Windakel (Vyndaqel)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTafamidisTafamidis
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  • Windakel
    capsules inwards 
    Pfizer Inc.     USA
    • Dosage form: & nbspcapsules
    Composition:

    Composition per 1 capsule:

    active substance:

    tafamidis meglumine 20.0 mg,

    Excipients:

    macrogol 400 481.0 mg, polysorbate 80 66.0 mg, sorbitan oleate 33.0 mg

    Composition of gelatin capsule:

    L3DXHBAHR Gelatine Transparent 366.6 mg (gelatin (195 AA 8) 216.6 mg, sorbitol special glycerin mixture 150.0 mg), iron dye oxide yellow 1.0 mg, titanium dioxide 2.1 mg

    Composition of ink "Opacode® (WB) NSP-78-10015":

    Ethanol denatured 31.89%, ammonia solution 28% 1.00%, isopropanol 9.40%, purified water 11.60%, macrogol 400 2.70%, polyvinyl acetate phthalate 13.31%, propylene glycol 25.90%, carmine 4.15%, the color of the brilliant blue is 0.05%.

    Description:

    Oblong, opaque, yellow soft gelatin capsules with a red inscription "VYN 20".

    The contents of the capsule are from a white to pink suspension.

    Pharmacotherapeutic group:Other drugs for the treatment of diseases of the nervous system
    ATX: & nbsp

    N.07.X.X.08   Tafamidis

    Pharmacodynamics:

    Tafamidis is a radically new selective stabilizer of transthyretin (TT). Tafamidis with negative co-operability is associated with two thyroxine-binding regions of TT in native (tetrameric) form, which prevents dissociation of the complex into monomers and slows amyloidogenesis.The inhibition of the dissociation of tetrameric forms of TT justifies the expediency of using tafamidis to slow the progression of transthyretine amyloidosis, mainly familial transthyretinamide amyloid polyneuropathy (TT-CTAP).

    Stabilization analysis of TT was used as a pharmacodynamic marker to assess the stability of tetramer TT under conditions of denaturation.

    Tafamidis stabilized both the non-mutant type of TT tetramer and the tetramers of 10 CT variants, within the framework of clinical trials, after a daily single application of tafamidis at a dose of 20 mg. Also tafamidis stabilized an additional 25 variants of the TT-tetramer in studies ex vivo, in aggregate demonstrating the stabilization of 36 amyloidogenic genotypes of TT.

    It was found that parameters such as age, gender, race, modifiable body mass index, variation of the TT gene, severity and duration of the ns disease affect the pharmacodynamics of tafamidis.

    The safety and efficacy of tafamidis at a dose of 20 mg were evaluated daily in a multicentre, randomized, double-blind, placebo-controlled study with a total of 128 patients.After 18 months of treatment, a group of patients taking tafamidis, showed no progression of the disease compared with the group of patients taking placebo. Also, in the first group of patients, the overall quality of life decreased less than in the placebo group.

    Pharmacokinetics:

    Suction

    With a single admission tafamidisa in a dose of 20 mg on an empty stomach the maximum concentration in the blood plasma (FROMmOh) was achieved after 1.75 h (tmax - the median time to reach the maximum concentration). Simultaneous food intake reduced the rate, but not the degree of absorption. The results confirmed the possibility of taking tafamidis as a joint food, and regardless of food intake.

    Distribution

    Tafamidis binds very well to proteins (99.9%) of the blood plasma. The observed equilibrium volume of distribution is 25.7 liters.

    The binding activity of tafamidis with plasma proteins was evaluated in studies with plasma of animals and humans. The affinity of tafamidis for TT is 1000 times higher than for albumin. In this way tafamidis predominantly binds to TT, despite the fact that the concentration of albumin in the blood plasma (600 μM) is much higher than the concentration of TT (3.6 μM).

    Metabolism and excretion

    Unambiguous evidence that tafamidis is excreted in a person with bile is absent, however, based on the results of preclinical studies, it is assumed that the metabolism of tafamidis proceeds by glucuronidation followed by excretion with bile. This pathway metabolism and excretion is most likely to humans since approximately 59% of the total dose received is output through the gut mainly unchanged and approximately 22% is excreted via the kidney, mainly in the form of a metabolite formed during glucuronidation. When taking tafamidis at a dose of 20 mg once a day for 14 days, the average half-life in the equilibrium state in healthy people was 59 hours, the average total clearance was 0.42 l / h.

