Date of approval.
Date of revision.
Glucosamine Clofentezolate Softgels Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Glucosamine chlorobenzolate softgels
Trade name: Vyndaqel® / Vyndaqel®
English Name: Tafamidis Meglumine Soft Capsules
Hanyu Pinyin: Lvbenzuosuan Pu’an Ruanjiaonang
Ingredients
The main ingredient of this product is: chlorobenzoate glucosamine
Chemical name: 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono(1-deoxy-1-methylamino-D-glucitol)
Chemical structure formula.
Molecular formula: C14H7Cl2NO3-C7H17NO5
Molecular weight: 503.33
Excipients: polyethylene glycol 400, polysorbate 80, dehydrated sorbitol monooleate, etc.
Excipients with known effects: each softgel contains no more than 44 mg sorbitol.
【Properties】.
This product is oval, opaque, yellow gelatin soft capsule, printed with red “VYN 20”, the contents of white to pink suspension.
Indications
This product is used for the treatment of adults with transthyretin amyloidosis polyneuropathy stage I symptoms, delaying peripheral nerve function impairment.
Specification
20mg (based on C14H7Cl2NO3-C7H17NO5)
Dosage]
Treatment should be initiated by and under the supervision of a physician experienced in the treatment of patients with transthyretin (TTR) amyloidotic polyneuropathy.
Dosage
The recommended dose of glucosamine clobenzolate is 20 mg orally once daily.
If vomiting occurs after administration and the vomitus contains an intact chlorphenzolamide capsule, an additional oral dose of chlorphenzolamide capsule should be administered if possible. If the vomitus does not contain a capsule, no additional medication is required and the dose continues as usual the next day.
Method of administration
Oral administration.
Softgels should be swallowed whole, not crushed or chopped, and taken on an empty stomach or with a meal.
Special Populations
Hepatic impairment and renal impairment
No dose adjustment is required in patients with renal impairment or mild and moderate hepatic impairment. Chlorpheniramine has not been studied in patients with severe hepatic impairment and therefore caution is advised (see [Pharmacokinetics]).
[Adverse Reactions].
Summary of Safety Characteristics
Overall clinical data reflect a mean exposure of 538 days (range 15 – 994 days) to 20 mg chlorphenzolamide per day in 127 patients with TTR amyloidosis polymyalgia. The severity of adverse reactions was usually mild or moderate.
Adverse Reaction List
Adverse reactions are listed according to MedDRA Systematic Organ Classification (SOC) and standard practice frequencies: very common (≥1/10), common (≥1/100 – <1/10), and occasional (≥1/1,000 – <1/100). Within each frequency grouping, adverse reactions are listed in decreasing order of severity. The table below shows the incidence of adverse reactions in the phase III, double-blind, placebo-controlled clinical study (Fx-005).
System Organ Classification (SOC) Very Common Infections and Infectious Diseases Urinary Tract Infections Vaginal Infections Gastrointestinal System Disorders Diarrhea Upper Abdominal Pain
Contraindications
Contraindicated in patients with hypersensitivity to the active ingredients or any of the excipients.
Precautions]
Women of childbearing potential should use appropriate contraception while receiving chlorpheneszolamide and continue to use appropriate contraception for 1 month after discontinuation of chlorpheneszolamide treatment (see [Use in Pregnant and Lactating Women]).
Chlorpheniramine should be added to the standard of care for patients with TTR amyloidosis polyneuropathy. As part of standard therapy, physicians should monitor patients and continue to evaluate the need for other treatments, including the need for liver transplantation. Glucosamine chlorobenzolate should be discontinued in patients receiving liver transplantation as there are no data on its use after liver transplantation.
This product contains sorbitol. This product should not be used in patients with a rare hereditary fructose intolerance.
Effects on the ability to drive and use machines
Based on pharmacodynamic and pharmacokinetic profiles, chlorpheneszolate glucosamine has no or negligible effects on the ability to drive or use machinery.
Pregnant and lactating women
Women of childbearing potential
Due to the long half-life of this product, women of childbearing potential should use contraception during chlorpheniramine treatment and for one month after discontinuation of treatment.
Pregnancy
There are no data on the use of this product in pregnant women. Animal studies have shown developmental toxicity (see [Pharmacologic Toxicology]). This product is not recommended for use during pregnancy and in women of childbearing potential who are not using contraception.
