英文药名：Vyndaqel（tafamidis capsules）

中文药名：氯苯唑酸软胶囊

生产厂家：辉瑞公司（德国上市）
药品介绍
辉瑞公司近日宣布，欧盟委员会已经批准Vyndaqel（通用名tafamidis）用于治疗转甲状腺素蛋白家族性淀粉样多发性神经病（TTR-FAP），适用于I期有多发性神经病症状的成年患者。TTR-FAP是种罕见的、渐进的致命神经退行性病变，全球累及大约8000名患者。
葡萄牙波尔图的圣安东尼奥医院的TeresaCoelho博士参与了Vyndaqel的临床试验，据他讲，至今没有批准治疗这种退行性致命疾病的药物，Vyndaqel为诊断为TTR-FAP的患者提供了新希望。
转甲状腺素蛋白（TTR）基因突变会产生不稳定的TTR蛋白，进而积累成为淀粉样纤维。淀粉样纤维可以在多器官沉积，包括神经、心脏和肾脏，妨碍它们正常工作。Vyndaqel是一种新型的特定TTR稳定剂，旨在预防形成这些折叠错误的蛋白质及随后的淀粉样沉积，淀粉样沉积会诱发神经变性及神经功能下降。在关键的试验中，在18个月时，可观察到98%的Vyndaqel组患者有TTR稳定性（由体外测定来显示），安慰剂组患者则没有。
对该药的批准是基于关键的临床试验（Fx–005）和公开标记的为期12个月的扩展研究（Fx–006）的结果，它们评估了Vyndaqel对TTR-FAP患者的长期安全性和疗效。在这些临床研究中，Vyndaqel显示出减缓外周神经损伤的疗效。这些研究的额外数据表明，Vyndaqel组患者与安慰剂组患者相比，神经功能、大纤维功能（用运动强度来衡量）和小纤维功能（用感觉来衡量）的退化减轻51%–81%。Vyndaqel导致营养状况改善（改进的身体质量指数或mBMI）；在关键的18个月研究中，mBMI下降表明与疾病进展相关。
Vyndaqel关键研究所报告的药品不良反应为腹泻、上腹痛、泌尿道感染及阴道感染。
用法与用量
该药为处方药，推荐剂量为每日一粒胶囊，整个咽下。Vyndaqel用于配合转甲状腺素蛋白淀粉样变性患者的标准治疗。医生需对患者进行监测并评价是否需要其它治疗方案（包括肝移植）。行肝移植的患者必须停止应用Vyndaqel。
不良反应
Vyndaqel最常见的副作用（见于10例患者中的1例以上）为尿路感染（运输尿液的结构感染）与腹泻。
Vyndaqel不可用于对氯苯唑酸或其它成份过敏的患者。
包装规格
20mgx30粒（2x15粒）
厂家：德国（Pfizer）