    Linearity of time points versus dose

    When tafamidis is used in doses of 15, 30 or 60 mg 1 p / day for 14 days, the value of CmOh and the area under the "concentration-time" curve (AUC) increased proportionately to the dose in the dose range of 15 to 30 mg and increased less intensively than the dose increased, in the dose range of 30 to 60 mg. After multiple administration tafamidisa 20mg average half-life and clearance orally were similar to those recorded at a single dose, indicating the absence of induction or inhibition tafamidisa metabolism.

    Achieving the equilibrium state (ss) was observed by the 14th day of tafamidis administration at a dose of 20 mg 1 r / day for 14 days. Values Cmax(ss) and Cmin(ss) were 2.7 and 1.6 μg / ml, respectively.

    Application in special populations

    Elderly patients

    According to the results of population pharmacokinetic analysis in patients older than 60 years, the estimated clearance of the drug in the equilibrium state was on average 19% lower than in patients younger than 60 years. However, it is assumed that this difference in clearance is not clinically significant and is not capable of causing clinically significant deviations in the equilibrium concentration of tafamidis in comparison with the concentration in younger people.

    Patients with impaired hepatic function

    In patients with impaired liver function of mild or moderate degree, dose adjustment is not required. Pharmacokinetic data indicated a decrease in systemic exposure (by approximately 40%) and an increase in total clearance (0.52 l / h compared to 0.31 l / h) of tafamidis in humans with impaired hepatic function (7-9 (inclusive) points on the Child-Pugh scale) compared to healthy people. Since the concentration of TT in patients with impaired liver function of moderate severity is reduced in comparison with healthy people, the exposure of tafamidis,relevant to the concentration of TT, will be sufficient to stabilize the TT tetramer in this group of patients. Exposure of tafamidis in patients with impaired liver function of mild degree was similar to exposure in healthy people.

    Information on the exposure of tafamidis in patients with impaired hepatic function is not available.

    Patients with impaired renal function

    The use of tafamidis in patients with impaired renal function has not been specifically studied. Tafamidis is mainly metabolized by glucuronidation and is presumed to be excreted via the hepatobiliary pathway. The effect of creatinine clearance (CK) on the pharmacokinetics (FC) of tafamidis was studied in a population pharmacokinetic analysis in patients with CK> 30 mL / min. When calculating the pharmacokinetic parameters, there were no differences in tafamidis clearance in the equilibrium state between patients with CC <80 ml / min and patients with CC> 80 ml / min. In patients with impaired renal function of mild or moderate degree, dose adjustment is not required. Data on the use of the drug in patients with severe renal dysfunction (CK ≤ 30 ml / min) are absent.

    Indications:

    Vindakel is indicated for the treatment of transthyretine amyloidosis in adults with clinically expressed polyneuropathy in order to delay the development of disorders in the peripheral nerves.

    Contraindications:

    - Hypersensitivity to tafamidis or to any auxiliary substance included in the preparation;

    - pregnancy, the period of breastfeeding;

    - congenital intolerance to fructose;

    - Children under 18 years.

    Carefully:

    Vindakel should be used with caution in patients with severe hepatic dysfunction.

    Pregnancy and lactation:

    Pregnancy

    It is not recommended the use of tafamidis during pregnancy, as well as in women with preserved reproductive potential, not using contraceptives.

    Women with preserved reproductive potential should use reliable contraceptive methods during the treatment period, and also within one month after the completion of tafamidis treatment.

    Information about the experience of tafamidis during pregnancy is absent. Studies in animals have revealed reproductive toxicity of the drug. The potential risk to humans is unknown.

    Breastfeeding period

    The effect of tafamidis on children who are breastfed in mothers receiving tafamidis therapy has not been studied. However, in preclinical studies it was found that tafamidis penetrates into the milk of nursing rats. No clinical data have been obtained that would indicate the penetration of tafamidis into the human breast milk. Because many drugs penetrate into breast milk, the potential risk to a breastfeeding baby can not be ruled out. Women receiving tafamidis. should not breast-feed and give breast milk to children.