Lactation
Pharmacodynamic/toxicological data from animal studies have indicated that chlorobenzolic acid is secreted in breast milk. This product should be contraindicated during lactation as the risk to the newborn/infant cannot be excluded.
Fertility
No impairment of fertility has been observed in non-clinical studies (see [Pharmacology and Toxicology]).
[Pediatric Use].
Not studied in pediatric population.
Geriatric Use
Data on use in elderly patients are very limited.
Dose adjustment is not required in elderly patients (≥ 65 years).
Drug Interactions]
In clinical studies in healthy volunteers, chlorphenzolamide did not induce or inhibit the cytochrome P450 enzyme CYP3A4.
In vitro data also indicate that chlorphenzolamide does not significantly inhibit the cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6.
In vitro studies with chlorphenzolamide have shown that chlorphenzolamide is unlikely to interact drug-wise with UDP glucuronosyltransferase (UGT), P-gp transporter protein or organic anion-transporting peptide transporter (OATP1B1 and 1B3) substrates at clinically relevant concentrations.
However, in vitro chlorobenzolozamide inhibits the efflux transporter protein BCRP (breast cancer resistance protein) with an IC50 = 1.16 µM and may interact with substrates of this transporter protein (e.g., methotrexate, resulvastatin, imatinib) at clinically relevant concentrations. Similarly, chlorphenesinamide inhibits the uptake transporters, organic anion transporter 1 (OAT1) and 3 (OAT3), with IC50s of 2.9 µM and 2.36 µM, respectively, and at clinically relevant concentrations may interact with substrates of these transporters (e.g., NSAIDs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir (cidofovir, zidovudine, zalcitabine).
No interaction studies have been conducted on the effects of other drugs on chlorpheniramine.
Drug overdose]
Symptoms
No cases of acute overdose have been reported. The highest dose of chlorpheneszolic acid given in clinical trials in healthy volunteers was 480 mg administered as a single dose and 60 mg administered as a multiple dose once daily for two weeks. Treatment-related adverse events reported were mild to moderate and included: headache, drowsiness, myalgia, insomnia, blepharitis, photosensitivity reactions, and syncope aura.
Treatment
In the event of an overdose, standard supportive therapy should be given as required.
[Clinical Trials].
Clinical efficacy and safety
The pivotal study of clobenzaprine is an 18-month, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of 20 mg clobenzaprine administered once daily in 128 patients with TTR amyloid polyneuropathy (usually without assisted ambulation) who carry the V30M mutation and have predominantly stage I disease. The primary endpoints were the Lower Extremity Neuropathy Impairment Score (NIS-LL – physician assessment of the lower extremity neurological examination) and Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL-DN – patient-reported outcomes, Total Quality of Life Score [TQOL]). Other endpoints included a composite score of large nerve fiber function (nerve conduction, vibration threshold, and heart rate response to deep breathing – HRDB), small nerve fiber function (thermal pain and cold threshold and HRDB), and nutritional assessment using modified body mass index (mBMI – BMI multiplied by serum albumin [in g/L]). Eighty-six of the 91 patients who completed the 18-month treatment period were subsequently enrolled in an open-label extension study to receive an extended period of 12 months of 20 mg once-daily chlorpheniramine gluconate.
After 18 months of treatment, more patients receiving chlorphenzolamide developed a NIS-LL response (NIS-LL change of less than 2 points), and the following table provides results for the primary endpoint (pre-specified analysis).
Chlorphenzolamide compared to placebo: NIS-LL and TQOL at month 18 (Study Fx-005) Placebo Vyndaqel pre-specified ITT analysis N=61N=64NIS-LL responders (% patients)
Difference (chlorobenzolate glucosamine minus placebo)
95% CI for difference (p-value) 29.5% 45.3% 15.8%
-0.9%, 32.5% (0.068) Change in TQOL relative to baseline LS mean (SE)
Difference in LS mean (SE)
95% CI for difference (p-value) 7.2 (2.36)2.0 (2.31)-5.2 (3.31)
-11.8, 1.3 (0.116) Pre-specified efficacy evaluable analysis N=42N=45NIS-LL responders (% patients)
Difference (chlorobenzolate glucosamine minus placebo)
95% CI for difference (p-value) 38.1% 60.0% 21.9%
1.4%, 42.4% (0.041) Change in TQOL relative to baseline LS mean (SE)
Difference in LS mean (SE)
95% CI for difference (p-value) 8.9 (3.08) 0.1 (2.98) -8.8 (4.32)
-17.4, -0.2 (0.045) In the pre-specified ITT NIS-LL responder analysis, patients who discontinued prior to the 18-month time point due to liver transplantation were categorized as non-responders. A pre-specified efficacy evaluable analysis was performed using observational data from patients who completed 18 months of treatment according to the regimen.
