Sowaldi (Sovaldi)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceSofosbuvirSofosbuvir
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  • Sowaldi
    pills inwards 
    Gilead Science International Co., Ltd.     United Kingdom
    • Dosage form: & nbspFilm-coated tablets.
    Composition:

    1 tablet contains:
    active substance: sophosbuvir 400.0 mg;
    Excipients:
    Core tablet:

    mannitol 360.0 mg, microcrystalline cellulose 356.0 mg, croscarmellose sodium 60.0 mg, silicon dioxide colloid 6.0 mg, magnesium stearate 18.0 mg;

    Tablet casing:

    Opadrai II yellow 36.0 mg, containing: polyvinyl alcohol (40.0%), titanium dioxide (23.33%), macrogol (20.20%), talc (14.8%), iron oxide oxide yellow (1 , 67%).

    Description:

    Capsule-shaped tablets, coated with a yellow film coating, engraved “GSI” on one side and "7977" on the other.

    Pharmacotherapeutic group:Antiviral agent
    ATX: & nbsp

    J.05.A.X.15   Sofosbuvir

    Pharmacodynamics:

    Mechanism of action

    Sophosbuvir is a pan-genotypic inhibitor of the RNA-dependent NS5B RNA polymerase of hepatitis C virus (HCV), which is necessary for viral replication. Sofosbuvir - a nucleotide prodrug that undergoes intracellular metabolism, during which a pharmacologically active analogue of uridine triphosphate (GS-461203) is formed. Through NS5B polymerase GS-461203 can be inserted into the under construction chain of HCV RNA and act as a chain sniffer. This active metabolite of sophosbuvira (GS-461203) inhibited the polymerase activity of genotypes 1b, 2a, 3a and 4a of HCV in concentrations that caused 50% inhibition (IC50), in the range from 0.7 to 2.6 μmol.The active metabolite of sophosbuvira (GS-461203) does not inhibit the polymerase of human DNA and RNA or the polymerase of mitochondrial RNA.

    Antiviral activity

    In studies using HCV replicons, the effective concentration values (EC50) cofosbuvira against full-length replicons of genotypes 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 micromolar, respectively, and the values EC50 cofosbuvira against chimeric replicons of genotype 1b bearing NS5B sequences from genotypes 2b, 5a or 6a were 0.014-0.015 μmol. The EU average50± SD somosbuvira with respect to chimeric replicons carrying sequences NS5B from clinical isolates, was 0.068 ± 0.024 μmol for genotype 1a; 0.11 ± 0.029 μmol for genotype 1b; 0.035 ± 0.018 μmol for genotype 2 and 0.085 ± 0.034 μmol for the genotype 3a. Antiviral activity of cofosbuvira in vitro in respect of less frequent genotypes 4, 5 and 6, was similar to genotypes 1, 2 and 3.

    There was no significant change in the antiviral activity of sophosbuvira in the presence of 40% human serum.

    Resistance

    In cell culture

    Reduced susceptibility to cofosbuvir was associated with the primary S282T mutation in NS5B of all HCV replicon genotypes investigated (1b, 2a, 2b, 3a, 4a, 5a and 6a).Site-directed mutagenesis confirmed that the S282T mutation in replicons of 8 genotypes is responsible for a 2-18-fold decrease in susceptibility to sophosbuvir and a decrease the ability of the virus to replicate by 89-99% compared with the corresponding wild-type virus. Recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a, expressing the substitution of S282T, showed a decreased sensitivity to the active metabolite of sophosbuvira (GS-461203) compared to similar wild-type polymerases.

    In clinical trials

    Of the 991 patients receiving sophosbuvier In clinical trials (CI), 226 patients were selected for resistance analysis due to virological inefficiency or early discontinuation of the study drug and HCV RNA concentration> 1,000 IU / mL. Sequence changes in NS5B compared with baseline were evaluated in 225 of 226 patients, with deep sequencing data (1% threshold) obtained in 221 of these patients. The mutation S282T, responsible for resistance to sophosbuyvir, was not determined in either of these patients either by deep sequencing or by population sequencing.The S282T mutation in NS5B was detected in a single patient who received monotherapy with Sovaldi's drug. The S282T mutation returned to the wild type within the next 8 weeks, and 12 weeks after cessation of therapy was not determined by the method of deep sequencing.

    Two mutations of NS5B, L159F and V321A were identified in the samples of several patients with genotype 3 of HCV in the period of relapse after discontinuation of therapy within the CI. Changes in phenotypic sensitivity to cofosbuvir or ribavirin in isolates of patients with such mutations were not detected. In addition, S282R and L320F mutations were determined by deep sequencing during treatment in a patient with partial response to therapy prior to transplantation. The clinical significance of this data is unknown.

    Effect of initial HCV polymorphisms on the effectiveness of treatment

    When analyzing the effect of the initial polymorphisms on the outcome of therapy, there was no statistically significant association between the presence of any original NS5B variant of HCV (S282T mutation) and the efficacy of treatment.

    Cross-resistance

    HCV replicas expressing the mutation S282T, responsible for resistance to sophosbuvir, were completely sensitive to other classes of drugs for the treatment of hepatitis C. Sofosbuvir remained active against viruses with L159F and L320F mutations in the NS5B polymerase gene associated with resistance to other nucleoside inhibitors. Sofosbuvir fully retained its activity against mutations associated with resistance to other direct antiviral drugs with various mechanisms of action, such as non-nucleoside NS5B polymerase inhibitors, NS3 protease inhibitors and NS5A inhibitors.

    The efficacy of sophosbuvir was evaluated in five studies involving 1568 patients aged 19 to 77 years with chronic hepatitis C (HCV) caused by viruses of genotypes from 1 to 6.

