Date of approval.
Date of revision.
Cabalatine Bitartrate Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Carbaplatin Bitartrate Capsules
English name: Rivastigmine Hydrogen Tartrate Capsules
Hanyu Pinyin: ZhongjiushisuanKabalatingJiaonang
Ingredients
Active ingredient: Carbaplatin
Chemical name: (S)-N-methyl-N-ethyl-carbamic acid-3-[1-(dimethylamino)ethyl]phenyl ester bicarbonate
Chemical structure formula.
Molecular formula: C14H22N2O2-C4H6O6
Molecular weight: 400.42
Properties
This product is a capsule, the contents of which are white or off-white granules and powder.
Indications】
It is used to treat the symptoms of mild and moderate Alzheimer’s type dementia.
Specification
According to Cabalatine (C14H22N2O2) (1) 1.5mg (2) 3.0mg
Dosage
Take with food in the morning and evening with meals, capsules need to be swallowed.
In three pivotal clinical studies, the twice daily dose was shown to be effective and well tolerated. One of these studies also included a trial of 3 times daily use and the results indicated that there may be benefit in terms of efficacy and tolerability. Therefore, patients who cannot tolerate the 2-times-daily usage should consider splitting the dose into 3 doses, provided the total daily dose is the same.
Dose: The starting dose of 3 mg/day (1.5 mg twice daily) should be increased at least every 2 weeks to reach the maximum tolerable dose, depending on individual differences, but should not exceed 12 mg daily. clinical studies have demonstrated better clinical efficacy with ≥6 mg daily, so the target dose value for most patients should be set in the range of 6-12 mg daily. One of the three phase III clinical studies showed that dosing below 6 mg daily was also effective and was supported by pooled efficacy data analysis.
Dose escalation: If 3 mg/day is well tolerated after a minimum of 2 weeks of treatment, then the dose may be increased to 6 mg/day, with subsequent daily dose increases to 9 mg and then to 12 mg, all dependent on good tolerance of the dose taken prior to adjustment, and an increase should only be considered after at least 2 weeks of treatment at the current dose level, and if adverse effects occur (e.g. nausea, vomiting, abdominal pain, or loss of appetite) or weight loss, may improve with one or more less doses of the drug. However, if these symptoms persist, the daily dose should be reduced back to the previously well-tolerated dose level.
Maximum recommended dose: 12 mg/day (6 mg twice daily).
Special Populations
Pediatric patients
Children and adolescents (age <18 years): Cabalatine bitartrate has not been studied in children and therefore its use in children is not recommended.
Application in patients with renal impairment or mild to moderate hepatic impairment: No dose adjustment is necessary in patients with renal impairment or mild to moderate hepatic impairment. When increasing the dose, individual tolerability must be closely monitored. However, because of elevated drug exposure in patients with moderate renal impairment and mild to moderate hepatic impairment, the recommended dose should be increased incrementally based on individual tolerability and closely monitored because more dose-dependent adverse reactions may occur in patients with clinically significant renal impairment or hepatic impairment. Studies have not been performed in patients with severe hepatic impairment (see [Pharmacokinetics] and [Precautions]).
Restart of therapy: The incidence and severity of adverse reactions usually increases at higher dose levels. If treatment is interrupted for more than 3 days, it should be restarted at the lowest daily dose, followed by dose escalation as described above.
Or as directed by your doctor.
[Adverse Reactions].
The most frequently reported adverse drug reactions were gastrointestinal reactions, including nausea (38%) and vomiting (23%), especially during dose escalation. In clinical trials, female patients were found to be more likely to experience gastrointestinal reactions and weight loss.
The adverse reactions listed in Table 1 are ranked by frequency of occurrence, with the most common coming first, using the following expressions: very common (≥10%); common (1% to 10% with 1%); occasional (0.1% to 1% with 0.1%); rare (0.01% to 0.1% with 0.01%); very rare (<0.01%), and case reports.
Table 1 Cumulative adverse drug reactions in patients with Alzheimer-type dementia treated with this product
Infections and infections
Very rare
Urinary tract infections Mental disorders
Common
Occasionally
Very rare
Agitation, confusion, nightmares, anxiety
Insomnia, depression
Hallucinations neurological abnormalities
Very common
Common
Occasionally
Rare
Dizziness
Headache, drowsiness, tremor
Syncope
Epileptic seizures cardiac abnormalities
Rare
Very rare
Angina pectoris, myocardial infarction
Arrhythmias (e.g. bradycardia, AV block, atrial fibrillation and tachycardia) Vascular abnormalities
Very rare
Hypertension Gastrointestinal system abnormalities
Very common
Common
Rare
Very rare
Nausea, vomiting, diarrhea, decreased appetite, anorexia
Abdominal pain and indigestion
Gastric and duodenal ulcers, peptic ulcers
Gastrointestinal bleeding, pancreatitis, severe vomiting associated with esophageal rupture Hepatobiliary abnormalities
Occasionally
Abnormal liver function tests Skin and subcutaneous tissue abnormalities
Common
Rare
excessive sweating
Rash, pruritus systemic abnormalities and administration site reactions
Common
Occasionally
Fatigue and weakness, malaise
Falls Other
Common
Weight loss
Other adverse drug reactions obtained from post-marketing active reports (frequency unknown)
The following other adverse drug reactions have been identified for this product based on post-marketing active reports. Because the source of the unsolicited reports of these reactions is a population of uncertain size, estimates of their incidence based on these reports are not necessarily reliable.
Metabolic and nutritional abnormalities.
Dehydration
Psychiatric disorders.
Aggression, restlessness
Neurological abnormalities.
Extrapyramidal symptoms in patients with Alzheimer’s dementia
Skin and subcutaneous tissue abnormalities.
Allergic dermatitis (disseminated)
Cardiac abnormalities.
Morbid sinus node syndrome
Hepatobiliary abnormalities.
Hepatitis
Other adverse drug reactions reported with other dosage forms of carbaplatin bitartrate
Common: Urinary incontinence
Uncommon: cerebrovascular accident, delirium, psychotic hyperactivity
Rarely reported: erythema, urticaria, blistering, allergic dermatitis
Information from clinical trials in patients with dementia due to Parkinson’s disease
Table 2 Reported adverse reactions in patients with dementia due to Parkinson’s disease taking capsule carbamate bitartrate in a 24-week clinical study
Study B 2315 Study B 2311 Adverse drug reactions Number of cases (%) of capsules of carbaplatin bitartrate Number of cases (%) of capsules of carbaplatin bitartrate Number of cases (%) of placebo Total number of cases in the trial 294 (100) 362 (100) 179 (100) Metabolic and nutritional abnormalities Common loss of appetite 14 (4.8) 28 (7.7) 8 (4.5) Common dehydration 2 ( 0.7)8 (2.2)2 (1.1) Mental disorders Common anxiety13 (4.4)11 (3.0)1 (0.6) Common insomnia7 (2.4)10 (2.8)4 (2.2) Common restlessness1 (0.3)10 (2.8)3 (1.7) Neurological abnormalities Very common tremor67 (22.8)37 (10.2)7 (3.9) Common dizziness24 (8.2)20 (5.5)2 ( 1.1)Common drowsiness18 (6.1)13 (3.6)5 (2.8)Common headache12 (4.1)15 (4.1)5 (2.8)Common Parkinson’s disease (worsening)*12 (3.3)2 (1.1)Common motor retardation9 (3.1)9 (2.5)3 (1.7)Common dyskinesia10 (3.4)5 ( 1.4)1 (0.6)Common cogwheel-like rigidity9 (3.1)1 (0.3)0 (0.0)Common hypokinesia7 (2.4)1 (0.3)0 (0.0)Occasional dystonia0 (0.0)3 (0.8)1 (0.6)Cardiac abnormalities Common bradycardia2 (0.7)5 (1.4)1 (0.6)Occasional atrial fibrillation1 (0.3)2 (0.6) 0 (0.0)Occasional atrioventricular block1 (0.3)0 (0.0)1 (0.6)Gastrointestinal abnormalities Very common nausea113 (38.4)105 (29.0)20 (11.2)Very common vomiting38 (12.9)60 (16.6)3 ( 1.7)Common diarrhea24 (8.2)26 (7.2)8 ( 4.5)Common abdominal pain and dyspepsia 12 (4.1)15 (4.1)1 (0.6)Common salivary hypersecretion6 (2.0)5 (1.4)0 (0.0)Skin and subcutaneous tissue abnormalities Common excessive sweating6 (2.0)8 (2.2)1 (0.6)Systemic abnormalities and administration site reactions Very common falls29 (9.9)21 (5.8)11 (6.1)Common fatigue
Weakness16 (5.4)
11 (3.7)14 (3.9)
6 (1.7)5 (2.8)
2 (1.1) Common gait disturbance0 (0.0)6 (1.7)0 (0.0)* In trial 2315, Parkinson’s deterioration was listed according to predefined adverse effects (tremor, bradykinesia, cogwheel-like tonicity, falls) and has been itemized according to the corresponding frequency of occurrence.
