Concomitant treatment
In patients treated with potent CYP2D6 or CYP3A4 inhibitors dose reductions can be considered.
Paediatric population
There is no relevant use of Гальнора СР in the paediatric population.
Method of administration
Гальнора СР oral solution should be administered orally twice a day, preferably with morning and evening meals. Ensure adequate fluid intake during treatment.
To open the bottle and use the pipette:
The bottle comes with a child-proof cap, and should be opened as follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.
Insert the pipette into the bottle.
While holding the bottom ring, pull the top ring up to the mark corresponding to the number of millilitres you need to give.
Holding the bottom ring, remove the entire pipette from the bottle.
Empty the pipette directly into the mouth or into any non-alcoholic drink by sliding the upper ring down and drink it immediately.
Close the bottle.
Rinse the pipette with some water.