    Fertility

    According to the results of pre-clinical studies. Tafamidis did not have a negative impact on reproductive function and fertility.

    Dosing and Administration:

    The recommended dose of Vindakel is 20 mg, by mouth, once a day, regardless of food intake.

    The capsule should be taken as a whole. Do not chew, break or cut the capsule.

    If a dose is missed, the patient should take the missed dose as soon as he remembers the omission.However, if it is time to take the next dose, do not take the missed dose; the patient should take the next dose according to the usual schedule. Do not take a double dose.

    Use in children

    Windacock should not be used in children, because transthyretinovaya amyloid polyneuropathy does not occur in this group of patients.

    Use in elderly patients

    Data on the use of the drug in elderly patients is extremely limited.

    In elderly patients (≥65 years of age), dose adjustment is not required.

    Use in patients with impaired function of nochek or liver

    In patients with impaired renal function or with a mild or moderate liver dysfunction, dose adjustment is not required.

    Tafamidis has not been studied in patients with severe impairment of liver function, so it should be used with caution in this group of patients.

    Side effects:

    TT-CTAP is a rare disease.

    The frequency of unwanted reactions is represented by the following classification:

    Very Frequent

    ≥ 10%

    Frequent

    ≥ 1% and <10%

    Infrequent

    ≥ 0.1% and <1%

    Rare

    ≥ 0.01% and <0.1%

    Very rare

    < 0,01 %

    From the digestive system: very frequent - diarrhea, pain in the upper abdomen.

    Infectious and parasitic diseases: very frequent - infection urinary tract pathways, vaginal infection.

    Overdose:

    Data on cases of an overdose with tafamidis are absent.

    In clinical studies in healthy volunteers tafamidisa maximum dose was 480 mg dose and 60 mg of 1 p / day daily for two weeks. When applying the drug at the indicated doses, no undesirable reaction was recorded.

    Interaction:

    In a clinical study among healthy volunteers tafamidis Not induced or inhibited isoenzyme CYP3A4. Research in vitro They also showed that tafamidis has no significant inducing or inhibitory effect on isoenzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

    According to the research results in vitro, tafamidisa unlikely drug interactions at clinically relevant doses substrates uridine 5-diphosphate glucuronyl transferase (UDP-GT), P-glycoprotein transporters, organic anion transporter (OAT3 and OAT1) or organic anion transporter polypeptide (OATR1V1 and OATR1V3).

    However, in studies in vitro tafamidis inhibits efflux carrier of breast cancer resistance protein (BCRP) and can increase the system exposure of substrates of this vector (eg, methotrexate, rosuvastatin and imatinib).

    The same way tafamidis inhibits the activity of the OAT1 and OAT3 capture vectors (carriers of organic anions). When found in the body at clinically significant concentrations, it can interact with the substrates of these carriers

    (eg nonsteroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, and zalcitabine).

    Studies of the effects of other drugs on tafamidis not conducted.

    With a single administration of midazolam (substrate isoenzyme CYP3A4) at a dose of 7.5 mg before and after a 14-day course of tafamidis at a dose of 20 mg per day, no significant effect on the pharmacokinetics of midazolam or on the formation of its active metabolite (1-hydroxymidazolam) was observed. General System Exposure (AUC0-∞) and the total ground clearance (CL/F) Midazolam were equivalent before and after taking the study drug. Besides, tafamidis did not induce isoenzyme activity CYP3A4 neither in men, nor in women.

    Special instructions:

    Clinical studies on the use of tafamidis in patients who underwent liver transplantation were not carried out. The efficacy and safety of the Vindakel preparation in patients who underwent liver transplantation has not been established.

    Effect on the ability to drive transp. cf. and fur:

    Studies on the effect of tafamidis on the ability to drive vehicles were not conducted.

    Form release / dosage:

    Capsules 20 mg.

    Packaging:

    15 capsules in a blister pack PBX/PHTFE / PVC / aluminum foil.

    2 blisters combined together for 15 capsules are placed in a cardboard box together with an instruction for use.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    18 months.

    Do not use the product after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004181
    Date of registration:15.03.2017
    Expiration Date:15.03.2022
    The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA
    Manufacturer: & nbsp
    Representation: & nbspPfizer LtdPfizer LtdUSA
    Information update date: & nbsp31.03.2017
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