Other adverse reactions: hypertension, hypotension (common) were also observed in a 76-week prospective, open trial investigating the use of carboplatin bitartrate capsules in patients with dementia due to Parkinson’s disease.
Other adverse reactions: agitation, depression (common) were reported in clinical trials of other dosage forms of carboplatin bitartrate in patients with Parkinson’s disease induced dementia.
Table 3 shows the number and proportion of patients who experienced a scheduled event that may reflect worsening of Parkinson’s disease in a special clinical study of patients with dementia due to Parkinson’s disease treated with capsule carboplatin bitartrate for 24 weeks.
Table 3 Predetermined events occurring in patients with dementia due to Parkinson’s disease that may reflect worsening of Parkinson’s disease (Study B2311)
Capsules of carboplatin bitartrate
Number of cases (%) Placebo
Number of cases (%) All patients studied 362 (100) 179 (100) All patients with a predetermined adverse event 99 (27.3) 28 (15.6) Tremor 37 ( 10.2) 7 ( 3.9) Falls 21 (5.8) 11 (6.1) Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) Hypersalivation 5 (1.4) 0 Dyskinesia 5 ( 1.4)1 (0.6)Parkinson’s syndrome8 (2.2)1 (0.6)Hypokinesia1 (0.3)0 Dyskinesia1 (0.3)0 Bradykinesia9 (2.5)3 (1.7)Tonicity disorder3 (0.8)1 (0.6)Gait abnormalities5 (1.4)0 Muscle rigidity1 (0.3)0 Balance disorder3 (0.8)2 (1.1)Musculoskeletal stiffness3 (0.8)0 stiffness1 (0.3)0 motor dysfunction1 (0.3)0
Adverse events found in other countries (not necessarily related to treatment with this product, most cases occurred at similar rates to the placebo group in placebo-controlled clinical trials)
Psychiatric disorders
Emotional indifference, suicide attempts, increased sexual desire, suicidal ideation, aggressive reactions
Metabolic and nutritional abnormalities
Hypokalemia, hyponatremia
Cardiac abnormalities
Palpitations, peripheral ischemia, supraventricular tachycardia, premature beats
Vascular abnormalities
Postural hypotension, intracranial hemorrhage
Neurological abnormalities
Ataxia, sensory abnormalities, convulsions, vocal difficulties, dullness of sensation, migraine, nystagmus, transient ischemic attack, loss of consciousness
Gastrointestinal abnormalities
gastritis, constipation, gastrointestinal gas, gastroesophageal reflux, hernia, black stool, rectal bleeding, hemoptysis, epigastric pain, bulbous hard stool, dysphagia
Hearing and vestibular abnormalities
Tinnitus
Musculoskeletal abnormalities
Muscle weakness, back pain, muscle stiffness
Reproductive abnormalities (male and female)
Breast pain
Immune function abnormalities
Herpes simplex, otitis media
Respiratory system
Bronchospasm, dyspnea, cough
Urinary system abnormalities
Hematuria, acute renal failure, difficulty in urination
Visual abnormalities
Cataract, diplopia, glaucoma, blurred vision
White blood cell and resistance abnormalities
Lymphadenopathy
Systemic diseases and administration site conditions
Allergies, hot flushes, chest pain
Skin and adnexa
All types of rashes (maculopapular, eczema, maculopapular, exfoliative, psoriasis, erythema), Stevens-Johnson syndrome
Hepatobiliary system abnormalities
Elevated γ-glutamyl transferase levels
Contraindications
Patients for whom this product is contraindicated include
Patients with known hypersensitivity to carbaplatin bitartrate, other carbamate derivatives or excipients. This product is contraindicated in patients with severe liver injury due to lack of studies.