    Children

    The efficacy and safety of using Sowaldi in children and adolescents under the age of 18 has not been established. No data available.

    Pharmacokinetics:

    Sofosbuvir is a nucleotide prodrug that undergoes intensive metabolism. An active metabolite, formed in hepatocytes, is not found in the blood plasma. The main (> 90%) metabolite, GS-331007, is not active. It is formed by successive and parallel ways of formation of the active metabolite.

    Suction

    After oral administration sophosbuvier quickly absorbed, and its maximum concentration (FROMmax ) in blood plasma was achieved after 0.5-2 hours, regardless of the magnitude of the dose taken. FROMmax inactive metabolite (GS-331007) in blood plasma was achieved in 2-4 hours after taking the drug. Based on the results of a population analysis of pharmacokinetic data in patients with genotypes 1-6 of the HCV, the area under the concentration-time curve (AUC0-24) of somosbuvira and an inactive metabolite (GS-331007) in equilibrium was 1010 ng∙hour / ml and 7,200 ng∙hour / ml, respectively. Compared with healthy volunteers, AUS0-24 sophosbuvira and inactive metabolite (GS-331007) in patients with CHC was 57% higher and 39% lower, respectively.

    Taking sophosbuvira in a single dose with a standardized, high-fat diet slowed the absorption rate of sophosbuvira. The completeness of absorption of cofosbuvir increased by about 1.8 times, with a slight effect on FROMmax. Eating high-fat foods did not affect the exposure of the inactive metabolite (GS-331007).

    Distribution

    Sophosbuvir is not a substrate for hepatic transporters, including the transport-transport-polypeptide (AAPP) 1B1 or 1B3 transporting organic anions. Undergoing active secretion of the renal tubules, an inactive metabolite (GS-331007) is neither a substrate nor an inhibitor of renal transporter, including the carrier of organic anions (OAT) 1 or 3, or the carrier of organic cations (OCT) 2, multiple drug resistance proteins (MRP2), glycoprotein P, breast cancer resistance protein (BCRP) or the MAT1 protein transfer protein.

    Sophosbuvir approximately 85% binds to human plasma proteins (data ex vivo), and binding does not depend on the drug concentration in the range of 1-20 μg / ml. Inactive metabolite (GS-331007) minimally binds to human plasma proteins. After a single dose of 400 mg [14C] -sophosbuvir by healthy volunteers, the ratio of radioactivity 14C in blood / plasma is approximately 0.7.

    Metabolism

    Sofosbuvir is extensively metabolized in the liver with the formation of a pharmacologically active nucleoside (uridine) analogue of triphosphate (GS-461203). The metabolic pathway of activation involves sequential hydrolysis of the carboxyletherase molecule with cathepsin A (CatA) or carboxyl esterase 1 (CES1) and cleavage of phosphoramidate by nucleotide-binding protein 1 with histidine triads (HINT1) with subsequent phosphorylation by biosynthesis of the pyrimidine nucleotide. Dephosphorylation leads to the formation of a nucleoside inactive (> 90%) metabolite, which can not be completely rephosphorylated, and has no activity against HCV in vitro. Sophosubwir and inactive metabolite (GS-331007) are neither substrates nor inhibitors UGT1A1 or cytochrome isoenzymes CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6.

    After a single oral intake of 400 mg [14C] -sosfosvira, the system exposure of sophosbuvira and the inactive metabolite (GS-331007) was approximately 4% and> 90%, respectively, from the system exposure of the material associated with the drug (the sum of AUC of sophosbuvira and its metabolites with a molecular weight correction).

    Excretion

    After a single oral intake of 400 mg [14C] -sosfosvir, the average total radioactive dose excretion was more than 92%, with approximately 80%, 14% and 2.5% excreted by the kidneys, intestines and lungs, respectively. Most of the dose of somosbuvira, excreted by the kidneys, represented an inactive metabolite (GS-331007) (78%), while 3.5% was excreted as sophosbuvir. These data show that renal clearance is the main way to inactivate the inactive metabolite (GS-331007) with predominantly active secretion.The mean half-life of sophosbuvira and an inactive metabolite (GS-331007) is 0.4 hours and 27 hours, respectively.

    It was found that when taking fasting sophosbuvir in doses from 200 mg to 400 mg AUC sophosbuvira and inactive metabolite (GS-331007) is practically proportional to the dose.

    Pharmacokinetics in specific patient groups

    Children

    Parameters of pharmacokinetics of sophosbuvira and inactive metabolite (GS-331007) in children are not established.

    Elderly patients

    In patients with CHC, it was shown that in the age range of 19 to 75 years, age had no clinically significant effect on the exposure of sophosbuvira and the inactive metabolite (GS-331007) . Within the CI, the response rate in patients aged 65 years and older and in young patients was similar.

    Sex and race

    There were no clinically significant differences in the pharmacokinetics of sophosbuvira and inactive metabolite depending on sex and race of patients.

    Renal insufficiency

    In comparison with patients with normal renal function (creatinine clearance, CC, > 80 ml / min), not infected with HCV, with renal insufficiency of mild, moderate and severe severity, AUC0-inf sophosbuvira was higher, respectively, by 61%, 107% and 171%, aAUC0-inf inactive metabolite (GS-331007) was higher by 55%, 88% and

    451%, respectively.In patients with chronic renal failure (CRF), compared with patients with normal renal function AUC0-inf sophosbuvira was 28% higher if sophosbuvier were taken 1 hour before the hemodialysis session, and 60% higher if sophosbuvier took 1 hour after the hemodialysis session. AUC0-inf inactive metabolite (GS-331007) in patients with CRF was not possible to reliably determine. However, the data show at least a 10-fold and 20-fold increase in the exposure of the inactive metabolite (GS-331007) in patients with CRF when receiving sophosbuvir 1 hour before the hemodialysis session or when taking sophosbuvir 1 hour after the hemodialysis session, respectively, compared with patients with normal renal function.

    The basic inactive metabolite (GS-331007) can be effectively removed by hemodialysis (clearance is about 53%). After a 4-hour hemodialysis session, approximately 18% of the dose taken is taken out. In patients with renal insufficiency, mild or moderate severity does not require a change in the dose of the drug. The safety of use of cofosbuvir has not been evaluated in patients with severe renal insufficiency and patients with end-stage renal failure (see "Dosage and Administration" and "Contraindications").

    Liver failure

    Compared with patients with normal liver function AUC0-inf fromOfosbuvir was 126% and 143% higher in patients with moderate to severe hepatic impairment, and AUC0-inf inactive metabolite (GS-331007) was higher by 18% and 9%, respectively. Population analysis of pharmacokinetic data in patients with CHC showed that cirrhosis had no clinically significant effect on the exposure of sophosbuvira and the inactive metabolite (GS-331007). Patients with hepatic insufficiency of mild, moderate and severe severity are not recommended to change the dose of sophosbuvira.

    The relationship of pharmacokinetics / pharmacodynamics

    It has been shown that the effectiveness of treatment in the form of rapid virologic response correlates with the exposure value of sophosbuvira and the inactive metabolite (GS-331007). However, none of these parameters is the main surrogate marker for effectiveness evaluation (CBO12) when applying a therapeutic dose of 400 mg.

    Indications:

    The drug Sowaldi is indicated for use in combination with other drugs for the treatment of chronic hepatitis C in adult patients.

    Contraindications:

    • Hypersensitivity to sophosbuvir or any other component of the drug;
    • Pregnancy;
    • Children under 18 years of age (efficacy and safety not established in this population);
    • Renal failure of severe severity (CK <30 ml / min) or terminal stage of renal failure when hemodialysis is required (safety not established in this population of patients);
    • Combined infection with hepatitis C and B viruses (HCV / HBV) (there is no data on the use of the drug Sowaldi in this patient population);
    • Decompensated hepatic cirrhosis (efficacy and safety not established in this population of patients);
    • In patients receiving potent inducers of the P-glycoprotein (for example, rifampicin, St. John's wort [Hypericum perforatum], carbamazepine and phenytoin, phenobarbital, oxcarbazepine).

    Carefully:

    - In patients with the genotype of 1.4.5 and 6 HCV who had previously received antiviral therapy, especially in cases where there were one or more factors historically associated with a low frequency of responses to interferon therapy (prevalent fibrosis / cirrhosis, initially high concentration virus, Negroid race, the presence of a non-CC allele of the genotype IL28B).

    - In patients who simultaneously take other antiviral drugs to treat hepatitis C (for example, telaprevir or boceprevir).

    - In patients receiving a combination of preparations of Sowaldi and Daklins, against the background of concomitant therapy with amiodarone.

    Pregnancy and lactation:

    Pregnancy

    There is insufficient data (less than 300 outcomes of pregnancies) about the use of somosbuvira during pregnancy. It is necessary to avoid the use of the drug Sowaldi during pregnancy.

    The results of preclinical studies did not reveal direct or indirect reproductive toxicity of sophosbuvira. The use of maximum doses in rats and rabbits showed no effect on the fetal development of the fetus. Nevertheless, it is impossible to fully evaluate the effect of limiting concentrations of sophosbuvira in animals and correlate it with the action of recommended clinical doses in humans.

    The use of the drug Sowaldi in combination with ribavirin or peginterferoic alfa / ribaviriiom

    However, if cofosbuvir is used simultaneously ribavirin, contraindications to the use of ribavirin during pregnancy are applicable (see also the instructions for the use of ribavirin).In cases where the drug Sovaldi is used in combination with ribavirin or with peginterferoic alpha / ribavirin, all necessary measures must be taken to prevent pregnancy in patients and partners of male patients. All experimental animals showed severe teratogenic and / or embryogenic effects with ribavirin (see section "Special instructions"). Women with preserved childbearing potential or their partners should apply effective methods of contraception during and after treatment for the required period of time, as recommended by the use of ribavirin (see the ribavirin supplementation for additional information).

    Breast-feeding

    It is not known whether sophosbuvier and its metabolites in human breast milk, although pre-clinical studies established the excretion of metabolites with breast milk.

    Since the risk to the fetus / newborn can not be ruled out, the Sowaldi drug should not be used during breastfeeding.

    Influence on reproductive function

    Data on the effect of the drug Sowaldi on the reproductive function of humans are absent.In animal studies, there is no adverse effect on reproductive function.

    Dosing and Administration:

    For oral administration.

    Treatment with the drug Sowaldi should begin and be controlled by a doctor who has experience in the treatment of chronic hepatitis C.

    One tablet, 400 mg, of the drug Sovaldi is recommended to be taken once a day, during meals. The tablet should be swallowed whole, washed down with water. Tablets can not be chewed or broken.

    If the delay in taking the drug Sowaldi was less than 18 hours, the patient should take the next dose as soon as possible, and then continue the usual intake of the drug.

    If the delay in taking the drug Sowaldi was more than 18 hours, the patient should wait and take the next pill at the usual time.

    If the patient has vomiting within 2 hours after taking the drug Sowaldi, it is necessary to take another dose of the drug.

    If the patient has vomiting 2 hours after taking the drug Sowaldi, there is no need to take another dose of the drug (most of the dose of the drug is absorbed within 2 hours).

    The drug Sowaldi should be used in combination with other medicines.

    Monotherapy with Sovaldi is not recommended. Drugs recommended for joint use with the preparation of Sowaldi, and the duration of the combination therapy are presented in Table 1.

    Table 1. Medications recommended for joint use with the drug Sowaldi, and the duration of combination therapy

    Patient population *

    Therapy

    Duration


    Sowaldi +
    ribavirin + peginterferon alfa

    12 weeksa, b

    Patients with chronic hepatitis C of genotypes 1,4, 5 or 6

    Sowaldi + ribavirin

    Only for use in patients who do not tolerate or are not suitable for the therapy with pegyuterferon alfa (see section "Special instructions")

    24 weeks

    Patients with chronic hepatitis C of genotype 2

    Sowaldi + ribavirin

    12 weeksb

    Patients with chronic hepatitis C of genotype 3

    Sowaldi +
    ribavirin + peginterferon alfa

    12 weeksb


    Sowaldi + ribavirin

    24 weeks

    Patients with chronic hepatitis C who are waiting for liver transplantation

    Sowaldi + ribavirin

    Before
    transplantation
    liverc

    * Includes patients who are simultaneously infected with the human immunodeficiency virus (HIV).

    a.For patients with chronic hepatitis C of genotype 1, who previously received therapy, there is no data on combination therapy with the drug Sowaldi, ribavirin and peginterferon alfa (see section "Special instructions"),

    b. Consider possible prolongation of therapy beyond 12 weeks and up to 24 weeks; especially for those subgroups of patients who have one or more factors historically associated with a lower response rate to interferon-based therapy (eg, advanced fibrosis / cirrhosis, high baseline viral load, black race, the presence of a non-CC allele of the IL28B gene , preceding the zero response to peginterferon alfa and ribavirin therapy).

    c. See below section "Special patient groups" - patients waiting for liver transplantation.

    The dose of ribavirin in combination with the drug Sowaldi is determined based on the patient's body weight (<75 kg = 1000 mg and> 75 kg = 1200 mg), and the drug is taken orally during meals in two divided doses.

    Data on the joint use with other antiviral drugs for the treatment of hepatitis C, see the section "Special instructions".

    Dose change

    It is not recommended to reduce the dose of Sovaldi.

    If sophosbuvier is used in combination with peginterferon alfa, and the patient developed a serious undesirable reaction potentially associated with peginterferon alfa, the dose of the latter should be reduced or stopped. For more information on the possibility of dose reduction and / or discontinuation of peginterferon alfa therapy, see the "Instructions for the medical use of the peginterferon alfa preparation."

    If the patient develops a serious undesirable reaction potentially associated with ribavirin, the dose of ribavirin should be reduced or discontinued, if appropriate, until the unwanted reaction disappears or its severity decreases. Table 2 provides recommendations for changing the dose of ribavirin and its withdrawal, taking into account the concentration of hemoglobin and the state of the cardiovascular system of the patient.

    Table 2: Guidelines for changing the dose of ribavirin when it is used together with the drug Sowaldi

    Laboratory values

    Reduce the dose of ribavirin to 600 mg / day if:

    Reject ribavirin if:

    Concentration of hemoglobin in patients without heart disease

    <10 g / dL

    <8.5 g / dL

    Concentration of hemoglobin in patients with a history of heart disease in a stable state

    decrease in hemoglobin concentration by ≥2 g / dl for any 4 weeks of therapy

    <12 g / dL, despite the use of the drug for 4 weeks in a reduced dose

    After abolishing ribavirin due to a deviation from the norm of the laboratory indicator or the development of clinical symptoms, you can try to resume therapy with ribavirin at a dose of 600 mg / day, and then increase the dose to 800 mg / day. However, it is not recommended to increase the dose of ribavirin to the initial dose (1000 mg - 1200 mg per day).

    Abolition of therapy

    If you stop using other medications prescribed in combination with the drug Sowaldi, then you should cancel and therapy with Sovaldi (see section "Special instructions").

    Special patient groups

    Elderly patients

    It is not necessary to change the dose of the drug in elderly patients.

    Renal insufficiency

    It is not necessary to change the dose of Sovaldi in patients with renal insufficiency of mild or moderate severity. Safety and the corresponding dose of the drug Sowaldi have not been established in patients with severe renal insufficiency (CK <30 ml / min) or terminalstage of renal failure requiring hemodialysis (see the section "Pharmacokinetics").

    Liver failure

    It is not necessary to change the dose of Sovaldi in patients with mild, moderate or severe hepatic insufficiency (class A, B or C on the Child-Pugh-Turkott scale). The safety and efficacy of the drug Sowaldi in patients with decompensated cirrhosis of the liver is not established.

    Patients awaiting liver transplantation

    In determining the duration of use of the drug Sovaldi in patients waiting for liver transplantation, it is necessary to be guided by an assessment of the benefit-risk relationship for a particular patient.

    Children

    The safety and effectiveness of therapy with the drug Sowaldi in children and adolescents under the age of 18 years are not established, data are not available (see the section "Contraindications").

    Side effects:

    Security Profile Overview

    The most frequent adverse drug reactions (NLR) that were recorded during CI were consistent with the known safety profile of ribavirin and peginterferon alfa without increasing the frequency or severity of the expected NLR.

    Due to the development of NLR, 1.4% of patients who received placebo, 0.5% of patients who received sophosbuvier + ribavirin within 12 weeks, 0% of patients receiving sophosbuvier + ribavirin for 16 weeks, 11.1% of patients receiving peginterferon alfa + ribavirin for 24 weeks, and 2.4% of patients receiving sophosbuvier + peginterferon alfa + ribavirin within 12 weeks.

    The preparation of Sowaldi was studied, mainly, in combination with ribavirin in combination or without peginterferon alfa. Against the backdrop of this combination therapy, NLPs specific for sophosbuvira have not been identified. The most frequent NLR observed in patients who received sophosbuvier and ribavirin, or sophosbuvier, ribavirin and peginterferon alfa, were fatigue, headache, nausea and insomnia.

    The following HLR were identified when using cofosbuvira in combination with ribavirin or in combination with peginterferon alfa / ribavirin (Table 3). NLRs are grouped below according to the classes of systems and organs and frequency of occurrence. The frequency of unwanted reactions was determined in accordance with the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), or very rarely (<1/10000).

    Table 3: NLRs identified using cofosbuvira in combination with ribavirin or with peginterferon alfa / ribavirin

    Frequency

    sophosbuvir + ribavirin

    sophosbuvir + peginterferon alfa + ribavirin

    Infectious and parasitic diseases:

    Often

    nasopharyngitis


    Violations from the blood and lymphatic system:

    Often

    decrease in hemoglobin concentration

    anemia, neutropenia, a decrease in the number of lymphocytes, a decrease in the number of platelets

    Often

    anemia


    Disorders from the metabolism and nutrition:

    Often


    Decreased appetite

    Often


    Weight loss

    Disorders of the psyche:

    Often

    insomnia

    insomnia

    Often

    depression

    depression, anxiety, agitation

    Impaired nervous system:

    Often

    headache

    dizziness, headache

    Often

    attention violation

    Migraine, impaired memory, impaired attention

    Disorders from the side of the organ of vision:

    Often


    blurred vision

    Disturbances from the respiratory system, chest and mediastinal organs:

    Often


    dyspnoea, cough

    Often

    shortness of breath, shortness of breath with physical exertion, cough

    dyspnoea with physical exertion

    Disorders from the gastrointestinal tract:

    Often

    nausea

    diarrhea, nausea, vomiting

    Often

    discomfort in the abdomen, constipation, indigestion

    constipation, dry mouth, gastroesophageal reflux

    Disorders from the liver and bile ducts:

    Often

    increase in bilirubin concentration in the blood

    increase in bilirubin concentration in the blood

    Disturbances from the skin and subcutaneous tissues:

    Often


    rash, itching

    Often

    alopecia, dry skin, itching

    alopecia, dry skin

    Disturbances from the musculoskeletal system and connective tissue:

    Often


    arthralgia, myalgia

    Often

    arthralgia, back pain, muscle spasms, myalgia

    back pain, muscle spasms

    Systemic disorders and complications at the site of administration:

    Often

    fatigability, irritability

    chills, fatigue, flu-like condition, irritability, pain, fever

    Often

    fever, asthenia

    chest pain, asthenia



    Other special patient groups

    Co-infection of HIV / HCV

    The safety profile of sophosbuvira and ribavirin in patients with co-infection with HIV / HCV was similar to that of patients infected with HCV only who received sophosbuvier and ribavirin during the CI.

    Patients awaiting liver transplantation

    The safety profile of sophosbuvira and ribavirin in patients with CHC waiting for liver transplantation was similar to that in patients who received sophosbuvier and ribavirin during the CI.

    Description of individual unwanted drug reactions

    Bradycardia and cardiac blockade

    There were cases of development of severe bradycardia and cardiac blockade with a combination of preparations of Sowaldi and Daklins (daklataswir) in combination with amiodarone and / or other drugs slowing down the heart rate (see the sections "Interaction with other medicines" and "Special instructions").


    Overdose:

    The largest, documented dose of sophosbuvira was a single, super therapeutic dosage of sophosbuvira 1200 mg, used in 59 healthy volunteers. Against this dose of the drug, unexpected NLR was not observed, all detected NLR were similar in frequency and severity to those in the placebo group and the group of somosbuvir (400 mg).

    Specific antidote for the drug Sowaldi is absent. In case of an overdose, the patient should be monitored for the timely detection of signs of toxicity.

    Treatment of an overdose of the drug Sowaldi includes general supportive measures, including monitoring of vital signs and clinical status of the patient.Hemodialysis can effectively remove (clearance 53%) the main inactive metabolite (GS-331007) from the blood. The hemodialysis session lasted 4 hours and removed 18% of the accepted dose of the drug.

    Interaction:

    Sophosbuvir is the substrate of the P-glycoprotein carrier and the breast cancer resistance protein (BCRP), whereas its inactive metabolite (GS-331007) is not. Drugs, powerful inducers of P-glycoprotein in the intestine (for example, rifampicin, St. John's wort, carbamazepine and phenytoin), can lower the plasma concentration of cofosbuvir, leading to a decrease in the therapeutic effectiveness of the drug Sowaldi, so do not use them simultaneously with the drug Sowaldi (see the sections "Contraindications" and "Special instructions"). The combined use of the drug Sovaldi with drugs, P-glycoprotein and / or BCRP inhibitors, can increase the concentration of cofosbuvir in the plasma without simultaneous increase in the concentration of the inactive metabolite (GS-331007). Thus, the Sowaldi preparation can be used concomitantly with P-glycoprotein and / or BCRP inhibitors.

    Sophosbuvir and inactive metabolite (GS-331007) are not inhibitors of P-glycoprotein and BCRP,therefore, it is not expected to increase the exposure of drugs that are substrates of these vectors.

    Intracellular activation of somosbuvir metabolism is mediated by a hydrolase with low affinity and high activity, as well as nucleotide phosphorylation routes, to which the joint use of other medications is practically unaffected.

    Other interactions

    Table 4 below provides information on the drug interaction of the drug Sowaldi with possible concomitant medications (where the 90% confidence interval (CI) of the adjusted geometric mean ratio (GLSM) was not changed "↔", increased"↑", or reduced"↓", in comparison with the pre-established boundaries of equivalence.) The table does not include all preparations.

    Table 4: Interactions between the drug Sowaldi and other drugs

    Medicinal preparation (therapeutic group)

    Effect on the concentration of the drug. The average ratio (90% confidence interval) for AUC, Cmax, Cmina, b

    Recommendation when combined with the drug Sowaldi

    ANALEPTICS

    Modafinil

    The interaction was not studied. It is proposed:
    ↓ Sofosbuvir
    ↓ GS-331007

    It is assumed that with the combined use of the drug Sowaldi with modafinil, the concentration of sophosbuvir decreases, which leads to a decrease in the therapeutic efficacy of the Sowaldi preparation. Such a joint use is not recommended.

    ANTIARITHMIKS

    Amiodarone

    The interaction was not studied.

    The use of amiodarone is permissible only in the absence of alternative therapies. When using amiodarone in combination with a combination of preparations of Sowaldi and Daklins, careful monitoring is recommended (see the sections "Side effects" and "Special instructions").

    ANTI-TREATMENT PREPARATIONS

    Carbamazepine
    Phenytoin
    Phenobarbital
    Oxcarbazepine

    Interaction is not was studied.
    It is proposed:
    ↓ Sofosbuvir
    ↓ GS-331007

    It is assumed that with the combined use of the drug Sowaldi with carbamazepine, phenytoin, phenobarbital or oxcarbazepine, the concentration of cofosbuvir decreases, which leads to a decrease in the therapeutic effectiveness of the Sowaldi preparation. Such a joint use is not recommended.The drug Sowaldi should not be used in combination with carbamazepine, phenytoin, phenobarbital or oxcarbazepine, powerful inducers of P-gp in the intestine.

    ANTIBIOTIC ANTIBIOTICS

    Rifabutin
    Rifampicin
    Rifapentin

    The interaction was not studied. It is proposed:
    ↓ Sofosbuvir
    ↓ GS-331007

    It is assumed that with the combined use of the drug Sowaldi with rifabutin or rifapentin, the concentration of cofosbuvir decreases, which leads to a decrease in the therapeutic efficacy of the Sowaldi preparation. Such a joint use is not recommended. Do not use the drug Sowaldi in conjunction with rifampicin, a powerful inducer of P-gp in the intestine.

    PREPARATIONS OF PLANT ORIGIN

    St. John's Wort perforated (Hypericum perforatum)

    The interaction was not studied. It is proposed:
    ↓ Sofosbuvir
    ↓ GS-331007

    Do not use the drug Sowaldi at the same time with preparations containing St. John's wort, a powerful inducer of P-gp in the intestine.

    Antiviral drugs for HCG treatment: HCV protease inhibitors

    Boceprevir (BOC)
    Telaprevir (TPV)

    The interaction was not studied. It is proposed:
    ↑ Sophosbuvir (TPV)
    ↔ Sofosbuvir (BOC)
    ↔ GS-331007 (TPV or BOC)

    There is no data on the drug interaction of the preparation of Sowaldi with bocetrevir or telaprevir.

    NARCOTIC ANALGETICS

    Methadonef (Maintenance therapy with methadone [30 to 130 mg / day])

    R-Methadone
    ↔ Cmax 0.99 (0.85, 1.16)
    ↔ AUC 1.01 (0.85, 1.21)
    ↔ Cmin 0.94 (0.77, 1.14)

    S-methadone
    ↔ Cmax 0.95 (0.79, 1.13)
    ↔ AUC 0.95 (0.77, 1.17)
    ↔ Cmin 0.95 (0.74, 1.22)

    Sofosbuvir
    ↓ Cmax 0.95c (0.68, 1.33)
    ↑ AUC 1.30c (1.00, 1.69)
    Cmin (NA)

    GS-331007
    ↓ Cmax 0.73c (0.65, 0.83)
    ↔ AUC 1.04c (0.89, 1.22)
    Cmin (NA)

    When cofosbuvira is combined with methadone, it is not necessary to adjust the dose of sophosbuvira or methadone.

    IMMUNODEPRESSANTS

    Cyclosporine (600 mg single dose)

    Cyclosporin
    ↔ Cmax 1.06 (0.94, 1.18)
    ↔ AUC 0.98 (0.85, 1.14)
    Cmin (NA)

    Sofosbuvir
    ↑ Cmax 2.54 (1.87, 3.45)
    ↑ AUC 4.53 (3.26, 6.30)
    Cmin (NA)

    GS-331007
    ↓ Cmax 0.60 (0.53, 0.69)
    ↔ AUC 1.04 (0.90, 1.20)
    Cmin (NA)

    When cofosbuvira is combined with cyclosporine, it is not necessary to adjust the dose of sophosbuvir or cyclosporine.

    Tacrolimuse (5 mg single dose)

    Tacrolimus
    ↓ Cmax 0.73 (0.59, 0.90)
    ↔ AUC 1.09 (0.84, 1.40)
    Cmin (NA)

    Sofosbuvir
    ↓ Cmax 0.97 (0.65, 1.43)
    ↑ AUC 1.13 (0.81, 1.57)
    Cmin (NA)

    GS-331007
    ↔ Cmax 0.97 (0.83, 1.14)
    ↔ AUC 1.00 (0.87, 1.13)
    Cmin (NA)

    When cofosbuvira is combined with tacrolimus, it is not necessary to adjust the dose of sophosbuvira or tacrolimus.

    Antiviral drugs for HIV treatment: Inhibitors of reverse transcriptase

    Efavirenzf (600 mg once daily)d

    Efavirenz
    ↔ Cmax 0.95 (0.85, 1.06)
    ↔ AUC 0.96 (0.91, 1.03)
    ↔ Cmin 0.96 (0.93, 0.98)

    Sofosbuvir
    ↓ Cmax 0.81 (0.60, 1.10)
    ↔ AUC 0.94 (0.76, 1.16)
    Cmin (NA)

    GS-331007
    ↓ Cmax 0.77 (0.70, 0.84)
    ↔ AUC 0.84 (0.76, 0.92)
    Cmin (NA)

    When cofosbuvira is used together with efavirenz it is not necessary to adjust the dose of sophosbuvira or efavirenz.

    Emtricitabinef (200 mg once daily)d

    Emtricitabine
    ↔ Cmax 0.97 (0.88, 1.07)
    ↔ AUC 0.99 (0.94, 1.05)
    ↔ Cmin 1.04 (0.98, 1.11)

    Sofosbuvir
    ↓ Cmax 0.8 1 (0.60, 1.10)
    ↔ AUC 0.94 (0.76, 1.16)
    Cmin (NA)

    GS-331007
    ↓ Cmax 0.77 (0.70, 0.84)
    ↔ AUC 0.84 (0.76, 0.92)
    Cmin (NA)

    When cofosbuvira is combined with emtricitabine, it is not necessary to adjust the dose of sophosbuvira or emtricitabine.

    Tenofovirf (300 mg once daily)d

    Tenofovir
    ↑ Cmax 1.25 (1.08, 1.45)
    ↔ AUC 0.98 (0.91, 1.05)
    ↔ Cmin 0.99 (0.91,1.07)

    Sofosbuvir
    ↓ Cmax 0.81 (0.60, 1.10)
    ↔ AUC 0.94 (0.76, 1.16)
    Cmin (NA)

    GS-331007
    ↓ Cmax 0.77 (0.70, 0.84)
    ↔ AUC 0.84 (0.76, 0.92)
    Cmin (NA)

    When cofosbuvira is combined with tenofovir, it is not necessary to adjust the dose of sophosbuvir or tenofovir.

    Rilpivirinef (25 mg once daily)

    Rilpivirine
    ↔ Cmax 1.05 (0.97, 1.15)
    ↔ AUC 1.06 (1.02, 1.09)
    ↔ Cmin 0.99 (0.94, 1.04)

    Sofosbuvir
    ↑ Cmax 1.21 (0.90, 1.62)
    ↔ AUC 1.09 (0.94, 1.27)
    Cmin (NA)

    GS-331007
    ↔ Cmax 1.06(0.99, 1.14)
    ↔ AUC 1.01 (0.97, 1.04)
    Cmin (NA)

    When cofosbuvir is used together with rilpivirin, it is not necessary to adjust the dose of sophosbuvir or rilpivirin.

    ANTI-VIRAL DRUGS FOR HIV TREATMENT: HIV PROTEASIS INHIBITORS

    Darunavir, boosted with ritonavir f 800/100 mg once daily)

    Darunavir
    ↔ Cmax 0.97 (0.94, 1.01)
    ↔ AUC 0.97 (0.94, 1.00)
    ↔ Cmin 0.86 (0.78, 0.96)

    Sofosbuvir
    ↑ Cmax 1.45 (1.10, 1.92)
    ↑ AUC 1.34 (1.12, 1.59)
    Cmin (NA)

    GS-331007
    ↔ Cmax 0.97 (0.90, 1.05)
    ↔ AUC 1.24 (1.18, 1.30)
    Cmin (NA)

    When cofosbuvir is used together with darunavir, it is not necessary to adjust the dosage of sophosbuvir or darunavir (ritonavir-boosted).

    ANTI-VIRAL DRUGS FOR HIV TREATMENT: INHIBITORS INTEGRATION

    Raltegravirf (400 mg once daily)

    Raltegravir
    ↓ Cmax 0.57 (0.44, 0.75)
    ↓ AUC 0.73 (0.59, 0.91)
    ↔ Cmin 0.95 (0.81,1.12)

    Sofosbuvir
    ↔ Cmax 0.87 (0.71, 1.08)
    ↔ AUC 0.95 (0.82, 1.09)
    Cmin (NA)

    GS-331007
    ↔ Cmax 1.09 (0.99, 1.20)
    ↔ AUC 1.03 (0.97, 1.08)
    Cmin (NA)

    When cofosbuvir is used together with raltegravir, it is not necessary to adjust the dosage of sophosbuvir or raltegravir.

    ORAL CONTRACEPTIVES

    Norgestimate /
    ethinyl estradiol

    Norgestromine
    ↔ Cmax 1.06 (0.93, 1.22)
    ↔ AUC 1.05 (0.92, 1.20)
    Cmin (NA)

    Norgestrel
    ↔ Cmax 1.1(0.99, 1.41)
    ↔ AUC 1.19 (0.98, 1.44)
    Cmin (NA)

    Ethinylestradiol
    ↔ Cmax 1.14 (0.96, 1.36)
    ↔ AUC 1.08 (0.93, 1.25)
    Cmin (NA)

    When cofosbuvira is combined with norgestimate / ethyl estradiol, it is not necessary to adjust the dose of norgestimate / ethinylestradiol.

    NA = none / not applicable

    a. The average ratio (90% CI) of the pharmacokinetics parameters of the drug used with / without cofosbuvir and the average ratio of the pharmacokinetics parameters of sophosbuvira and GS-331007 with or without the concomitant drug. Lack of effect = 1.00;

    b. All interaction studies were conducted on healthy volunteers;

    c. Comparison based on historical control;

    d. Used in the form of the drug Atripla;

    e. The limit of bioequivalence is 80-125%;

    f. The equivalence limit is 70-143%.


    Special instructions:

    Are common

    Preparation Sowaldi it is not recommended to use in the form of monotherapy, it should be administered in combination with other drugs for the treatment of chronic hepatitis C.When you stop taking other medications prescribed in combination with the drug Sowaldi, the drug Sowaldi should also be canceled. Before starting to use the drug Sowaldi, you should carefully read the instructions for medical use for co-prescribing medications.

    Bradycardia and cardiac blockade

    Reported cases of development of severe bradycardia and cardiac blockade with a combination of drugs Sowaldi and Daklins (daklataswir) in combination with amiodarone and / or other drugs slowing down the heart rate. The mechanism of development of this reaction is not established.

    In clinical trials of the combination of sophosbuvira and direct antivirals, the concomitant use of amiodarone was limited. Adverse reactions arising from the use of such combination therapy, potentially life threatening, so the use of amiodarone, along with a combination of preparations of Sowaldi and Daklins, is acceptable only with intolerance or the presence of contraindications to alternative antiarrhythmic therapy.

    In cases where concomitant use of amiodarone is necessary, close monitoring of patients at the beginning of treatment with a combination of preparations of Sowaldi and Daklins is recommended. Patients at high risk for bradyarrhythmia should be monitored continuously for 48 hours in an appropriately equipped clinic.

    If necessary, start a combination therapy with preparations of Sowaldi and Daklins to patients who had previously taken amiodarone, appropriate monitoring should be performed for those who stopped taking amiodarone in the last few months, since amiodarone has a long half-life.

    All patients taking a combination of Sowaldi and Daklins preparations together with amiodarone should be warned about the symptoms of bradycardia and heart block and the need for immediate Seek medical attention in the event of such symptoms.

    Patients with chronic hepatitis C genotypes 1.4. 5 and 6, previously treated

    There was no CI of the Sovaldi drug in patients with chronic hepatitis C of genotypes 1, 4, 5 and 6 who received therapy before.Therefore, the optimal duration of treatment in this patient population has not been established.

    The tactics of treating these patients require discussion, possibly with regard to the extension of therapy beyond 12 weeks and up to 24 weeks; especially for those subgroups of patients who have one or more factors historically associated with a lower response rate to interferon therapy (eg, severe fibrosis / cirrhosis, high baseline viral load, black race, non-CC allele presence of the IL28B gene).

    Treatment of patients with CHC 5 or 6 genotype

    The volume of CI data in support of the use of Sowaldi in patients with HCV genotype 5 or 6 is very limited.

    Treatment of patients with CHC 1, 4, 5 and 6 genotypes without interferon

    Regimens of therapy with the drug Sowaldi without interferon patients with HCV genotypes 1, 4, 5 or 6 have not been studied. The optimal regimen and duration of therapy are not established. Such regimens should be used only in patients who do not tolerate or are not suitable for interferon therapy, and urgently need treatment.

    Joint use with other direct antiviral drugs for the treatment of hepatitis C

    The drug Sowaldi should be used in conjunction with other antiviral drugs of direct effect only if the benefit of such a combination outweighs the risks according to available data. There is no data to support the joint use of the drug Sowaldi and telaprevir or boceprevir. This combination of drugs is not recommended.

    Pregnancy and simultaneous use of ribavirin

    In cases where the drug Sovaldi is used in combination with ribavirin or with peginterferon alfa / ribavirin, women with preserved reproductive potential or their partners should use effective contraceptive methods during and after the treatment period for the required period of time, as recommended by the use of ribavirin (see the ribavirin supplementation for additional information).

    Simultaneous use with inducers of P-glycoprotein

    Drugs that are potent inducers of P-glycoprotein in the intestine (for example, rifampicin, St. John's Wort [Hypericum perforatum], carbamazepine and phenytoin), can significantly reduce the concentration of cofosbuvir in the blood plasma, which, in turn, lowers the therapeutic effectiveness of the drug Sowaldi.Such medications should not be used in conjunction with the drug Sowaldi.

    Renal insufficiency

    The safety of the use of the Sowaldi preparation has not been studied in patients with severe renal insufficiency (CK <30 ml / min) or with end stage renal insufficiency requiring hemodialysis. Moreover, the appropriate dose of the drug has not been established. When using Svaldi in combination with ribavirin or peginterferon alfa / ribavirin in patients with CC <50 ml / min, see also the medical instructions for the drug ribavirin (section "Pharmacokinetics").

    Patients with co-infection with HCV / HBV

    Data on the use of the drug Sovaldi in patients with co-infection of HCV / HBV are absent.

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

    The drug Sowaldi has a moderate effect on the ability to manage vehicles and mechanisms. Patients should be informed that during the application of sophosbuvira in combination with peginterferon alfa and ribavirin, attention disorder, development of fatigue, dizziness and decreased vision are possible.In the event of these symptoms, patients should refrain from carrying out potentially hazardous activities such as driving and using mechanisms.

    Form release / dosage:

    Tablets, film-coated, 400 mg.

    Packaging:

    28 tablets in a white bottle with a capacity of 100 ml of high-density polyethylene, sealed with aluminum foil, sealed with a polypropylene cover with an anti-tamper protection system, containing a container or sachet with silica gel, with the inscription (in Latin letters) “DO NOT EAT” and a polyester tab.

    1 bottle together with instructions for use in a pack of cardboard.

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003527
    Date of registration:25.03.2016
    Expiration Date:25.03.2021
    The owner of the registration certificate:Gilead Science International Co., Ltd. Gilead Science International Co., Ltd. United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspGilead Sciencez Rasha, OOOGilead Sciencez Rasha, OOO
    Information update date: & nbsp23.08.16
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