Secondary endpoints demonstrated reduced neurological deterioration and improved nutritional status (mBMI) with chlorpheniramine treatment compared to placebo. This is shown in the table below.
Change from Baseline in Secondary Endpoints at Month 18, LS Mean (Standard Error) (ITT) (Study Fx-005) Placebo
N=61 chlorobenzoate glucosamine
N=64
P-value % change in chlorpheneszolate glucosamine relative to placebo
NIS-LL change relative to baseline
LS mean (SE) 5.8 (0.96) 2.8 (0.95) 0.027-52% change in large fibers relative to baseline
LS mean (SE) 3.2 (0.63)1.5 (0.62)0.066-53% change in small fibers relative to baseline
LS mean (SE) 1.6 (0.32)0.3 (0.31)0.005-81% change in mBMI relative to baseline
LS mean (SE) -33.8 (11.8)39.3 (11.5)<0.0001NAmBMI is derived by multiplying serum albumin by body mass index.
NA = not applicable
Based on a repeated measures ANOVA with change from baseline as the dependent variable in the model, fixed effect factors including treatment group, month of visit, interaction of treatment group and month of visit, and subjects as a random effect, using an unstructured covariance matrix.
In the open-label extension study, the rate of change in NIS-LL during 12 months of treatment was similar to that of patients treated with chlorobenzolic acid during the previous double-blind 18-month period.
Despite the limited data (one open-label study in 21 patients), chlorobenzolic acid glucosamine is expected to be beneficial in patients with stage I TTR amyloidosis polyneuropathy due to non-V30M mutations, considering the mechanism of action of chlorobenzolic acid and the results of TTR stabilization.
In healthy volunteers, single-dose oral administration of supratherapeutic doses (400 mg) of chlorphenzolamide solution showed no prolongation of the QTc interval.
Pharmacology and Toxicology]
Pharmacological effects
Chlorphenzolic acid is a selective stabilizer of transthyretin (TTR). Clobenzolic acid binds to TTR at the thyroxine binding site, stabilizing the tetramer and slowing its dissociation into monomers (which is the rate-limiting step in amyloid formation).
Toxicological studies
Genotoxicity
The Ames test for clobenzolic acid glucosamine, the in vitro human peripheral blood lymphocyte chromosome aberration test, and the in vivo rat bone marrow micronucleus test were negative.
Reproductive toxicity
Dexrazoxane 15, 30 and 45 mg/kg/day were administered orally to rats from 28 days before to during mating in males and from 15 days before to day 7 of gestation in females, and no toxicity was observed in parental rats. amyloidosis polyneuropathy) at 15 times the recommended dose of 20 mg/day].
In pregnant SD rats, oral administration of dexrazoxane 15, 30, and 45 mg/kg/day during organogenesis resulted in reduced fetal body weight at doses ≥30 mg/kg/day (approximately 32 times the human recommended dose of 20 mg/day in terms of AUC) and a NOAEL of 15 mg/kg/day (approximately the human recommended dose of 20 mg/day in terms of AUC) for rat embryo/fetus development. The NOAEL for rat embryo/fetus development was 15 mg/kg/day (approximately 22 times the recommended human dose of 20 mg/day in terms of AUC).
In pregnant rabbits, oral administration of dexrazoxane 0.5, 2, and 8 mg/kg/day during organogenesis and 8 mg/kg (approximately 31 times the human recommended dose of 20 mg/day in AUC) resulted in increased embryo/fetal mortality, decreased fetal weight, and increased incidence of fetal malformations, with maternal toxicity also seen at this dose; ≥0.5 mg/kg/day (approximately 31 times the human recommended dose of 20 mg/day in AUC). AUC, which is approximately 3 times the recommended human dose of 20 mg/day, resulted in an increased incidence of fetal skeletal variation.
In a perinatal developmental toxicity test in rats, gestational rats were given chlorobenzothionate glucosamine 5, 15, and 30 mg/kg/day orally from day 7 of gestation to day 20 of lactation, and reduced offspring survival and body weight loss, delayed male sexual maturation, and neurobehavioral effects (learning and memory impairment). The NOAEL for perinatal development in rats was 5 mg/kg/day (approximately 2.5 times the recommended human dose of 20 mg/day in terms of body surface area).
Carcinogenicity
Transgenic Tg.rasH2 mice were administered 10, 30, and 90 mg/kg/day of chlorobenzothionate glucosamine orally for 26 consecutive weeks and no increase in tumor incidence was observed. In a 2-year oral carcinogenicity test in rats, the highest dose of 30 mg/kg/day (61 times the exposure at the recommended human dose of 20 mg/day in terms of AUC), no increase in tumor incidence was observed.
Pharmacokinetics]
Absorption
After oral administration of glucosamine clobenzolate softgels in fasting state, the median time to peak (tmax) 2 hours to reach peak plasma concentration (Cmax). Administration with food reduced the rate of absorption, but did not affect the extent of absorption. These results support the administration of chlorobenzolic acid on an empty stomach or after a meal.
Distribution
Chlorobenzolic acid is highly bound to plasma proteins (99.9%). The apparent steady-state volume of distribution was 25.7 L.
Biotransformation and elimination
There is no clear evidence that chlorobenzolic acid is excreted via bile in humans. Based on preclinical data, it is suggested that chlorobenzolic acid is metabolized via glucuronidation and excreted via bile. This biotransformation pathway is reasonable in humans as approximately 59% of the total administered dose is recovered in the feces and approximately 22% in the urine. The mean steady-state half-life after 14 days of once-daily administration of 20 mg chlorpheniramine in healthy subjects was 59 h, with a mean total clearance of 0.42 l/h.
Dose and time linearity
Results for 14 days of once-daily dosing of chlorpheneszolate glucosamine 15, 30 or 60 mg showed a dose-dependent increase in Cmax and AUC between the 15 mg – 30 mg dose; between the 30 – 60 mg dose, the increase was in a less-than-dose ratio, indicating saturation of the absorption process at doses above 30 mg.
Pharmacokinetic parameters were similar after single and repeated doses of 20 mg, indicating that multiple dose administration did not induce or inhibit chlorpheneszolic acid metabolism.
The results of chlorpheneszolate glucosamine 20 mg administered once daily for 14 days showed that steady state was reached on day 14. the Cmax(ss) and Cmin(ss) were 2.7 and 1.6 µg/ml, respectively.
Special Populations
Hepatic impairment
Pharmacokinetic data indicate reduced systemic exposure (~40%) and increased total clearance (0.52 l/h vs. 0.31 l/h) of chlorpheneszolic acid in patients with moderate hepatic impairment (Child-Pugh score of 7-9) compared to healthy subjects due to a higher unbound fraction of chlorpheneszolic acid in patients with moderate hepatic impairment. Since TTR levels were lower in patients with moderate hepatic impairment than in healthy subjects, the stoichiometry of chlorpheneszolic acid with its target protein TTR was sufficient to stabilize the TTR tetramer and therefore no dose adjustment was required. The exposure of chlorobenzolic acid in patients with severe hepatic impairment is unknown.
Renal Impairment
Chlorobenzolic acid has not been evaluated in patients with renal impairment, but no dose adjustment is considered necessary in patients with renal impairment.
Older adults
Based on population PK results, the estimated steady-state clearance was on average 19% lower in subjects over 60 years of age compared to subjects under 60 years of age. However, this difference in clearance was not clinically significant compared to younger subjects and did not result in clinically meaningful differences in drug steady-state levels.
[Storage].
Store under 25°C in a sealed container.
Packaging
Aluminum-plastic blister packaging (blister material: PVC/aluminum foil/oPA/PVC; cover material: aluminum foil).
Each blister contains 15 softgels.
Package specification: 30 capsules/box
【Expiration date】.
24 months
【Execution standard
Import registration standard: JX20190246
Approval number】
[Marketing authorization holder
Holder’s name: Pfizer Europe MA EEIG
Holder’s address: Boulevard de la Plaine17, 1050 Bruxelles, Belgium
Manufacturer
Company name: Catalent Pharma Solutions, LLC
Production Address: 2725 Scherer Drive, St. Petersburg, FL 33716, USA
Domestic Contact Address
8-13F, Block B, Minmetals Plaza, 3-7 Chaoyangmen North Street, Dongcheng District, Beijing, China
Zip code: 100010
Tel: 010-85167000
Product Inquiry Hotline：400 910 0055