Patients who have experienced a site reaction suggestive of allergic contact dermatitis after the use of other dosage forms (see [Precautions]).
Precautions]
Treatment should be started at 1.5 mg twice daily and increased to the patient’s maintenance dose. If dosing is interrupted for more than 3 days, treatment should be restarted at the lowest daily dose to reduce the incidence of adverse reactions (e.g., severe vomiting) (see [Dosage]).
Gastrointestinal abnormalities, such as nausea, vomiting and diarrhea, may occur with initiation of therapy and/or dose increases. Improvement may occur with lower doses. Patients with signs or symptoms of dehydration due to prolonged vomiting or diarrhea should have the dose reduced or discontinued and be given intravenous fluids (see [ADVERSE REACTIONS]). Dehydration may have serious consequences (see [ADVERSE REACTIONS]).
As with all cholinesterase inhibitors, weight loss may occur in patients treated with cabalactam for Alzheimer’s disease. The patient’s weight should be monitored closely during treatment with this product.
Patients weighing less than 50 kg may experience more adverse events and are more likely to discontinue treatment due to adverse events.
As with other cholinergic drugs, extreme caution must be exercised when this product is given to patients with sick sinus node syndrome (SSS) or other heart block (sinus atrial block, AV block) (see [Adverse Reactions]).
Cholinergic excitation can cause increased gastric acid secretion and may also aggravate urinary tract obstruction and seizures; caution is advised when treating patients with such conditions.
As with other cholinomimetic drugs, carbaplatin bitartrate should be used with caution in patients with a history of asthma or other obstructive pulmonary disease.
As with other cholinomimetics, carbaratine may cause or exacerbate extrapyramidal reactions in patients with dementia due to Parkinson’s disease treated with capsule capsules or oral solutions of carbaratine bitartrate, and worsening of Parkinson’s symptoms, particularly tremor, has been observed.
Skin reactions
Patients who develop suspected allergic contact dermatitis topically with other dosage forms of medication should be referred to oral treatment with carbaplatin after a negative allergy test only, while under close medical observation. It is possible that some patients exposed to other dosage forms of carbaplatin, to which they are sensitive, may not be able to use any form of carbaplatin.
The development of allergic contact dermatitis should be considered if the reaction at the site of administration spreads beyond the range of use of the other formulations, if more severe local reactions occur (e.g., increased erythema, edema, papules, blisters) and if symptoms do not resolve significantly within 48 hours of removal. In the above cases, treatment should be discontinued (see [Contraindications]).
Post-marketing surveillance has identified case reports of allergic dermatitis (disseminated) associated with the use of carbaprost (regardless of route of administration, oral or otherwise). In these cases, treatment should be discontinued (see [Contraindications]). Appropriate instructions should be given to patients and caregivers.
Special Populations
Additional adverse reactions may occur in patients with clinically significant renal impairment or hepatic impairment. The recommended dose and escalating doses should be closely monitored according to individual tolerability (see [DOSAGE]).
Studies have not been conducted in patients with severe hepatic impairment. However, subject to close monitoring, capsule capsules or oral solution formulations of carbaplatin bitartrate may be used in this patient population.
Driving or operating machinery
Patients with dementia due to Alzheimer’s and Parkinson’s disease may cause progressive impairment of driving ability or affect the ability to use machinery. It may cause dizziness and insomnia, mainly during periods of initiation of treatment or dose increases. Therefore, the ability to continue driving or operating complex machinery should be evaluated periodically by the treating physician in patients with dementia treated with carbaplatin bitartrate capsules.
Contact with the eyes needs to be avoided after touching other dosage forms. Wash hands with soap and rinse well after removal. If eyes become red after contact with other agents, flush with plenty of water and seek medical attention as soon as possible if symptoms do not resolve.
Pregnant women and nursing mothers
Women of childbearing age
There is no information on the effect of carbaratine on women of childbearing age.
Pregnancy
In pregnant animals, carbaratine and/or metabolites can cross the placenta. It is not clear if this also occurs in humans. Animal studies have shown that carbaratine bitartrate is not teratogenic. Because there is a lack of data on the safety of this product in human pregnancy, it should be weighed against the advantages and disadvantages of taking it in pregnant women.
Lactation
In animals, carbaratine and/or metabolites may be secreted into breast milk. It is not known whether this product is secreted from human breast milk. It is recommended that breastfeeding should be discontinued in patients taking this product.
Fertility
In male and female rats, no adverse effects of carbaratine on the fertility or reproductive capacity of the rat parent or offspring were observed (see [Pharmacology and Toxicology]). No information is available on the effects of carbaratine on human fertility.
Pediatric Use]
This product is not recommended for children.
Geriatric Use
Although the bioavailability of carboplatin bitartrate is higher in the elderly than in younger healthy volunteers, the results of a trial in patients aged 50-92 years with Alzheimer’s disease showed that the bioavailability of carboplatin bitartrate did not change with increasing age.
[Drug Interactions].
Carboplatin bitartrate is mainly metabolized by cholinesterase hydrolysis. The isoenzymes of cytochrome P450 are rarely involved in its metabolism. Therefore, there are no pharmacokinetic interactions between this product and other drugs metabolized by these enzymes.
Drugs not recommended for combination due to anticipated drug interactions
Metoclopramide
The combination of metoclopramide and carboplatin is not recommended due to the potential for extrapyramidal additive effects.
Drugs acting on the cholinergic system
Given the pharmacokinetic effects of carbaratine, it should not be combined with other cholinergic drugs because of possible additive effects. Carbaplatin may also interfere with the activity of anticholinergic drugs (e.g., oxybutynin, tolterodine).
Succinylcholine-type muscle relaxants
As a cholinesterase inhibitor, during anesthesia, carbaplatin may potentiate the effects of succinylcholine-type muscle relaxants.
Observed interactions to be considered
Beta-blockers
Bradycardia (possibly leading to syncope) due to additive effects has been reported in the combination of multiple beta-blockers (including atenolol) and carbaratine. The greatest risk is expected with cardioselective beta-blockers, but has been reported in patients on other beta-blockers.
Interactions with Nicotine
Population pharmacokinetic analysis showed that in patients with Alzheimer’s dementia (n=75 smokers, 549 nonsmokers), the use of nicotine increased oral clearance of carbaratine by 23% following oral administration of carbaratine capsules at doses up to 12 mg/day.
Interactions with Common Drugs
Studies in healthy volunteers have found no pharmacokinetic interactions between this product (single dose of 3 mg) and digoxin, warfarin, valium or fluoxetine. Prolongation of prothrombin time due to warfarin was not affected by this product. No adverse effects on cardiac conduction were observed with the combination of digoxin and this product.
In clinical studies in patients with Alzheimer’s disease, no clinically relevant increase in the risk of adverse reactions was observed in combination with some commonly prescribed drugs (e.g., antacids, antiemetics, antidiabetics, centrally acting hypotensive agents, calcium channel blockers, drugs affecting myocardial contractility, anti-anginal agents, NSAIDs, estrogens, analgesics, tranquilizers, antihistamines, etc.).
[Drug overdose].
Signs and Symptoms.
Most cases of accidental overdose do not show any clinical signs or symptoms, and almost all overdose patients can continue to use the product. The main symptoms that have appeared are nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, drowsiness, bradycardia, confusion, excessive sweating, depression, hypertension, and hallucinations. Bradycardia and/or syncope can occur due to the known vagal stress effect of cholinesterase inhibitors on cardiac activity. Cholinesterase inhibitor overdose can lead to cholinergic crisis characterized by severe nausea, vomiting, salivation, excessive sweating, bradycardia, hypotension, respiratory depression, and convulsions. Myasthenia gravis may occur and may lead to death if the respiratory muscles are involved.
Fatal outcomes have rarely been reported in carbaratine overdose, and the relationship to carbaratine is unclear. Symptoms and outcomes of overdose vary from patient to patient, and the severity of outcomes (predictably related to overdose) varies.
Treatment.
Because of the plasma half-life of carboplatin bitartrate of approximately 1 hour. Acetylcholinesterase inhibition lasts approximately 9 hours, so it is recommended that the product should not be continued in asymptomatic overdose patients for the next 24 hours. Antiemetics should be considered in patients with severe nausea or vomiting associated with overdose. Provide symptomatic treatment for other adverse reactions as necessary.
Atropine may be used in patients with severe overdose. The recommended initial dose of atropine sulfate is 0.03 mg/kg intravenously, with subsequent dose adjustment based on its clinical efficacy. Scopolamine is not recommended for use as an antidote.
[Clinical Trials].
The efficacy of this product in the treatment of Alzheimer’s disease has been demonstrated in a controlled trial with placebo. Results from two pivotal, 26-week, multicenter studies comparing 1-4 mg/day and 6-12 mg/day with placebo and a meta-analysis of phase III studies determined that carboplatinium bitartrate capsules significantly improved cognitive primary scores, overall impression and ability to perform daily activities, and disease severity. Both low and high dose ranges showed benefits on cognition, overall impression and disease severity; in addition, higher dose ranges also produced benefits on daily activity.
The following key outcome indicators were used in these studies.
Alzheimer’s Disease Assessment Scale-Cognitive Component (ADAS-cog): a behavioral ability-based testing system that measures cognitive domains of functioning relevant to Alzheimer’s patients, such as attention, learning, memory, and language.
Clinician Interview-Based Inventory of Overall Impression Change (CIBIC-Plus): A clinician-rated scale for assessing overall changes in patient cognition, behavior, and functioning, combining information entered by the patient and caregiver separately.
Progressive Decline Scale (PDS): A caregiver-rated assessment of the patient’s ability to perform activities of daily living, such as toileting, washing, eating, and helping with household chores and shopping.
The results of the study showed that efficacy generally occurred as early as week 12 and lasted until the end of the 6-month treatment period. Improvements in cognition, ability to perform daily activities and overall function occurred in patients receiving 6-12 mg of treatment, while patients in the placebo group showed deterioration. The effect of carbamate bitartrate capsules on these indicators (e.g. ADAS-cog, 5 points difference from the placebo group at week 26) suggests a delay in the rate of disease deterioration of at least 6 months.
Analyses were conducted to separately examine improvements in ADAS-cog and CIBIC-Plus subtests and symptoms in patients treated with carbaplatin bitartrate capsules, and showed that all ADAS-cog subtests (Conceptual Behavior, Orientation, Test Guidance, Word Memory, Verbal Ability, and Word Recognition) and all CIBIC-Plus items (except Anxiety), were significantly improved in patients treated with carbaplatin bitartrate capsules. Significant improvement was seen at week 26 of treatment with carboplatin tartrate capsules 6-12 mg. Among patients who completed treatment, items that improved by at least more than 15% in the carboplatin bitartrate capsule group over the placebo group included word memory, functioning, agitation, tearing or crying, delusions, hallucinations, sense of purposelessness and inappropriate behavior, physical threat, and/or violence.
Similar results were observed in a controlled study conducted in Chinese patients with mild to moderate Alzheimer’s type dementia when cabalactin tartrate capsules 6 mg were given twice daily.
Pharmacology and Toxicology]
Pharmacological effects
The pathological changes in Alzheimer’s disease mainly involve the cholinergic pathways that emanate from the basal forebrain to the cerebral cortex and hippocampus. These pathways are known to be involved in attention, learning ability, memory and other cognitive processes. Carbaplatin bitartrate, a carbamate selectively acting as an inhibitor of acetyl and butyrylcholinesterase in the brain, promotes cholinergic neurotransmission by delaying the degradation of acetylcholine released from functionally intact cholinergic neurons. Animal tests have shown that carbaratine increases the availability of acetylcholine in cortical and hippocampal regions of the brain. Therefore, carbaplatin may improve cholinergic-mediated cognitive dysfunction in patients with Alzheimer’s disease and Parkinson’s disease. Amyloid plaques are considered one of the main pathological features of Alzheimer’s disease, and some evidence suggests that acetylcholinesterase inhibitors can slow down the formation of amyloid due to beta-amyloid precursor protein (APP) fragment deposition.
Carbaplatin temporarily inactivates the latter by binding to the target enzyme in a covalent complex. After administration of 3 mg of carbaplatin bitartrate to healthy young men, acetylcholinesterase activity in the cerebrospinal fluid decreased by nearly 40% within the first 1.5 hours. It took approximately 9 hours for the enzyme activity to return to basal levels after the drug reached its maximum inhibitory effect. In the healthy young volunteers studied, a temporary inhibition of butyrylcholinesterase activity in the cerebrospinal fluid occurs, with this enzyme activity returning to baseline levels after the 3.6 hour mark. The inhibition of acetylcholinesterase by carbaplatin in the cerebrospinal fluid of patients with Alzheimer’s disease was dose-dependent, and the maximum dose tested was 6 mg twice daily, which was the highest dose applied in the experiment. The inhibition of butyrylcholinesterase activity in the cerebrospinal fluid of patients with Alzheimer’s disease by carbaplatin was similar to that of acetylcholinesterase activity, with a change in butyrylcholinesterase activity of more than 60% relative to baseline after administration of 6 mg twice daily. After twelve months of administration (the longest period studied), carbaplatin consistently inhibited acetylcholinesterase and butyrylcholinesterase activities in the cerebrospinal fluid. A statistically significant correlation was found between the degree of inhibition of acetylcholinesterase and butyrylcholinesterase activity in cerebrospinal fluid by carbaplatin and changes in a range of measures of cognitive performance in patients with Alzheimer’s disease. However, only the inhibition of butyrylcholinesterase activity in the cerebrospinal fluid was consistently and significantly correlated with improvements in the speed-attention- and memory-related subassays.
Toxicological studies
Genotoxicity
In vitro chromosomal aberration assays in mammalian cells have shown that carbaplatin is chromosome-disruptive under metabolically activated conditions. The Ames test, HGPRT test and mouse micronucleus test were negative for carbaratine.
Reproductive toxicity
No effects on fertility or reproductive capacity were seen with carbalactam in rats (at doses up to 1.1 mg base/kg/day administered orally), a dose level below the maximum recommended human dose (MRHD, 12 mg/day) in mg/m2.
Reproductive toxicity studies in pregnant rats and pregnant rabbits showed no teratogenic effects at oral doses up to 2.3 mg bases/kg/day (approximately twice the MRHD (rats) and four times the MRHD (rabbits) in mg/m2).
Studies in pregnant rats have shown mild fetal/pup weight loss with carbaratine at dose levels below MRHD but with some maternal toxicity.
Carcinogenicity
No carcinogenicity was seen with cabalentine in oral administration carcinogenicity studies in rats (at doses up to 1.1 mg base/kg/day) and mice (at doses up to 1.6 mg base/kg/day). In mg/m2, these dose levels are lower than MRHD.
Pharmacokinetics]
Absorption
Carboplatin bitartrate is rapidly and completely absorbed, reaching peak plasma concentration in approximately 1 hour. As a result of the interaction of the drug with its target enzyme, bioavailability increases approximately 1.5 times as much as would be expected based on the dose increase. The absolute bioavailability of 3 mg is approximately 36%; the absorption (Tmax) of carbaratine bitartrate capsules is prolonged by 90 minutes when taken with food, reducing the Cmax and increasing the AUC by approximately 30%. Oral solution of carbaratine taken with food delayed absorption (Tmax) by 74 minutes, reduced Cmax by 43% and increased AUC by approximately 9%.
Distribution
Carboplatin bitartrate is weakly bound to plasma proteins (approximately 40%). Carbaplatin is equally distributed in blood and plasma in the concentration range 1 to 400 ng/mL with a blood to plasma fraction distribution ratio of 0.9. It readily crosses the blood-brain barrier and reaches its highest concentration after 1 to 4 hours with a cerebrospinal fluid to plasma AUC ratio of 40%. The range of volume of distribution after intravenous administration is 1.8 to 2.7 L/kg.
Metabolism
Carbaplatin bitartrate is rapidly and extensively metabolized (plasma half-life of approximately 1 hour) primarily through cholinesterase-mediated hydrolysis, and this metabolism is readily saturated. In vitro experiments have shown that this metabolite has only a weak acetylcholinesterase inhibitory effect (<10%). Based on in vitro studies, there are no pharmacokinetic interactions with drugs metabolized by the following cytochrome isozymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Results from animal studies indicate that the major isozymes of cytochrome P450 are rarely involved in the metabolism of carbaplatin bitartrate. metabolism. Consistent with these observations, no cytochrome P450-related drug interactions were observed in humans (see [Drug Interactions]).
Clearance
No prototype of carboplatin bitartrate was found in the urine. Its metabolites are mainly cleared by the kidneys. The vast majority (>90%) of isotope 14C-labeled carboplatin bitartrate is rapidly excreted by the kidneys within 24 hours of administration, with less than 1% excreted in the feces. No accumulation of carboplatin bitartrate or its metabolites has been observed in patients with Alzheimer’s disease.
Special Populations
Elderly patients
In a study evaluating the role of age on the pharmacokinetics of 1 and 2.5 mg oral carboplatin, higher plasma concentrations of carboplatin were found in older subjects (24, aged 61-71 years) than in younger subjects (24, aged 19-40 years) after 1 mg dose administration. This difference was more pronounced after high dose (2.5 mg) administration, at which dose level plasma concentrations of carbaratine were 30% higher in healthy elderly subjects than in healthy young subjects. Plasma levels of the desmocarbamate metabolite were not significantly affected by age. However, in a study conducted in patients with Alzheimer’s disease in the age group 50 to 92 years, no age-related differences in bioavailability were found in this age group.
Impairment of renal function
Following a single oral dose of 3 mg, there were no significant differences in plasma levels of carboplatin in patients with severe renal impairment (10 patients with a glomerular filtration rate (GFR) <10 mL/min) compared to control subjects (10 patients with a glomerular filtration rate (GFR) ≥60 mL/min). In patients and healthy subjects, the clearance of carbaplatin was 4.8 L/min and 6.9 L/min, respectively. However, in patients with moderate renal impairment (8 patients, GFR=10-50 mL/min), plasma concentrations of carbaplatin were elevated nearly 2.5-fold, and the overall plasma level (AUC) of the deaminocarbamylated phenol metabolite was approximately 50% higher. The clearance of carbaplatin was 1.7 L/min. The reason for this difference between patients with severe and moderate renal impairment is unclear.
Hepatic impairment
Following oral administration, Cmax was approximately 60% higher and AUC was approximately twice as high in patients with mild to moderate hepatic impairment compared to healthy subjects. After a single oral dose of 3 mg of carboplatin or 6 mg of carboplatin administered twice daily consecutively, the mean oral clearance was approximately 60-65% lower in patients with mild (7 cases, Child-Pugh score 5-6) and moderate (3 cases, Child-Pugh score 7-9) hepatic impairment (10 cases, as evidenced by biopsy) compared to healthy subjects (10 cases). These pharmacokinetic changes had no effect on the incidence or severity of adverse reactions.
[Storage].
Store under 30℃, sealed.
Packaging
Aluminum-plastic blister with pure aluminum composite film bag
(1) 1.5mg: 10 capsules/plate×3 plates/box; 10 capsules/plate×5 plates/box; 14 capsules/plate×2 plates/box
(2) 3.0mg: 10 capsules/plate x 3 plates/box; 14 capsules/plate x 2 plates/box
Expiration date
24 months
Execution standard
Approval number
[Drug Marketing Licensee
Unit name: Beijing Sihuan Pharmaceutical Co.
Registered Address: East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing
Tel: 010-61563510
【Manufacturing enterprise】 【Manufacturing enterprise
Company Name: Beijing Sihuan Pharmaceutical Co.
Production Address: No. 13, Guangyuan West Street, Zhangjiawan Town, Tongzhou District, Beijing
Postal Code: 101113
Telephone number: 010-61563510
Fax Number: 010-61563510
Website: www.sihuanpharm.com.cn