Vyndaqel 20 mg soft capsules
1. Name of the medicinal product
Vyndaqel ▼20 mg soft capsules
2. Qualitative and quantitative composition
Each soft capsule contains 20 mg of tafamidis (as meglumine).
Excipients: Each soft capsule contains 77.2 mg of sorbitol (E420).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Soft capsule.
Off-white to light yellow, opaque, oblong (approximately 21.5 mm) capsule imprinted with “FX 6A” in black ink.
4. Clinical particulars
4.1 Therapeutic indications
Vyndaqel is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.
4.2 Posology and method of administration
Treatment should be initiated by and remain under the supervision of a physician knowledgeable in the management of patients with transthyretin amyloid polyneuropathy.
Posology
The recommended dose of Vyndaqel is 20 mg orally once daily.
Vyndaqel should be added to the standard of care for the treatment of the transthyretin familial amyloid polyneuropathy (TTR-FAP) patient. Physicians should monitor patients and continue to assess the need for other therapy, including the need for liver transplantation, as part of this standard of care. As there are no data available regarding the use of Vyndaqel post-liver transplantation, Vyndaqel should be discontinued in patients who undergo liver transplantation.
Special populations
Paediatric population
There is no relevant use of tafamidis in the paediatric population.
Elderly
Data in the elderly patients are very limited.
No dosage adjustment is required for elderly patients (≥ 65 years).
Patient with hepatic and renal impairment
No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment Tafamidis has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).
Method of administration
Oral use.
The soft capsules should be swallowed whole, not crushed or cut, and taken with or without food.
If vomiting occurs shortly after dosing, and Vyndaqel capsule is identified, then an additional dose of Vyndaqel should be administered if possible. If no capsule is identified, then no additional dose is necessary, with resumption of Vyndaqel dosing the next day as usual.
4.3 Contraindications
Hypersensitivity to the active substance (s) or to any of the excipients listed in section 6.1..
4.4 Special warnings and precautions for use
Women of childbearing potential should use appropriate contraception when taking Vyndaqel (see section 4.6).
Vyndaqel contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
In a clinical study in healthy volunteers, tafamidis did not induce or inhibit CYP3A4 enzyme.
In vitro data also indicated that tafamidis does not significantly inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
No interaction studies have been performed evaluating the effect of other medicinal products on tafamidis.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Contraceptive measures should be used by women of childbearing potential during treatment with Vyndaqel, and for one month after stopping treatment, due to the prolonged half life.
Pregnancy
There are no data on the use of Vyndaqel in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Vyndaqel is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
Available pharmacodynamic/toxicological data in animals have shown excretion of tafamidis in milk. A risk to the newborns/infants cannot be excluded. Vyndaqel should not be used during breast-feeding.
Fertility
No impairment of fertility has been observed in nonclinical studies (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects of tafamidis on the ability to drive or use machines have been performed.
4.8 Undesirable effects
TTR amyloid polyneuropathy is a rare disorder.The overall clinical data reflect exposure of 127 TTR amyloid polyneuropathy patients to 20 mg of tafamidis administered daily for an average of 538 days (ranging from 15 to 994 days). The adverse reactions were generally mild or moderate in severity.
Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common (≥1/10), Common (≥1/100 to <1/10), and Uncommon (≥1/1,000 to <1/100). Within the frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme in the tabular listing below reflect the rates at which they occurred in the Phase 3, double-blind, placebo-controlled study (Fx-005)

System Organ Class	Very Common
Infections and infestations	Urinary tract infection
	Vaginal infection
Gastrointestinal disorders	Diarrhoea
	Upper abdominal pain

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
United Kingdom
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at
www.mhra.gov.uk/yellowcard.
4.9 Overdose
 No cases of acute overdose have been reported. In clinical trials of healthy volunteers, the highest dose of tafamidis given was 120 mg in a single dose and 60 mg once daily for two weeks. Four treatment-related adverse events were reported at these doses levels in healthy volunteers: headache (mild), somnolence (mild), myalgia (moderate), and insomnia (mild).
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other nervous system drugs, ATC code N07XX08
Mechanism of action
Tafamidis is a novel specific stabilizer of transthyretin.
Pharmacodynamic effect
TTR amyloid polyneuropathy is a multi-faceted, progressive, axonal degenerative neuropathy characterized by sensory, motor and autonomic impairment. The dissociation of the transthyretin tetramer to monomers is the rate limiting step in the pathogenesis of TTR amyloid polyneuropathy, also known as TTR familial amyloid polyneuropathy (TTR-FAP). The folded monomers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates. These intermediates then misassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds non-cooperatively to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of transthyretin tetramer dissociation forms the rationale for the use of tafamidis to slow disease progression.
Clinical efficacy and safety
The pivotal study of Vyndaqel was an 18-month, multicenter, randomized, double-blind, placebo-controlled study that evaluated the safety and efficacy of once-daily 20 mg tafamidis in 128 patients with TTR amyloid polyneuropathy with the V30M mutation and primarily stage 1 disease (do not routinely require assistance with ambulation). The primary outcome measures were the Neuropathy Impairment Score of the Lower Limb (NIS-LL – a physician assessment of the neurologic exam of the lower limbs) and the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN – a patient reported outcome, total quality of life score [TQOL]). Other outcome measures included composite scores of large nerve fiber (nerve conduction, vibration threshold and heart rate response to deep breathing - HRDB) and small nerve fiber function (heat pain and cooling threshold and HRDB) and nutritional assessments utilizing the modified body mass index (mBMI – BMI multiplied by serum albumin in g/L). Eighty-six of the 91 patients completing the 18 month treatment period subsequently enrolled in an open label extension study, where they all received once daily 20 mg tafamidis for an additional 12 months.
Following 18 months of treatment, more Vyndaqel-treated patients were NIS-LL Responders (change of less than 2 points on NIS-LL) Outcomes for the pre-specified analyses of the primary endpoints are provided in the following table:

Vyndaqel versus Placebo: NIS-LL and TQOL at Month 18 (Study Fx-005)
	Placebo	Vyndaqel
Pre-specified ITT Analysis	N=61	N=64
NIS-LL Responders (% Patients)	29.5%	45.3%
Difference (Vyndaqel minus Placebo) 95% CI of Difference (p-value)	15.8% -0.9%, 32.5% (0.068)
TQOL Change from Baseline LSMean (SE)	7.2 (2.36)	2.0 (2.31)
Difference in LSMeans (SE) 95% CI of Difference (p-value)	-5.2 (3.31) -11.8, 1.3 (0.116)
Pre-specified Efficacy Evaluable Analysis	N=42	N=45
NIS-LL Responders (% Patients)	38.1%	60.0%
Difference (Vyndaqel minus Placebo) 95% CI of Difference (p-value)	21.9% 1.4%, 42.4% (0.041)
TQOL Change from Baseline LSMean (SE)	8.9 (3.08)	0.1 (2.98)
Difference in LSMeans (SE) 95% CI of Difference (p-value)	-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. The pre-specified Efficacy Evaluable analysis used observed data for those patients who completed the 18 month treatment per protocol.

The secondary endpoints demonstrated that Vyndaqel treatment resulted in less deterioration of neurologic function and improved nutritional status (mBMI) compared with placebo, as shown in the following table.

Secondary Endpoints Changes from Baseline to Month 18 LSMean (Standard Errors) (Observed Cases) (Study Fx-005)
	Placebo	Vyndaqel	P-value	Vyndaqel % change relative to Placebo
NIS-LL change from BL LSMean (SE)	5.8 (0.96)	2.8 (0.95)	0.027	-51%
Large Fiber change from BL LSMean (SE)	3.2 (0.63)	1.5 (0.62)	0.066	-53%
Small Fiber change from BL LSMean (SE)	1.6 (0.32)	0.3 (0.31)	0.005	-81%
mBMI change from BL LSMean (SE)	-33.8 (11.8)	39.3 (11.5)	<0.001	NA
mBMI was derived as the product of serum albumin and Body Mass Index. NA=Not applicable

In the open-label extension study, the rate of change in the NIS-LL during the 12 months of treatment was similar to that observed in those patients randomised and treated with tafamidis in the previous double blind 18 month period.
Although data are limited, (one open label study in 21 patients), taking into account the mechanism of action of tafamidis and the results on TTR stabilisation, Vyndaqel is expected to be beneficial in patients with stage 1 TTR amyloid polyneuropathy due to mutations other than V30M.
The effects of tafamidis on cardiac disease progression have not yet been adequately characterised.
The European Medicines Agency has waived the obligation to submit the results of studies with Vyndaqel in all subsets of paediatric population in neuropathic heredofamilial amyloid polyneuropathy (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under 'exceptional circumstances'.
This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
5.2 Pharmacokinetic properties
Absorption
After oral administration of the soft capsule, the maximum plasma concentration (Cmax) is achieved at a median time (tmax) of 1.75 hours after dosing in the fasted state. Concomitant administration of food decreased the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.
Distribution
Tafamidis is highly protein bound (99.9%) in plasma. The apparent steady state volume of distribution is 25.7 liters.
Biotransformation
There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Following daily administration of a 20 mg dose of tafamidis for 14 days in healthy subjects, mean steady-state half-life was 59 h and mean total clearance was 0.42 l/h.
Dose and time linearity
Results from once-daily dosing with tafamidis 15, 30, or 60 mg for 14 days demonstrated dose-dependent increases in Cmax and AUC between doses of 15 mg and 30 mg and less than dose proportional between 30 and 60 mg, indicating saturation of absorption process beyond 30 mg.
Pharmacokinetic parameters were similar after single and repeated administration of 20 mg dose, indicating a lack of induction or inhibition of tafamidis metabolism.
Results of once-daily dosing with tafamidis 20 mg for 14 days demonstrated that steady-state was achieved by Day 14. Cmax(ss) and Cmin(ss) was 2.7 and 1.6 µg/ml, respectively.
Special populations
Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and increased total clearance (0.52 l/h vs. 0.31l/h) of tafamidis in patients with moderate hepatic impairment (Child-Pugh Score of 7-9 inclusive) compared to healthy subjects due to a higher unbound fraction of tafamidis. As patients with moderate hepatic impairment have lower TTR levels than healthy subjects, dosage adjustment is not necessary as the stoichiometry of tafamidis with its target protein TTR would be sufficient for stabilization of the TTR tetramer.
Tafamidis has not specifically been evaluated in patients with renal impairment, but a dosage adjustment in patients with renal impairment is considered not necessary. Based on population PK results, subjects older than 60 years old had an average 19% lower estimate of clearance at steady-state compared to subjects less than 60 years old. However, the difference in clearance would not be clinically significant and would not result in clinically relevant different steady-state levels compared to younger subjects.
5.3 Preclinical safety data
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity.
In repeated dose toxicity studies the liver appeared as a target organ for toxicity in the different species tested. Liver effects were seen at doses above (>3) human exposure and have generally been shown to be reversible.
There was no evidence of adverse reactions of tafamidis on fertility, reproductive performance or mating behaviour in the rat at any dose level.
In a developmental toxicity study in rabbits, a slight increase in skeletal malformations and variations, abortions in few females, and reduction in foetal weights were observed at an AUC0-24 ratio of 3.2-fold, based on the human AUC at steady state.
In the rat peri- and post-natal development study with tafamidis, decreased pup survival and reduced pup weights were noted following maternal treatment during pregnancy and lactation at doses of 15 and 30 mg/kg. Decreased foetal weights in males were associated with delayed sexual maturation (preputial separation) and impaired performance in a water-maze test for learning and memory. The NOAEL for viability and growth in the F1 generation offspring following maternal treatment during pregnancy and lactation with tafamidis was 5 mg/kg (HED=0.8 mg/kg), a dose approximately 4.6-times the anticipated clinical human dose.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule shell
Gelatin
Glycerin
Sorbitol liquid (E420)
Titanium dioxide (E171)
Purified water
Capsule contents
Macrogol
Sorbitan monooleate
Polysorbate 80
Printing ink (Opacode black)
Shellac glaze 45% (20% esterified) in ethanol
Isopropyl alcohol
Iron oxide black (E172)
Propylene glycol
Ammonium hydroxide 28%
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original container in order to protect from light.
6.5 Nature and contents of container
Two polyvinyl chloride/aluminum blisters each containing 15 soft capsules, in a box, giving a total of 30 soft capsules per box.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Pfizer Limited
Ramsgate Road
Sandwich, Kent
CT13 9NJ
United Kingdom
8. Marketing authorisation number(s)
EU/1/11/717/001
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 16th November 2011
10. Date of revision of the text
20 August 2013
Ref: VY 5_0
Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu