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NATCO

"Velpanat" NATCO

"Hepsinat LP" NATCO

"Hepcinat Natdac" NATCO 

<span style="font-weight: bold;">Sofosbuvir + Velpatasvir (400mg + 100mg)</span>&nbsp; <span style="font-weight: bold;">3 bottles</span>
Sofosbuvir + Velpatasvir (400mg + 100mg)  3 bottles
Price 12 weeks course :  950 $
Shipping to United States 7-14 days
<span style="font-weight: bold;">Sofosbuvir + Ledipasvir (400mg + 100mg)&nbsp;3 bottles</span>
Sofosbuvir + Ledipasvir (400mg + 100mg) 3 bottles
Price 12 weeks course : 820 $
Shipping to United States  7-14 days
<span style="font-weight: bold;">Sofosbuvir + Daclatasvir (400mg + 60mg)&nbsp;3 + 3 bottles</span>
Sofosbuvir + Daclatasvir (400mg + 60mg) 3 + 3 bottles
Price 12 weeks course : 760 $
Shipping to United States 7-14 days

ZYDUS CADILA

"Sovihep V"  ZYDUS HEPTIZA 

<span style="font-weight: bold;">Sofosbuvir + Velpatasvir (400mg + 100mg)  3 bottles</span><br>
Sofosbuvir + Velpatasvir (400mg + 100mg) 3 bottles
Price 12 weeks course : 950 $
Shipping to United States 7-14 days

" LediHep"  ZYDUS HEPTIZA

<span style="font-weight: bold;">Sofosbuvir + Ledipasvir (400mg + 100mg) 3 bottles</span>
Sofosbuvir + Ledipasvir (400mg + 100mg) 3 bottles
Price 12 weeks course : 625 $
Shipping to United States 7-14 days

"Ledifos" ZYDUS HEPTIZA

<span style="font-weight: bold;">Ledipasvir + Sofosbuvir (400mg + 90mg)&nbsp;3 bottles</span><br>
Ledipasvir + Sofosbuvir (400mg + 90mg) 3 bottles
Price 12 weeks course : 820 $
Shipping to United States 7-14 days

Sofosbuvir instruction

Name Sofosbuvir The Latin name of the substance is Sofosbuvir Sofosbuvirum ( born in Sofosbuviri)

Chemical name propan-2-yl (2S) [[[(2R, 3R, 4R, 5R) -5- (2,4-dioxopyrimidin-1-yl) -4-fluoro-3-hydroxy-4-methyloxolan-2-yl ] methoxy-phenoxyphosphoryl] amino] propanoate

Gross formula C 22 H 29 FN 3 O 9 P

Pharmacological group of substance SofosbuvirAntiviral drugs  Description: Antiviral drugs are designed to treat various viral diseases (influenza, herpes, HIV infection, etc.). They are also used for preventive purposes.Depending on the disease and properties, various antiviral agents are used orally, parenterally or topically (in the form of ointments, creams, drops).According to sources of reception and chemical nature, they are divided into the following groups: 1) interferons (endogenous origin and obtained genetically engineered, their derivatives and analogs); 2) synthetic compounds (amantadines, arbidol, bonaffton, etc.); 3) substances of vegetable origin (alpizarin, flakozid, etc.).A large group of antiviral agents are derived from nucleosides (acyclovir, stavudine, didanosine, ribavirin, zidovudine, etc.).One of the first nucleosides was idoxuridine, which effectively suppresses the herpes simplex virus and vaccine (vaccine disease). However, the side effect limited its systemic application. On the contrary, acyclovir, zidovudine, didanosine and others are prescribed as chemotherapeutic agents (that is, they expect resorptive effects). The mechanism of action of various nucleosides is very close. All of them in cells infected with the virus are phosphorylated, converted into nucleotides, competing with "normal" nucleotides for insertion into viral DNA and stopping the replication of the virus.Interferons are a group of endogenous low molecular weight proteins (molecular weight from 15,000 to 25,000), which possess antiviral, immunomodulating and other biological properties, including antitumor activity.Currently, different types of interferon are known. The main ones are alpha-interferon (with varieties of alpha 1 and alpha 2), beta-interferon, gamma-interferon. Alfa-interferon is a protein, and beta and gamma interferons are glycoproteins. Alfa-interferon is produced mainly by peripheral blood B-lymphocytes and lymphoblastoma lines, beta-interferon-fibroblasts, and gamma-interferon by peripheral blood T-lymphocytes. Initially, natural (leukocyte-human) interferon was used to prevent and treat influenza and other viral infections. Recently, a number of recombinant alpha interferons have been obtained by genetic engineering (Interlock, Reaferon, interferon alfa-2a, interferon alfa-2b, etc.), beta interferons (interferon beta, interferon beta-1b, etc.), gamma interferons (imkin and others). The effect of some antiviral agents (Poludan, kridanimod, partly arbidol, etc.) is associated with their interferonogenic activity, i.e.,Widespread use for the treatment and prevention of influenza and other viral diseases have rimantadine, adapromine and others (derivatives of amantadine), metisazone, bonafthon.Nosological classification (ICD-10)B18.2 

Chronic viral hepatitis C Nosological classification (ICD-10)B18.2 Chronic viral hepatitis C 

Characteristics of the substance Sofosbuvir Nucleotide pagenotypic inhibitor of RNA- dependent RNA polymerase NS5B of hepatitis C virus. Molecular weight 529.45. A white or off-white solid crystalline substance with a solubility ≥ 2 mg / ml in the pH range of 2-7.7 at 37 ° C, slightly soluble in water. 

Pharmacology  Pharmacological action - antiviral .PharmacodynamicsMechanism of action.Sophosbuvir is a panthenotypic inhibitor of the RNA- dependent NS5B RNA polymerase of hepatitis C virus (HCV), which is necessary for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form a pharmacologically active analogue of uridine triphosphate (GS-461203). With the NS5B polymerase, the GS-461203 can be inserted into a growing chain of HCV RNA and act as a chain sniffer. This active metabolite of sophosbuvir (GS-461203) inhibited the polymerase activity of genotypes 1b, 2a, 3a and 4a of HCV in concentrations that caused 50% inhibition (IC 50 ) in the range of 0.7 to 2.6 μmol. The active metabolite of sophosbuvira (GS-461203) does not inhibit the polymerase of DNA and RNAhuman and polymerase mitochondrial RNA .Antiviral activityIn studies using the HCV Replicon the effective concentration (EC 50 ) against the full-length replicon sofosbuvir genotypes 1a, 1b, 2a, 3a and 4a HCV accounted 0.04; 0.11; 0.05; 0.05 and 0.04 μmol respectively, and the EC 50 values ​​of sofosbuvir against the chimeric replicons of genotype 1b bearing NS5B sequences from genotypes 2b, 5a or 6a were 0.014-0.015 μmol. The mean EC 50 ± standard deviation (SD) of sofosbuvir for chimeric replicons carrying NS5B sequences from clinical isolates was (0.068 ± 0.024) μmol for genotype 1a, (0.11 ± 0.029) μmol for genotype 1b, (0.035 ± 0.018 ) for the genotype 2 and (0.085 ± 0.034) for the genotype 3a. Antiviral activity of sofosbuvir 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.ResistanceIn cell culture. Reduced susceptibility to sofosbuvir was associated with the primary S282T mutation in NS5B of all investigated genotypes of HCV replicons (1b, 2a, 2b, 3a, 4a, 5a and 6a).Site-directed mutagenesis confirmed that the S282T mutation in replicons of the 8 genotypes is responsible for a 2-18-fold decrease in susceptibility to sofosbuvir and a decrease in the virus's ability to replicate by 89-99% compared to the corresponding wild-type virus. Recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a, expressing the substitution of S282T, showed a reduced sensitivity to the active metabolite of sophosbuvira (GS-461203) compared to similar wild-type polymerases.In clinical studies. Of the 991 patients receiving somosbuvir in clinical trials, 226 patients were selected for resistance analysis due to virological inefficiency or early termination of the study drug and HCV RNA concentration > 1000 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 sofosbuvir, 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 receiving sofosbuvir monotherapy. The S282T mutation returned to the wild type within the next 8 weeks and after 12 weeks after cessation of therapy it 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 HCV genotype 3 during the recurrence period after discontinuation of therapy in clinical trials. Changes in phenotypic sensitivity to sofosbuvir 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.The 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 (mutation S282T) and the efficacy of treatment.Cross-resistance. HCV replicas expressing the mutation S282T responsible for resistance to sofosbuvir were completely sensitive to other classes of drugs for the treatment of hepatitis C. Sofosbuvir remained active against viruses with mutations of L159F and L320F in the NS5B polymerase gene associated with resistance to other nucleoside inhibitors. Sophosbuvir has fully retained its activity against mutations associated with resistance to other direct-acting 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 effectiveness and safety of the use of sophosbuvira in children and adolescents under the age of 18 has not been established. No data available.PharmacokineticsSofosbuvir is a nucleotide substance that is activated by undergoing intensive metabolism. An active metabolite, formed in hepatocytes, is not found in the blood plasma. The main (> 90%) metabolite, GS-331007, is inactive.Suction. After ingestion, sofosbuvir was rapidly absorbed, and its C max in the blood plasma was reached after 0.5-2 hours, regardless of the magnitude of the dose taken. With mа of inactive metabolite (GS-331007) in plasma of blood it was reached in 2-4 hours after reception софосбувира. Based on the results of a population analysis of pharmacokinetic data in patients with genotypes 1-6 of the HCV, the values ​​of AUC 0-24 of sofosbuvir and the inactive metabolite (GS-331007) in equilibrium were 1010 and 7200 ng · h / ml, respectively. Compared with healthy volunteers, AUC 0-24 of sofosbuvir and an 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 sophosbuvir increased by approximately 1.8 times, with a slight effect on C max . 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 . Being exposed to active secretion of the renal tubules, the inactive metabolite (GS-331007) is neither a substrate nor an inhibitor of renal transporter, including carriers of organic anatoms ( OAT ) 1 or 3 or organic cations ( OCT ) 2, multiple drug resistance ( MRP2 ) proteins , P -gp, breast cancer resistance protein ( BCRP ) or the carrier protein MATE1 .Sophosbuvir binds approximately 85% to human plasma proteins ( ex vivo data ), and binding is independent of its concentration in the range of 1-20 μg / ml. The inactive metabolite (GS-331007) binds to a minimal extent with human plasma proteins. After a single intake of 400 mg of 14 C-somosbuvir by healthy volunteers, the radioactivity ratio of 14 C in blood / plasma is approximately 0.7.Metabolism. Sophosbuvir is extensively metabolized in the liver with the formation of a pharmacologically active nucleoside (uridine) triphosphate analogue (GS-461203). The metabolic pathway of activation involves sequential hydrolysis of the molecule with cathepsin A or carboxyl esterase 1 and cleavage of phosphoramidate with nucleotide-binding protein 1 with histidine triads ( HINT1 ) followed by 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 HHC in vitro . Sophosubwir and the inactive metabolite (GS-331007) are neither substrates nor inhibitors of UGT1A1 or cytochrome isoenzymesCYP3A4 , CYP1A2 , CYP2B6 , CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 .After a single oral intake of 400 mg of 14 C-somosbuvir, the system exposure of sophosbuvira and the inactive metabolite (GS-331007) was approximately 4 and> 90%, respectively, of the system exposure of the drug- related material (the sum of AUC of somosbuvira and its metabolites, corrected for molecular weight) .Excretion. After a single oral intake of 400 mg of 14 C- sofosbuvir, the average total radioactive dose excretion was more than 92%, with approximately 80, 14 and 2.5% excreted by the kidneys, intestine and lungs, respectively. Most of the dose of sofosbuvir, excreted by the kidneys, was represented by the inactive metabolite (GS-331007) (78%), while 3.5% was excreted as sophosbuvir. These data show that renal clearance is the main way of excretion of an inactive metabolite (GS-331007) with a predominantly active secretion. The mean T 1/2 of sophosbuvira and the inactive metabolite (GS-331007) is 0.4 and 27 hours, respectively.It was found that when taking fasting sophosbuvir in doses of 200 to 400 mg AUC of sofosbuvir and an inactive metabolite (GS-331007) are practically proportional to the dose. 

Special patient groups Children Parameters of pharmacokinetics of sophosbuvir and inactive metabolite (GS-331007) in children are not established.Elderly patients. In patients with HCV, 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). In clinical trials, 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 failure Compared to patients with normal renal function ( Cl creatinine> 80 ml / min) not infected with HCV, in the case of renal insufficiency of mild, moderate and severe AUC 0-inf in sofosbuvir were 61, 107 and 171%, respectively, and AUC 0 -inf inactive metabolite (GS-331007) - by 55, 88 and 451%, respectively. In patients with CRF , compared with patients with normal renal function, AUC 0-inf in sofosbuvir was 28% higher if sofosbuvir was taken 1 h before the hemodialysis session and 60% higher if sofosbuvir was taken 1 h after the hemodialysis session. AUC 0-infinactive 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 1 hour after the hemodialysis session, respectively, compared with patients with normal function kidney.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 is taken. Patients with mild to moderate renal insufficiency do not require a change in the dose of the drug. The safety of use of sofosbuvir was not assessed in patients with severe renal failure and terminal stage of renal failure (see Contraindications). 

Liver failure Compared to patients with normal liver function, AUC 0-24 of somosbuvir was 126 and 143% higher in patients with moderate to severe hepatic insufficiency, and AUC 0-24 inactive metabolite (GS-331007) by 18 and 9%, respectively. A population-based 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). In patients with mild, moderate and severe hepatic insufficiency, it is not recommended to change the dose of sophosbuvira.The relationship of pharmacokinetics / pharmacodynamics. It was shown that the effectiveness of treatment in the form of a rapid virologic response correlated with the exposure value of sophosbuvira and an inactive metabolite (GS-331007). Nevertheless, none of these parameters is the main surrogate marker for efficacy evaluation ( CB012 ) when applying a therapeutic dose of 400 mg.

Pharmacodynamics Electrophysiology of the heart. The effect of sofosbuvir 400 and 1200 mg (3 times the recommended dose) per QTc interval was evaluated in a randomized placebo-controlled and active control (moxifloxacin 400 mg) 4-step cross-over clinical trial with single doses in 59 healthy subjects. In a dose exceeding the maximum recommended by 3 times, sofosbuvir had no clinically significant effect on the increase in the QTc interval. 

Pharmacokinetics Absorption The pharmacokinetic properties of sophosbuvira and its ever-circulating metabolite (GS-331007) were evaluated in healthy adult volunteers and patients with CHC. After oral administration sofosbuvir C max was reached within about 0.5-2 hours, regardless of the dose. C max GS-331007 was observed in the range of 2-4 hours after application. According to population pharmacokinetic analysis, in patients with genotypes 1-6 of the HCV who received ribavirin simultaneously (together with or without peginterferon), the geometric mean values ​​in the equilibrium stage are AUC 0-24were 969 (N = 838) and 6790 ng · h / ml for sophosbuvira and GS-331007 (N = 1695), respectively. Compared with healthy volunteers who received sofosbuvir as monotherapy (N = 272), in patients infected with HCV, AUC 0-24 of sofosbuvir was 60% higher and AUC 0-24 GS-331007 was 39% lower, respectively. The values ​​of AUC of sofosbuvir and GS-331007 are approximately proportional to the dose in the dose range of 200-1200 mg.Effect of food. The use of a single dose of sofosbuvir concomitantly with a high-fat meal did not significantly affect C max and AUC 0-inf infrasulfur. Exposition GS-331007 did not depend on food intake with a high fat content. Thus, sofosbuvir can be used regardless of food intake.Distribution. Approximately 61-65% of sofosbuvir binds to human plasma proteins, and this binding is independent of the concentration in the range of 1-20 μg / ml. The binding of GS-331007 to human plasma proteins was minimal. After a single application of 400 mg of 14 C-somosbuvir in healthy volunteers, the plasma-blood ratio for 14 C-somosbuvir with a radioactive label was approximately 0.7.Metabolism. Sofosbuvir is extensively metabolized in the liver to form a pharmacologically active triphosphate nucleoside analogue GS-461203. The metabolic pathway of activation includes sequential hydrolysis of the carboxyl group of the ester fragment catalyzed by human cathepsin A or carboxyl esterase and cleavage of phosphoramidate with nucleotide-binding protein 1 with histidine triads ( HINT1 ) followed by phosphorylation along the pathway for the biosynthesis of the pyrimidine nucleotide. Dephosphorylation leads to the formation of the nucleoside metabolite GS-331007, which can not be effectively rephosphorylated and in vitro has no activity against HCV.After a single application of 400 mg of 14 C-somosbuvir, the systemic exposure (adjusted for the molecular weight of sophosbuvira and all its metabolites AUC value ) of somosbuvira and GS-331007 was approximately 4 and> 90% of the radioactivity of all metabolites and unchanged sophosbuvir.Elimination. After a single application of 400 mg of 14 C-somosbuvir, the average dose recovery was> 92%, incl. in urine, feces and exhaled air approximately 80, 14 and 2.5%, respectively. The bulk of the dose found in the urine was GS-331007 (78%), while unchanged sofosbuvir was 3.5%. These data indicate that renal clearance is the main route of excretion for the GS-331007. The average terminal T 1/2 of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. 

Special patient groups Race. According to population pharmacokinetic analysis, in individuals infected with HCV, belonging to a particular race did not have a significant clinical effect on the exposure of sophosbuvira and GS-331007.Floor. There were no clinically significant differences in the pharmacokinetics of sophosbuvira and GS-331007 in men and women. 

Children The pharmacokinetics of sophosbuvira in children have not been established. 

Elderly patients According to population pharmacokinetic analysis, among subjects aged 19-75 years infected with HCV, there were no clinically significant differences in the exposure of sophosbuvira and GS-331007.Renal failure. The pharmacokinetics of sofosbuvir were studied in patients with mild (GFR 50- <80 mL / min / 1.73 m 2 ) moderate (GFR 30- <50 mL / min / 1.73 m 2 ), severe (GFR < 30 ml / min / 1.73 m 2 ) and terminal (requiring hemodialysis) stage of renal failure after a single application of 400 mg of somosbuvira. Compared to patients with normal renal function (GFR> 80 ml / min / 1.73 m 2 ), AUC 0-inf in sofosbuvir was 61, 107 and 171% greater in subjects with mild, moderate and severe renal insufficiency, and AUC 0-infGS-331007 - by 55, 88 and 451% more respectively. In subjects with terminal renal failure, compared with patients with normal renal function, AUC 0-infra sofosbuvir and GS-331007 were 28 and 1280% higher for 1 h before hemodialysis and 60% and 2070% higher for admission through 1 h after hemodialysis, respectively. The hemodialysis session lasted 4 hours and removed approximately 18% of the dose taken. In patients with mild or moderate renal failure, dose adjustment is not required. The safety of sophosbuvira in patients with severe or terminal renal failure has not been established and there is no recommendation for dosing for these patient groups. 

Liver failure The pharmacokinetics of sophosbuvir was studied after 7 days of use at a dose of 400 mg for HCV-infected subjects with moderate and severe hepatic insufficiency (Child-Pugh classes B and C). Compared with patients with normal liver function, AUC 0-24 of somosbuvira was 126 and 143% higher for moderate and severe hepatic insufficiency, respectively, while for GS-331007 this was 18% and 9% higher, respectively. According to population pharmacokinetic analysis, in HCV-infected subjects, cirrhosis did not exert a clinically significant effect on the exposure of sophosbuvira and GS-331007. In patients with mild, moderate or severe hepatic insufficiency, dosage adjustment of sophosbuvira is not recommended. 

Application of substance Sofosbuvir Treatment of chronic hepatitis C in adult patients in combination with other drugs Contraindications Hypersensitivity to sophosbuvir, pregnancy, children under 18 years of age (efficacy and safety not established), severe renal insufficiency ( Cl creatinine <30 ml / min) or terminal stage of renal failure when hemodialysis is required (safety not established), combined infection with hepatitis C and B viruses (HCV / HBV) (there is no data on the use of sophosbuvira in this patient population), decompensated hepatic cirrhosis (efficacy and safety not established); joint use of powerful inducers P-gp (for example rifampicin, St. John's wort ( Hypericum perforatum ), carbamazepine, phenytoin, phenobarbital, oxcarbazepine).

Restrictions on the use Patients with HCV genotypes 1, 4, 5 and 6 who received antiviral therapy, especially in cases where there were one or more factors historically associated with a low frequency of responses to interferon therapy (widespread fibrosis / cirrhosis, initially high concentration of the virus, Negroid race, the presence of a non-SS allele of the genotype IL28B); patients concurrently taking other antiviral drugs to treat hepatitis C (eg, telaprevir or bocepreviros); patients receiving a combination of sophosbuvira and daclatasvir against a background of concomitant amiodarone therapy. 

Application in pregnancy and lactation 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 sophosbuvira 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 did not reveal an 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.Use of sofosbuvir in combination with ribavirin or peginterferon alfa / ribavirin.If ribavirin is used concomitantly with sophosbuvir, contraindications to the use of ribavirin during pregnancy are applicable (see instructions for the use of ribavirin). In cases where sofosbuvir is used in combination with ribavirin or peginterferon alfa / ribavirin, all necessary measures must be taken to prevent pregnancy in patients and partners of patients. All experimental animals showed severe teratogenic and / or embryogenic effects when using ribavirin (see "Precautions"). 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 Ribavirin's instructions for use).It is not known whether sophosbuvir and its metabolites penetrate the human breast milk, although preclinical studies have established the excretion of metabolites with breast milk.Since the risk to the fetus / newborn can not be ruled out, sofosbuvir should not be used during breastfeeding.Influence on reproductive function. There is no data on the effect of sofosbuvir on human reproductive function. In animal studies, adverse effects on reproductive function have not been established.

Side effects of substance Sofosbuvir Security Profile Overview The most frequent adverse drug reactions (HLP) that were recorded during clinical trials corresponded to the known safety profile of ribavirin and peginterferon alfa without increasing the frequency or severity of the expected NLP.Due to the development of NLR, 1.4% of patients receiving placebo, 0.5% of patients receiving sophosbuvir + ribavirin for 12 weeks , 0% of patients receiving sofosbuvir + ribavirin for 16 weeks , 11.1% who received peginterferon alfa + ribavirin for 24 weeks , and 2.4% of patients receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks .Sofosbuvir 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 NLRs observed in patients receiving sofosbuvir and ribavirin, or sofosbuvir, ribavirin and peginterferon alfa, were increased fatigue, headache, nausea, and insomnia.The following are the HLRs identified using sofosbuvir in combination with ribavirin or sophosbuvira in combination with peginterferon alfa and ribavirin. NLR are grouped 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).Infectious and parasitic diseases- Sofosbuvir + ribavirin: often - nasopharyngitis.On the part of the blood and lymphatic system- Sophosbuvir + ribavirin: very often - a decrease in the concentration of Hb; often anemia.- Sophosbuvir + peginterferon alfa + ribavirin: very often - anemia, neutropenia, a decrease in the number of lymphocytes, a decrease in the number of platelets.From the side of metabolism and nutrition- Sofosbuvir + peginterferon alfa + ribavirin: very often - decreased appetite; often - weight loss.Disorders of the psyche- Sofosbuvir + ribavirin: very often - insomnia; often - depression.- Sofosbuvir + peginterferon alfa + ribavirin: very often - insomnia; often - depression, anxiety, agitation.From the nervous system- Sophosbuvir + ribavirin: very often - a headache, often - a violation of attention.- Sofosbuvir + peginterferon alfa + ribavirin: very often - dizziness, headache; often - migraine, memory impairment, attention violation.From the side of the organ of vision- Sofosbuvir + peginterferon alfa + ribavirin: often - an unclear vision.On the part of the respiratory system, the organs of the thorax and the mediastinum- Sofosbuvir + ribavirin: often - shortness of breath, shortness of breath with physical exertion, cough.- Sofosbuvir + peginterferon alfa + ribavirin: very often - shortness of breath, cough; often shortness of breath when exercising.From the gastrointestinal tract- Sofosbuvir + ribavirin: very often - nausea; often - discomfort in the abdomen, constipation, indigestion.- Sofosbuvir + peginterferon alfa + ribavirin: very often - diarrhea, nausea, vomiting; often - constipation, dry mouth, gastroesophageal reflux.From the liver and biliary tract- Sofosbuvir + ribavirin: very often - an increase in the concentration of bilirubin in the blood.- Sofosbuvir + peginterferon alfa + ribavirin: very often - an increase in the concentration of bilirubin in the blood.From the skin and subcutaneous tissues- Sophosbuvir + ribavirin: often - alopecia, dry skin, itching.- Sophosbuvir + peginterferon alfa + ribavirin: very often - rash, itching; often - alopecia, dry skin.From the musculoskeletal system and connective tissue- Sophosbuvir + ribavirin: often - arthralgia, back pain, muscle spasms, myalgia.- Sophosbuvir + peginterferon alfa + ribavirin: very often - arthralgia, myalgia; often - back pain, muscle spasms.Systemic disorders and complications at the site of administration- Sofosbuvir + ribavirin: very often - fatigue, irritability; often - fever, asthenia.- Sofosbuvir + peginterferon alfa + ribavirin: very often - chills, fatigue, flu-like condition, irritability, pain, fever; often - chest pain, asthenia.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 in patients infected with HCV only receiving sofosbuvir and ribavirin during clinical trials.Patients awaiting liver transplantation. The safety profile of sophosbuvira and ribavirin in patients with CHC waiting for liver transplantation was similar to that of patients receiving sofosbuvir and ribavirin in clinical trials.Description of individual NLR Bradycardia and heart block. There have been cases of development of severe bradycardia and cardiac blockade with the combination of sophosbuvira and daclatasvir in combination with amiodarone and / or other drugs slowing heart rate (see "Interaction" and "Precautions").RxList.comThe following serious adverse reactions are described elsewhere in this description:- Severe symptomatic bradycardia when combined with amiodarone and other antiviral agents for the treatment of direct-acting HCV (see "Precautions").Results of clinical trialsSince clinical trials have been conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not coincide with those obtained in other studies and observed in clinical practice.When sofosbuvir is used together with ribavirin or a combination of peginterferon alfa + ribavirin, appropriate instructions for the use of these drugs should be consulted to describe the adverse reactions associated with their use.The safety profile of sophosbuvira is based on the data set of the clinical trial of the 3rd phase (both controlled and uncontrolled), which included:- 650 participants who received sofosbuvir + ribavirin in combination therapy for 12 weeks ;- 250 participants who received sofosbuvir + ribavirin in combination therapy for 24 weeks ;- 327 participants who received sofosbuvir + peginterferon alfa + ribavirin in combination therapy for 12 weeks ;- 243 participants who received peginterferon + ribavirin within 24 weeks ;- 71 participants who received a placebo for 12 weeks .The proportion of participants who had to stop treatment due to side effects was 4% in the placebo group, 1% in the group receiving sophosbuvir + ribavirin for 12 weeks , <1% in the group receiving sophosbuvir + ribavirin for 24 weeks 11% in the group receiving peginterferon alfa + ribavirin for 24 weeks , and 2% in the group receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks .The following are side effects observed in at least 15% of the participants in the 3rd phase of the clinical trials described above. A consecutive enumeration is provided to facilitate the perception, a direct comparison of test results was not made due to differences in their design.When using a combination of sofosbuvir + ribavirin, most adverse events (≥20%) were observed, such as fatigue and headache; when using a combination of sofosbuvir + peginterferon alfa + ribavirin - increased fatigue, headache, nausea, insomnia and anemia.Adverse reactions (all severity, regardless of causation) were noted in ≥15% of participants with HCV in any of the study groups (the incidence rate is given in percentages in the following order: placebo (12 weeks , N = 71), sofosbuvir + ribavirin 1 (12 weeks , N = 650), sofosbuvir + ribavirin 1 (24 weeks , N = 250), peginterferon alfa + ribavirin 2 (24 weeks , N = 243) and sofosbuvir + peginterferon alfa + ribavirin 1 (12 weeks , N = 327 )Increased fatigue: 24, 38, 30, 55 and 59%.Headache: 20, 24, 30, 44 and 36%.Nausea: 18, 22, 13, 29 and 34%.Insomnia: 4, 15, 16, 29 and 25%.Itching: 8, 11, 27, 17 and 17%.Anemia: 0, 10, 6, 12 and 21%.Asthenia: 3, 6, 21, 3 and 5%.Rash: 8, 8, 9, 18 and 18%.Decreased appetite: 10, 6, 6, 18 and 18%.Chills: 1, 2, 2, 18 and 17%.Grippopodobny syndrome: 3, 3, 6, 18 and 16%.Fever: 0, 4, 4, 14 and 18%.Diarrhea: 6, 9, 12, 17 and 12%.Neutropenia: 0, <1, <1, 12 and 17%.Myalgia: 0, 6, 9, 16 and 14%.Irritability: 1, 10, 10, 16 and 13%.1 Patients received a dose of ribavirin, corrected for body weight (1000 mg / day with body weight <75 kg and 1200 mg / day with body weight ≥ 75 kg).2 Patients received 800 mg / day of ribavirin regardless of body weight.In groups using sophosbuvir, most of the adverse reactions listed above, with the exception of anemia and neutropenia, were the 1 st degree of severity.Adverse reactions noted in clinical trials with a frequency of <1%The following adverse reactions occurred in <1% of participants in any of the trials receiving sophosbuvir as part of the combination therapy. These cases are included in the description because of their seriousness or potential connection with the use of this drug .Hematologic effects. Pancytopenia (especially in patients receiving co-peginterferon alfa).Mental disorders. severe depression (especially in patients with a previous history of mental illness), including suicidal thinking and suicide.Deviations of laboratory indicators. Changes in individual hematological parameters are given below. A consecutive enumeration is provided to facilitate the perception, a direct comparison of test results was not made due to differences in their design. The frequency of cases is given in percentages in the following order: placebo (12 weeks , N = 71), sofosbuvir + ribavirin 1 (12 weeks , N = 647), sophosbuvir + ribavirin 1 (24 weeks , N = 250), peginterferon alfa + ribavirin 2 (24 weeks , N = 242) and sofosbuvir + peginterferon alfa + ribavirin 1 (12 weeks , N = 327).Hb <10 g / dL - 0, 8, 6, 14 and 23%; <8.5 g / dL - 0, 1, <1, 2 and 2%.Neutrophils ≥ 0.5 - <0.75 × 10 9 / l - 1, <1, 0, 12 and 15%; <0.5 × 10 9 / l - 0, <1, 0, 2 and 5%.Platelets ≥ 25- <50 × 10 9 / l - 3, <1, 1, 7 and <1%; <25 × 10 9 / l - 0, 0, 0, 0 and 0%.1 Patients received a dose of ribavirin corrected for body weight (1000 mg / day for body weight <75 kg and 1200 mg / day for body weight ≥ 75 kg).2 Patients received 800 mg / day of ribavirin regardless of body weight.Increased bilirubin concentrationAn increase in the concentration of total bilirubin> 2.5 × HBV was not observed in any participant in the group receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks , and was observed in 1, 3 and 3% of the participants in the groups receiving peginterferon alfa + ribavirin in for 24 weeks , sofosbuvir + ribavirin for 12 weeks and sophosbuvir + ribavirin for 24 weeks, respectively. The level of bilirubin reached a maximum during the first 1-2 weeks of treatment and subsequently decreased and returned to baseline by the 4th week after discontinuation of treatment. An increase in the concentration of bilirubin was not associated with an increase in the level of transaminases.Increased concentration of creatine kinaseThe creatine kinase level was evaluated in the clinical trials of FISSION and NEUTRINO . Separate cases of asymptomatic increase in the level of creatine kinase ≥ 10 × UGH were observed in less than 1; 1 and 2% of participants in the groups receiving peginterferon alfa + ribavirin for 24 weeks , sofosbuvir + peginterferon alfa + ribavirin for 12 weeks and sofosbuvir + ribavirin for 12 weeks, respectively.Increased lipase levelsSeparate cases of asymptomatic increase in lipase level> 3 × IGN were observed in less than 1; 2; 2 and 2% of participants in groups receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks , sofosbuvir + ribavirin for 12 weeks , sophosbuvir + ribavirin for 24 weeks and peginterferon alfa + ribavirin for 24 weeks, respectively.Patients with co-infection of HCV and HIV- 1Sophosbuvir was used in combination with ribavirin in 223 patients with co-infection with HCV and HIV- 1. The safety profile of sofosbuvir in co-infected patients was similar to that observed in patients infected with HCV alone. In 30 of 32 (94%) patients who received atazanavir as a component of antiretroviral therapy, there was an increase in the concentration of total bilirubin (severity 3 or 4). None of these patients had a concomitant increase in transaminase levels. Among patients who did not receive atazanavir, an increase in the concentration of total bilirubin up to the 3rd or 4th degree of severity was observed in 2 (1.5%) people, which was similar to the frequency of this side effect observed in the 3rd phase of the clinical combination test sofosbuvir + ribavirin in patients infected with HCV only.Postmarketing observationsIn the period after the resolution of sophosbuvira, the following adverse reactions were identified for medical use. Since these data were obtained on a voluntary basis in a population of an unidentified size, it is not always possible to really assess their frequency or establish a causal relationship with the exposure of drugs .Heart disorders. In patients taking amiodarone, who started treatment with sophosbuvir in combination with other antiviral agents for the treatment of direct-acting HCV, cases of severe symptomatic bradycardia have been reported (see "Precautions" and "Interaction").

Interaction Sophosbuvir is a carrier substrate of P-gp and BCRP , whereas its inactive metabolite (GS-331007) is not. LS - powerful P-gp inducers in the intestine (eg rifampicin, St. John's wort, carbamazepine and phenytoin) - can lower the plasma concentration of sofosbuvir, leading to a decrease in therapeutic efficacy, so do not use them simultaneously with sophosbuvir (see "Contraindications" and "Measures precautions "). The combined use of sofosbuvir with drugs that are P-gp and / or BCRP inhibitors can increase the concentration of somosbuvir in the plasma without simultaneous increase in the concentration of the inactive metabolite (GS-331007). Thus, sofosbuvir can be used concomitantly with P-gp inhibitors and / orBCRP .Sofosbuvir and inactive metabolite (GS-331007) are not inhibitors of P-gp and BCRP , therefore, an increase in the exposure of drugs that are substrates of these vectors is not expected .Intracellular activation of somosbuvir metabolism is mediated by a hydrolase with low affinity and high activity, as well as nucleotide phosphorylation pathways, to which the joint use of other drugs is practically unaffected.Other interactionsThe following information about drug interactions sofosbuvir with concomitant drugs (cases where 90% CI ratio adjusted geometric mean values calculated by the least squares method ( geometric least squares mean, GLSM ), for the parameters of AUC , C max and C min was not changed, increased or reduced compared to pre-established equivalence limits). The list of included concomitant drugs is incomplete.The average ratio (90% CI) of the pharmacokinetics parameters of the concomitant drug used with / without sofosbuvir was assessed and the average ratio of the pharmacokinetics parameters of sophosbuvira and GS-331007 with or without concomitantly used drugs . Lack of effect - 1.All interaction studies were conducted in healthy volunteers.Modafinil (analeptic) : the interaction has not been studied. It is assumed that the concentration of sophosbuvira and GS-331007 decrease. It is possible to decrease the therapeutic efficacy of sophosbuvira. Such a joint use is not recommended.Amiodarone (antiarrhythmic agent) : 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 sophosbuvira and daclatasvir, careful monitoring is recommended (see "Side effects" and "Precautions").Carbamazepine, phenytoin, phenobarbital, oxcarbazepine (anticonvulsants) : the interaction has not been studied. It is assumed that the concentration of sophosbuvira and GS-331007 decrease. It is possible to reduce the therapeutic efficacy of somosbuvira when combined with carbamazepine, phenytoin, phenobarbital or oxcarbazepine. Sofasbuvir should not be used in combination with carbamazepine, phenytoin, phenobarbital or oxcarbazepine - powerful P-gp inducers in the intestine.Rifabutin, rifampicin, rifapentin (ansamycins) : the interaction has not been studied. It is assumed that the concentration of sophosbuvira and GS-331007 decrease. It is possible to reduce the therapeutic efficacy of sophosbuvira when combined with rifabutin or rifapentin. Such a joint use is not recommended. Do not use cofasbuvir together with rifampicin - a powerful inducer of P-gp in the intestine.Hypericum perforatum (Hypericum perforatum): the interaction was not studied. It is assumed that the concentration of sophosbuvira and GS-331007 decrease. Do not use sofosbuvir concomitantly with drugs containing St. John's wort, a potent P-gp inducer in the intestine.Boceprevir, telaprevir (HCV protease inhibitors) : the interaction has not been studied. It is suggested that the concentration of sophosbuvir increases when combined with telaprevir. It is not expected to change the concentration of sofosbuvir when combined with bocetrevir and change the concentration of GS-31007 when combined with telaprevir or bocetrevir. Data on the drug interaction of sofosbuvir with bocetrevir or telaprevir are absent.Methadone (narcotic analgesic) , maintenance therapy from 30 to 130 mg / day (border of equivalence 70-143%). When sofosbuvir is combined with methadone, dosage adjustment of sofosbuvir or methadone is not required.- R-methadone. No change C max - 0.99 (0.85, 1.16), AUC - 1.01 (0.85, 1.21), C min - 0.94 (0.77, 1.14).- S-methadone. No changes in C max - 0.95 (0.79; 1,13), AUC - 0.95 (0.77; 1.17), C min - 0.95 (0.74; 1.22).- Sofosbuvir (comparison based on historical control). Reduction of C max - 0.95 (0.68; 1.33), the increase in AUC - 1,3 (1; 1.69), C min - unknown.- GS-331007 (comparison based on historical control). Reduction of C max - 0.73 (0.65; 0.83), no change AUC - 1.04 (0.89; 1.22), C min - unknown.Immunosuppressants (border of bioequivalence of 80-125%)Ciclosporin , a single dose of 600 mg. When sofosbuvir is administered together with cyclosporin, dosage adjustment of sofosbuvir or cyclosporine is not required.- Cyclosporine. No change C max - 1.06 (0.94, 1.18), AUC - 0.98 (0.85, 1.14), C min - no data.- Sofosbuvir. The increase C max - 2.54 (1.87; 3,45), the increase in AUC - 4.53 (3.26; 6,3), C min - unknown.- GS-331007. Reduction of C max - 0.6 (0.53; 0.69), no change AUC - 1.04 (0.9; 1,2), C min - unknown.Tacrolimus , a single dose of 5 mg. When sofosbuvir is combined with tacrolimus, dosage adjustment of sofosbuvir or tacrolimus is not required.- Tacrolimus. The decrease in C max is 0.73 (0.59, 0.9), there are no changes AUC - 1.09 (0.84, 1.4), C min - no data.- Sofosbuvir. Reduction of C max - 0.97 (0.65; 1.43), the increase in AUC - 1,13 (0.81; 1.57), C min - unknown.- GS-331007. No changes in C max - 0.97 (0.83; 1,14), no change AUC - 1 (0.87; 1,13), C min - unknown.Antiviral drugs for HIV treatment - inhibitors of reverse transcriptase (equivalence limit 70-143%)Efavirenz , 600 mg once a day (in the form of the drug Atripla). When sofosbuvir is used together with efavirenz, correction of the dose of sofosbuvir or efavirenz is not required.- Efavirenz. No changes in C max - 0.95 (0.85; 1.06), AUC - 0.96 (0.91; 1.03), C min - 0.96 (0.93; 0.98).- Sofosbuvir. Reduction of C max - 0.81 (0.6; 1,1), no change AUC - 0.94 (0.76; 1,16), C min - unknown.- GS-331007. Reduction of C max - 0.77 (0.7; 0.84), no change AUC - 0.84 (0.76; 0.92), C min - unknown.Emtricitabine , 200 mg once a day. When sofosbuvir is combined with emtricitabine, dosage adjustment of sofosbuvir or emtricitabine is not required.- Emtricitabine. No change C max 0.97 (0.88, 1.07), AUC 0.99 (0.94, 1.05), C min = 1.04 (0.98, 1.11).- Sofosbuvir. Reduction of C max - 0.81 (0.6; 1,1), no change AUC - 0.94 (0.76; 1,16), C min - unknown.- GS-331007. Reduction of C max - 0.77 (0.7; 0.84), no change AUC - 0.84 (0.76; 0.92), C min - unknown.Tenofovir , 300 mg once a day. When sofosbuvir is combined with tenofovir, dosage correction of sofosbuvir or tenofovir is not required.- Tenofovir. The increase C max - 1.25 (1.08; 1.45), no change AUC - 0.98 (0.91; 1.05), C min - 0.99 (0.91; 1.07).- Sofosbuvir. Reduction of C max - 0.81 (0.6; 1,1), no change AUC - 0.94 (0.76; 1,16), C min - unknown.- GS-331007. Reduction of C max - 0.77 (0.7; 0.84), no change AUC - 0.84 (0.76; 0.92), C min - unknown.Rilpivirine , 25 mg once a day. When sofosbuvir is used together with rilpivirin, dosage adjustment of sofosbuvir or rilpivirin is not required.- Rilpivirin. No change C max - 1.05 (0.97, 1.15), AUC - 1.06 (1.02, 1.09), C min - 0.99 (0.94, 1.04).- Sofosbuvir. The increase C max - 1.21 (0.9; 1.62), no change AUC - 1.09 (0.94; 1.27), C min - unknown.- GS-331007. No change C max - 1.06 (0.99, 1.14), AUC - 1.01 (0.97, 1.04); C min - no data.Antiviral drugs for treatment of HIV - protease inhibitors, HIV (equivalence boundary 70-143%)Darunavir , boosted with ritonavir, 800/100 mg once a day. When sofosbuvir is used together with darunavir, dosage adjustment of sofosbuvir or darunavir (ritonavir-boosted) is not required.- Darunavir. No change C max 0.97 (0.94, 1.01), AUC 0.97 (0.94, 1), C min 0.86 (0.78, 0.96).- Sofosbuvir. The increase C max - 1.45 (1,1; 1.92), AUC - 1.24 (1,12; 1.59); C min - no data.- GS-331007. No change C max - 0.97 (0.9, 1.05), AUC - 1.24 (1.18, 1.3); C min - no data.Antiviral drugs for HIV treatment - integrase inhibitors (equivalence limit 70-143%)Raltegravir , 400 mg once a day. When sofosbuvir is combined with raltegravir, dosage adjustment of sofosbuvir or raltegravir is not required.- Raltegravir. Reduction of C max - 0.57 (0.44; 0.75), AUC - 0.73 (0.59; 0.91), C min - 0.86 (0.78; 0.96).- Sofosbuvir. No change C max - 0.87 (0.71, 1.08), AUC - 0.95 (0.82, 1.09); C min - no data.- GS-331007. No change C max - 1.09 (0.99, 1.2), AUC - 1.03 (0.97, 1.08); C min - no data.Oral contraceptivesNorgestimate / Ethinylestradiol. When sofosbuvir is combined with norgestimate / ethinyl estradiol, dosage adjustment of sofosbuvir or norgestimate / ethinylestradiol is not required.RxList.comPotentially significant drug interactionsSophosbuvir is the substrate of P-gp and BCRP , while its main metabolite, CS331007, is not. The drugs that are inducers of P-gp in the intestine (for example rifampicin or St. John's wort) can reduce the concentration of sofosbuvir in the blood plasma, leading to a decrease in its therapeutic effect, so the concomitant use of such drugs with sophosbuvir is not recommended (see "Precautions").Below is summarized information on possible drug interactions between sofosbuvir, the listed list of drugs is incomplete (see "Precautions").Amiodarone (antiarrhythmic drugs ) . The effect on the concentration of amiodarone and sofosbuvir is unknown. The combined use of amiodarone with sophosbuvir in combination with other direct antiviral agents can lead to severe symptomatic bradycardia. The mechanism of this action is unknown. The joint use of amiodarone with sophosbuvir in combination with other direct antiviral agents is not recommended, if such a joint application is necessary, cardiac monitoring is recommended (see "Precautions" and "Side effects").Carbamazepine, phenytoin, phenobarbital, oxcarbazepine (anticonvulsant drugs ) . The concentration of sofosbuvir and CS331007 in the blood plasma decreases. It is assumed that the joint use of sofosbuvir with carbamazepine, finitooin, phenobarbital or oxcarbazepine will lead to a decrease in the therapeutic effect of sophosbuvira. Joint use is not recommended.Rifabutin, rifampicin, rifapentin (antimycobacterial drugs ) . The concentration of sofosbuvir and CS331007 in the blood plasma decreases. It is suggested that the combined use of sofosbuvir with rifabutin or rifapentin will reduce the therapeutic effect of sophosbuvira. Joint use is not recommended. It is not recommended to use sofosbuvir together with rifampicin, P-gp inducer in the intestine (see "Precautions").St. John's Wort ( Hypericum perforatum ) ( plant-derived drugs ) . The concentration of sofosbuvir and CS331007 in the blood plasma decreases. It is not recommended to use sofosbuvir and St. John's wort in combination with the P-gp inductor in the intestine.Tipranavir / Ritonavir (protease inhibitors, HIV ) . The concentration of sofosbuvir and CS331007 in the blood plasma decreases. It is suggested that the combined use of sofosbuvir with tipranavir / ritonavir will reduce the therapeutic effect of sophosbuvira. Joint use is not recommended.Drugs that do not have clinically significant interactions with sophosbuvirIn addition to the drugs listed above, the interactions of sofosbuvir with the following medicines were evaluated in clinical trials : cyclosporine, darunavir / ritonavir, efavirenz, methadone, oral contraceptives, raltegravir, rilpivirin, tacrolimus and tenofovir dizoproxil fumarate.

Routes of administration Inside.

Precautions for the substance Sofosbuvir Are common. Sophosbuvir is not recommended for use as a monotherapy; it should be given in combination with other drugs to treat HCV. If you stop taking other drugs , prescribed in combination with sophosbuvir, it should also be canceled. Before starting the application of sophosbuvira, you should carefully read the instructions for medical use for concomitant drugs .Bradycardia and heart block. There have been reports of development of severe bradycardia and cardiac blockade with a combination of sophosbuvira and daclatasvir in combination with amiodarone and / or other drugs that slow 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, therefore the use of amiodarone together with the combination of sophosbuvira and daclatasvir 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 sophosbuvira and daclatasvir is recommended. Patients at high risk for bradyarrhythmia should be monitored continuously for 48 hours in an appropriately equipped clinic.If necessary, start combination therapy with sophosbuvir and daclatasvir in patients who had previously taken amiodarone, appropriate follow-up should be performed for those who stopped taking amiodarone in the last few months, Amiodarone has a long T 1/2 .All patients taking the combination of sophosbuvira and daclatasvir together with amiodarone should be warned about the symptoms of bradycardia and cardiac blockade and the need for immediate medical attention in the event of such symptoms.Patients with HCV genotypes 1, 4, 5 and 6, previously treated. Sophosbuvira was not clinically tested in patients with HCV genotypes 1, 4, 5, and 6 who had previously received therapy. Therefore, the optimal duration of treatment in this patient population has not been established.The treatment of these patients requires discussion, possibly with regard to the prolongation of therapy beyond 12 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 initial viral load level, Negroid race, presence of non-SS allele of IL28B gene).Treatment of patients with HCV genotype 5 or 6. The amount of clinical research data supporting the use of sophosbuvira in patients with HCV genotype 5 or 6 is very limited.Treatment of patients with HCV genotypes 1, 4, 5 and 6 without interferon. The regimens of therapy with cofosbuvir without interferon in 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 who are urgently in need of treatment.Joint use with other direct antivirals for the treatment of hepatitis C. Sofosbuvir should be used in conjunction with other antiviral drugs of direct action only if the benefit of such a combination outweighs the risks according to available data. There is no evidence to support the co-administration of sophosbuvira and telaprevir or boceprevir. This combination of drugs is not recommended.Pregnancy and simultaneous use of ribavirin. In cases where cofosbuvir 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 for the required period of time, as recommended by ribavirin.Simultaneous application with inductors P-gp. LS , which are powerful inducers of P-gp in the intestine (eg rifampicin, Hypericum perforatum , carbamazepine and phenytoin), can significantly reduce the concentration of cofosbuvir in the blood plasma, which in turn lowers the therapeutic efficacy of sophosbuvir. Such drugs should not be used in combination with sophosbuvir.Renal failure. The safety of use of sophosbuvir has not been studied in patients with severe renal insufficiency ( Cl creatinine <30 ml / min) or with end stage renal insufficiency requiring hemodialysis. Moreover, the corresponding dose of sophosbuvir has not been established. When using cofosbuvira in combination with ribavirin or peginterferon alfa / ribavirin in patients with Cl creatinine <50 ml / min, see also the medical instructions for the preparation of ribavirin (see "Pharmacokinetics"). Patients with co-infection with HCV / HBV. Data on the use of cofosbuvir in patients with HCV / HBV coinfection are not available.Influence on the ability to drive vehicles, mechanisms. Sofosbuvir has a moderate effect on the ability to drive 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.RxLixt.comSevere symptomatic bradycardia when combined with amiodarone and other direct antiviral agents for the treatment of HCVIn post-marketing observations, there were cases of symptomatic bradycardia and cases requiring the use of a pacemaker when combined use of amiodarone and sophosbuvira in combination with an NS5A inhibitor or a simeprevir. A fatal case of cardiac arrest in a patient treated with lepidavir + sophosbuvir was noted. Bradycardia usually occurred within a few hours or days, but there were cases of bradycardia developing for up to 2 weeksafter initiation of HCV treatment. To the group of increased risk of bradycardia in the joint use of amiodarone may include patients who also take beta-blockers, or patients with concomitant heart disease and / or liver disease at a late stage. Bradycardia was usually resolved after discontinuing HCV treatment. The mechanism of this effect is unknown.It is not recommended to use amiodarone together with sophosbuvir together with other direct antiviral drugs . Patients taking amiodarone who do not have alternative treatment options and will jointly use somosbuvir with other antiviral agents of direct action should:- report a possible risk of developing severe symptomatic bradycardia;- monitor cardiac activity in a hospital during the first 48 hours of combined use, then monitor the heart rate daily on an outpatient basis or by self- management for at least the first 2 weeks of treatment.Patients receiving cofosbuvir in combination with other direct-acting antiviral drugs who are forced to initiate amiodrone treatment because of the lack of alternative treatment options need to carry out the same cardiac monitoring as described above.Since amiodarone has a prolonged T 1/2 , patients who have stopped taking amiodarone immediately before commencing treatment with sophosbuvir in combination with a direct-acting antiviral drug also need to carry out the same cardiac monitoring as described above.Patients who develop signs or symptoms of bradycardia should undergo an immediate medical examination.Symptoms may include a pre-fainting or fainting condition, dizziness or mild headache, malaise, weakness, excessive fatigue, confused breathing, chest pain, confusion, or memory problems (see "Side effects" and "Interaction").The risk of a decrease in the therapeutic effect associated with the concomitant use of inducers P-gpLS , which are inducers of P-gp in the intestine (for example, rifampicin, St. John's wort), can significantly reduce the concentration of cofosbuvir in the blood plasma and lead to a decrease in its therapeutic effect. The concomitant use of rifampicin and St. John's wort is not recommended (see "Interaction").The risk associated with combination therapySince cofosbuvir is used to treat HCV infection as part of combination therapy with other antiviral drugs , it is necessary to take into account information from the instructions for the use of these drugs used in combination with sophosbuvir. Precautions relating to these drugs should also be taken into account when used in combination with sophosbuvir.The use of cofosbuvir in combination with other drugs containing sophosbuvir is not recommended.Special patient groupsChildren. The safety and efficacy of sophosbuvira in children younger than 18 years of age have not been established.Elderly patients. Sophosbuvir was used in 90 patients aged 65 years and older. The response rate observed in patients older than 65 years and younger patients was similar in all study groups. Sofosbuvir dosage adjustment is not required in elderly patients.Renal failure. There is no need to adjust the dose of sophosbuvira in patients with mild or moderate renal failure. The safety and efficacy of sophosbuvira in patients with severe renal insufficiency ( Cl creatinine <30 ml / min / 1.73 m 2 ) or terminal stage of renal failure requiring hemodialysis are not established. There are no recommendations for dosage for patients with severe or terminal renal failure. To guide patients with Cl creatinine <50 ml / min should also use information from the instructions for the use of ribavirin and peginterferon alfa.Liver failure. No dosage adjustment for sophosbuvira is required in patients with mild, moderate or severe hepatic insufficiency (Child-Pugh Childhood A, B and C grades). In patients with decompensated liver cirrhosis, the safety and efficacy of using cofosbuvir are not established. With decompensated hepatic insufficiency, information on contraindications for peginterferon alfa should be used.Patients with hepatocellular carcinoma waiting for liver transplantation. An open clinical trial to investigate the safety and efficacy of cofosbuvira and ribavirin before liver transplantation to prevent post-transplantation reinfection of HCV in HCV-infected patients with hepatocellular carcinoma showed that the safety profile of sophosbuvira and ribavirin was comparable to that observed in patients receiving cofosbuvir and ribavirin at the 3 rd stage of clinical trials.Patients after liver transplantation. The safety and efficacy of sophosbuvira in these patients has not been established.Patients with genotypes of 5 or 6 HCV. Available data for subjects with genotypes of 5 or 6 HCV are not sufficient for dosage recommendations.

Daclatasvir instruction

The Latin name of the substance Daclatasvir Daclatasvirum ( genus. Daclatasviri)

Chemical name methyl N - [(2S) -1 - [(2S) -2- [5- [4- [4- [2 - [(2S) -1 - [(2S) -2- (methoxycarbonylamino) -3-methylbutanoyl ] pyrrolidin-2-yl] -1H-imidazol-5-yl] phenyl] phenyl] -1H-imidazol-2-yl] pyrrolidin-1-yl] -3-methyl-1-oxobutan-2-yl] carbo

Molecular formula  C40H50N8O6 

Therapeutic agents Daclatasvir Antiviral (excluding HIV ) agent Nosological classification (ICD-10)B18.2 Chronic viral hepatitis C CAS code1009119-64-5Nature of substance Daclatasvir Antiviral means of direct action against the hepatitis C virus

Pharmacology Pharmacological action - an antiviral .pharmacodynamicsDaclatasvir is a highly specific means for direct action against the hepatitis C virus and has no marked activity against other RNA - and DNA -containing viruses, including HIV . Daclatasvir is an inhibitor of nonstructural protein 5A (NS5A), a multifunctional protein required for replication of the virus of hepatitis C, and thus suppresses the two stages of the viral life cycle - the replication of viral RNA and virion assembly. Based on data obtained in vitroAnd computer modeling data showed that daclatacvir reacted with N-end within domain 1 protein, which may cause structural distortions affecting the implementation of the function of the protein NS5A. Established that daclatasvir pangenotipicheskim is a potent inhibitor of the replication complex of HCV genotypes 1a, lb, 2a, 3a, 4a, 5a and 6a with the values of the effective concentration (50% reduction, EC 50 ) by picomolar to low nanomolar. In cellular assays the values Replicon EC 50 daclatasvir range from 0.001 to 1.25 nmol / l at genotypes la, 1b, 3a, 4a, 5a and 6a and from 0.034 to 19 nmol / L with genotype 2a. Furthermore, daclatasvir inhibits hepatitis C virus of genotype 2a (JFH-1) under the EC value of 50equal to 0.02 nmol / L. When genotype 1a infected patients, not previously treated with the treatment, a single dose of 60 mg daclatasvir leads to an average reduction in viral load, as measured after 24 hours, at 3,2 log 10 IU / ml.Studies in cell culture also showed amplification of the antiviral action daclatasvir when combined with interferon alpha and NS3 protease inhibitors, non-nucleoside inhibitors of the NS5B hepatitis C virus, the NS5B nucleoside analogues. With all of these groups of drugs has not been observed antagonism of antiviral effect.Resistance in cell kulutreAmino acid substitutions that cause resistance to daclatasvir in genotypes of HCV 1-6 were isolated in cell replicon system and observed in the N-terminal region of 100 amino acid residues NS5A. L31V Y93H injury and were frequently observed in the genotype 1b, and substitutions M28T, L31V / M, Q30E / H / R and U93S / H / N were frequently observed in the genotype 1a. Single amino acid substitutions generally cause low level resistance (EC 50 <1 nmol / l to L31V, Y93H) for genotype 1b and higher levels of resistance for genotype 1a (up to 350 nmol / L for Y93N). The principles of emergence, resistance in clinical practice were similar to the principles of resistance observed in vitro .Resistance in clinical trialsEffect of polymorphism starting HCV therapy. During the study the connection between naturally occurring source substitutions NS5A (polymorphism) and outcome of treatment, it was found that the effect depends on the NS5A polymorphism regimens.Combination therapy daclatasvir + asunaprevir. In clinical studies, phase II-III efficacy of the combination daclatasvir + asunaprevir was decreased in patients infected with HCV genotype 1b with baseline NS5A L31 substitutions and / or Y93H. 40% (48/119) of patients with substitutions NS5A L31 and / or Y93H achieved sustained virological response (UVO12) compared with 93% (686/742) of patients without these types of polymorphism. Background prevalence substitutions and NS5A L31 Y93H was 14 and 4% for L31 alone, 10% for Y93H separately and 0.5% for L31 Y93H +. Of the 127 cases of virological failure at the initial NS5A replacing 16% of the replacement was observed only L31, 38% - only Y93H substitution and a 2% - replacing L31 + Y93H.Combination therapy daclatasvir asunaprevir + + peginterferon alfa and ribavirin. Of the 373 patients who had undergone sequencing in this combination study, 42 patients had starting replacement associated with resistance to daclatasvir. Of these 42 patients 38 reached UVO12, 1 patient was nevirusologicheskaya inefficiency, and 3 patients had virologic failure (1 patient with genotype 1a were replacement NS5A L31M and 1 patient - NS5A Y93F at baseline, 1 patient with genotype 1b had replaced NS5A L31M at baseline).pharmacokineticsPharmacokinetic properties daclatasvir evaluated in healthy adult volunteers and patients with chronic hepatitis C virus infection after repeated oral administration in dosage daclatasvir 60 mg 1 time per day in combination with peginterferon alfa and ribavirin mean value (coefficient of variation,%) C max daclatasvir was 1534 (58%) ng / mL, AUC 0-24 - 14122 (70%) ng · h / ml and C min - 232 (83%) ng / mL.Suction. Fast absorption. C max daclatasvir observed 1-2 hours after ingestion. The AUC , the C max and the C min of blood are dose-dependent, daclatasvir stable level in the blood plasma is observed on the 4th day of oral administration 1 time per day. Studies have found no differences in the pharmacokinetics daclatasvir in patients with hepatitis C and healthy volunteers. Studies in vitro , performed with human Caco-2 cells showed that daclatasvir is a substrate of P-gp. Daclatasvir absolute bioavailability is 67%.In studies in healthy volunteers it was found that the single dose daclatasvir 60 mg 30 minutes after eating a high fat (about 1000 kcal from fat content of about 50%) reduces C max daclatasvir blood by 28% AUC by 23%. Receiving daclatasvir after a light meal (275 kcal from fat content of about 15%) did not change in blood concentration.Distribution. V ss daclatasvir after a single I / administration of 100 micrograms of 47 liters. Communication with the plasma protein does not depend on the dose (studied range of 1 to 100 mg) is 99%.Metabolism. In studies in vitro found that a substrate daclatasvir isoenzyme CYP3A , wherein CYP3A is the major isoform of CYP, responsible for the metabolism daclatasvir. Metabolites containing more than 5% of the concentration of the starting material available.Withdrawal. Following oral administration in healthy volunteers receiving single doses daclatasvir labeled with radioactive carbon ( 14 C-daclatasvir), 88% of the radioactivity was excreted in the feces (53% unchanged).After multiple administration daclatasvir patients infected with hepatitis C virus, T 1/2 daclatasvir ranged from 12 to 15 hours. In patients who took daclatasvir in tablets of 60 mg, followed by / in 100 micrograms of 13 C, 15 N-daclatasvir, total clearance was 4.24 l / h.Patients with impaired renal function. Comparison of the AUC in patients with infection of HCV and normal renal function ( Cl creatinine 90 ml / min) and patients with infection of HCV with impaired renal function ( Cl creatinine 60, 30 and 15 ml / min) showed an increase in AUC of 26 , 60 and 80% (unbound AUC - 18, 39 and 51%), respectively. Patients with end-stage renal disease requiring hemodialysis, there was an increase AUC by 27% (related - 20%) compared with patients with normal renal function. Statistical analysis of the data population of patients with hepatitis C virus infection showed an increase in AUCin patients with mild to moderate renal insufficiency, but the magnitude of this increase is not clinically significant for pharmacokinetics daclatasvir. Due to the high degree of binding daclatasvir to plasma proteins, hemodialysis has no effect on its concentration in the blood. Daclatasvir change the dose in patients with renal impairment is not required.Patients with impaired liver function. Pharmacokinetic studies daclatasvir 30 mg was performed in patients with hepatitis C with mild, moderate and severe hepatic impairment (classes A-C in Child-Pugh) compared to patients without liver function abnormalities. The values of C max and AUC daclatasvir (free and bound to proteins) were lower in the presence of hepatic insufficiency in comparison with the values of these parameters in healthy volunteers, however, this concentration decrease was not clinically significant. No need to change the dose in patients with impaired liver function.Elderly patients. In clinical studies, patients taking older part (310 persons were aged 65 years or older, and 20 - 75 years of age and older). Altered pharmacokinetics, and efficacy and safety profile of the drug in elderly patients were observed.Floor. There are differences in the total clearance ( Cl / F) daclatasvir, thus Cl / F is lower in women, but this difference is not clinically significant.

Application of the substance Daclatasvir Treatment of chronic hepatitis C in patients with compensated liver disease (including cirrhosis) in the following combinations:- with asunaprevirom in patients with HCV genotype 1b;- with asunaprevirom, peginterferon alfa and ribavirin in patients with HCV genotype 1.

Contraindications Daclatasvir should not be used as monotherapy.Hypersensitivity to daclatasvir.In combination with the strong inducers isoenzyme CYP3A4 (due to a decrease daclatasvir concentration in the blood and reduce efficiency), such as antiepileptics (phenytoin, carbamazepine, phenobarbital, oxcarbazepine), antibacterial drugs (rifampicin, rifabutin, rifapentine), systemic glucocorticosteroids (dexamethasone), vegetable PM (on the basis of Hypericum perforatum, Hypericum perforatum ).Simultaneous application of moderate isoenzyme inducers of CYP3A4 in the application schemes involving asunaprevir (see. The corresponding formulation instructions).Contraindications to the use of drugs combined scheme - asunaprevir and / or peginterferon alpha plus ribavirin (see instructions for use of the drugs instructions.).Lactase deficiency, lactose intolerance, glucose-galactose malabsorption, pregnancy and lactation, age under 18 years (effectiveness and safety have been studied).

Limitations to the use of Since daclatasvir used in a combination therapy, it should be used with caution in conditions described in the operating instructions of each drug in the combination (asunaprevir and / or peginterferon alfa and ribavirin).Safety of combined therapy has not been studied in patients with liver uncompensated illnesses, as well as in patients after liver transplantation.Daclatasvir The combined use with other drugs may lead to changes in concentration of both daclatasvir and active agents other drugs (see. "Contra" and "interaction").

Application of pregnancy and breastfeeding Daclatasvir asunaprevirThere are no adequate and well-controlled studies in pregnant women. In animal studies, the application daclatacvir in doses exceeding the recommended therapeutic (4.6 times (rats) and 16 times (rabbits), were observed negative influence on fetal development, while still higher concentrations daclatasvir (in 25 times (rats) and 72 times (rabbits) showed negative effects for the mother and the fetus. Women of childbearing age must use effective contraception during treatment daclatasvir and within 5 weeks after its completion.Use of a combination daclatasvir + asunaprevir contraindicated in pregnancy.It is unknown whether daclatasvir into breast milk. Daclatasvir passes into breast milk of lactating rats at concentrations greater than the maternal plasma concentrations in 1.7-2 times, so during treatment daclatasvir breast-feeding should be discontinued.Daclatasvir asunaprevir + + + ribavirin, peginterferon alfaUse of ribavirin can cause birth defects, intrauterine death, abortion, so care should be taken when applying rigorous regimen consisting of ribavirin. The need to prevent pregnancy like themselves patients and women whose sexual partners have indicated therapy. Therapy with ribavirin should not begin until as long as the patient, fertility, and sexual male partners will not use at least two effective methods of contraception, which is necessary both throughout therapy and for at least 6 months after its completion. During this period necessary to perform the standard tests for pregnancy.A study of interferon in animal studies has been associated with the abortive effects, the possibility of which in humans can not be ruled out. Therefore, when used as a therapy to patients and their partners should use adequate contraception.

Side effects of substance Daclatasvir Daclatasvir applied only as part of combination regimens. Should read side effect PM included in the treatment regimen, before initiation of therapy. Adverse drug reactions (ADRs) associated with asunaprevira, peginterferon alfa and ribavirin are described in the instructions for use of data PM .Safety of daclatasvir evaluated in 5 clinical studies in patients with chronic hepatitis C who received 60 mg daclatasvir 1 times a day in combination with asunaprevirom and / or peginterferon alfa and ribavirin. Data are presented below apply security of treatment regimes.Daclatasvir asunaprevirSafety daclatasvir use in combination with asunaprevirom evaluated in 4 studies with a median duration of treatment of 24 weeks . The most common (incidence 10% or higher) NAL observed in clinical trials using treatment regimen daclatasvir + asunaprevir were headache (15%) and fatigue (12%). Most ADRs were mild to moderate in severity; 6% of patients experienced serious adverse events; 3% of patients discontinued treatment due to occurrence of ADRs. The most common adverse events leading to discontinuation of treatment have been increasing ALT activity and ACT. In a clinical study of therapy daclatasvir combination + asunaprevir during the first 12 weeksfrequency of treatment reported ADRs were similar in patients receiving placebo and patients receiving said therapy. NLP, arising from greater than or equal to 5% of patients with chronic hepatitis C with the combination daclatasvir + asunaprevir, presented below (side reactions, whose connection with the use of at least daclatasvir available, the combined data from several studies). Incidence HLR is shown in accordance with the scale: very often (greater than or equal to 1/10); often (greater than or equal to 1/100 and less than 1/10).From the nervous system: very often - headache (15%).On the part of the digestive tract : often - diarrhea (9%), nausea (8%).General disorders: often - fatigue (12%).Results of laboratory and instrumental investigations: often - increased activity of ALT (7%), elevated AST (5%).NAL, occurs less than 5% of patients with chronic hepatitis C with the combination daclatasvir + asunaprevir were skin rash, pruritus, alopecia; eosinophilia, thrombocytopenia, anemia; fever, malaise, chills; insomnia; loss of appetite, abdominal discomfort, constipation, pain in the upper abdomen, stomatitis, abdominal distension, vomiting; increase in blood pressure ; pain and joint pain, muscle stiffness; nasopharyngitis, pain in the oropharynx; increased activity of gamma globulintransferazy, alkaline phosphatase , lipase, hypoalbuminemia.Daclatasvir in combination with asunaprevirom, peginterferon alfa and ribavirinSafety daclatasvir use in combination with asunaprevirom, peginterferon alfa and ribavirin was evaluated in a clinical trial HALLMARK QUAD with a median duration of therapy to 24 weeks. The most common HLR (frequency of 15% and higher), the observed and clinical trials using treatment regimen daclatasvir + asunaprepir + peginterferon alfa and ribavirin, were fatigue (39%), headache (28%), pruritus (25%), asthenia (23%), influenza-like state (22%), insomnia (21%), anemia (19%), rash (18%), alopecia (16%), spleen (16%), nausea (15%.). Further side effects arising in patients with chronic hepatitis C using regimens daclatasvir + asunaprevir + peginterferon alfa and ribavirin, were dry skin (15%), anorexia (12%), muscle pain (14%), fever (15 %), cough (13%), dyspnea (11%), neutropenia (14%), lymphopenia (1%), diarrhea (14%), arthralgia (9%). Most ADRs were mild to moderate in severity; 6% of patients experienced serious adverse events; 5% of patients discontinued treatment due to ADRs, the most common ADRs leading to discontinuation were rash, malaise, dizziness and neutropenia. In a clinical study therapy daclatasvir asunaprevir + + + ribavirin, peginterferon alfa frequency reported ADRs were similar in patients receiving placebo and patients receiving said therapy, except for two NAL - asthenia and flu-like state. Given ADRs were the only occurs with a frequency of at least 5% higher than among patients receiving placebo. In a clinical study therapy daclatasvir asunaprevir + + + ribavirin, peginterferon alfa frequency reported ADRs were similar in patients receiving placebo and patients receiving said therapy, except for two NAL - asthenia and flu-like state. Given ADRs were the only occurs with a frequency of at least 5% higher than among patients receiving placebo. In a clinical study therapy daclatasvir asunaprevir + + + ribavirin, peginterferon alfa frequency reported ADRs were similar in patients receiving placebo and patients receiving said therapy, except for two NAL - asthenia and flu-like state. Given ADRs were the only occurs with a frequency of at least 5% higher than among patients receiving placebo.Laboratory resultsAbnormal laboratory abnormalities from normal grade 3/4 observed among patients with hepatitis C treated with combination therapy daclatasvirom presented below (the results of laboratory tests Percentage classified by System Division of Acquired Immunodeficiency Syndrome, DAIDS , version 1.0).Daclatasvir + asunaprevir (N = 918): increased activity of ALT (above 5.1 times ULN ) - 4%, increase in AST (5.1-fold higher in ULN ) - 3% increase in total bilirubin (above 2, 6 times ULN ) - 1%.Daclatasvir asunaprevir + + peginterferon alpha plus ribavirin (N = 398): increased activity of ALT (above 5.1 times ULN ) - 3%, the increase in AST (5.1-fold higher in ULN ) - 3% increase in total bilirubin (above 2.6 times ULN ) - 1%. Next severe adverse reactions are also described in the following sections of the description:- severe symptomatic bradycardia when combined with sofosbuvir and amiodarone (see "Safety precautions.").Results of clinical trialsSince clinical tests performed with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not coincide with that obtained in other studies, and observed in clinical practice.In clinical trials involved about 1900 patients with chronic hepatitis C virus infection treated daclatasvir the recommended dose in combination with other drugs for the treatment of hepatitis C.The study ALLY-3 152 patients infected with HCV genotype 3, not previously exposed and untreated, was prepared daclatasvir 60 mg 1 time per day in combination with sofosbuvir for 12 weeks . The most common adverse reactions (with a frequency of 10% or higher) were headache and fatigue. All adverse events were of mild to moderate severity. One patient had a serious adverse reaction, which communicate with daclatasvir not been established; abolition of therapy due to adverse reactions was not made in any patient.Adverse reactions, presumably associated with treatment daсlatasvirom and arose at a frequency of 5% or above were observed in this study (N = 152 in brackets data in percent) were as follows: Headache 21 (14%), fatigue 21 (14% ) nausea 12 (8%), diarrhea 7 (5%).Changes in laboratory parametersIncreasing levels of lipase. In studies ALLY-3 2% of asymptomatic patients had a temporary increase in lipase is more than 3 times the ULN .Post-marketing studiesCardiac abnormalities. In patients receiving amiodarone, which was scheduled sofosbuvir treatment in combination with other antiviral drugs direct action for the treatment of hepatitis C, including daсlatasvir, it was marked by severe symptomatic bradycardia.

Interaction Because daсlatasvir used in combined therapeutic regimens should be familiar with possible interactions with each of the PM circuit. In the appointment of concomitant therapy should follow the most conservative recommendations.daсlatasvir is a substrate of isoenzyme CYP3A4 , therefore, moderate and strong inducers of CYP3A4 may reduce daсlatasvir plasma level and therapeutic effect. Strong inhibitors of CYP3A4 may increase serum concentrations daсlatasvir. Daсlatasvir substrate is also P-gp, but the joint use drug , only affecting the properties of P-gp (without a simultaneous effect on CYP3A ), not enough to obtain clinically significant effect on daсlatasvir concentration in blood plasma. daсlatasvir an inhibitor of P-gp, organic anions transport polypeptide 1B1 and 1B3 and the protein resistant breast cancer (BCRP). Application daсlatasvir may increase systemic exposureDrugs that are substrates of P-gp polypeptide or transport of organic anions 1B1 / 1B3 or BCRP, which may increase or prolong their therapeutic effect and increase undesirable phenomena. Care must be taken when used together daсlatasvir these isoenzymes and substrates / carriers, particularly in the case of the last narrow therapeutic range.The combined use of daсlatasvir contraindicated for the following drugs that are potent inducers of CYP3A (a partial list of drugs that induce CY3A4), as their combined use can lead to a reduction daсlatasvir concentration in blood plasma, which can lead to a lack of viral response (see also "Contra."):- protivoэpilepticheskie Message - carbamazepine, oxcarbazepine, phenobarbital, phenytoin;- antibacterial drugs - rifampicin, rifabutin, rifapentine;- systemic corticosteroids - dexamethasone;- herbal medicines - Hypericum perforatum preparations ( of Hypericum perforatum ).Further summarized clinical guidelines established for potentially significant daсlatasvir drug interactions with other drugs .Antiviral drugs for the treatment of hepatitis C.Asunaprevir. There are no clinically significant changes in the concentration and daclatasvir asunaprevira; asunaprevira change in dose is required.Peginterferon alfa 180 mg 1 time per week and ribavirin is 500 or 600 mg 2 times a day. There are no clinically significant changes daclatasvir concentration peginterferon alfa and ribavirin; change in dose daclatasvir, peginterferon alfa and ribavirin is required.Simeprevir. There are no clinically significant changes in the concentration and daclatasvir simeprevira; change the dose and daclatasvir simeprevira not required.Sofosbuvir. There are no clinically significant changes daclatasvir concentration and GS-331007 (main metabolite sofosbuvir); change the dose and daclatasvir sofosbuvir not required.Telaprevir. Combined use daclatasvir increases the concentration in plasma; There are no clinically significant changes in concentrations of telaprevir.Antiviral drugs for treating HIV and hepatitis B different mechanism of actionAtazanavir / ritonavir. Combined use daclatasvir increases the concentration in plasma; daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use of atazanavir / ritonavir or other potent inhibitors of CYP3A4 .Darunavir / ritonavir, lopinavir / ritonavir. Interaction not studied. In view of inhibiting CYP3A4 protease inhibitors are expected to increase daclatasvir concentration in blood plasma. Due to insufficient data combined use daclatasvir and darunavir or lopinavir is not recommended.Boceprevir. Interaction not studied. Due to inhibition of CYP3A4 boceprevir daclatasvir expected to increase plasma concentrations. Daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use boceprevir or other potent inhibitors of CYP3A4 .Tenofovir. There are no clinically significant changes in the concentration daclatasvir and tenofovir; daclatasvir change the dose and tenofovir is not required.Lamivudine, zidovudine, emtricitabine, abacavir, didanosine, stavudine. Interaction not studied. It expected no clinically significant changes in the concentration daclatasvir and nucleoside reverse transcriptase inhibitors (NRTIs); change in dose daclatasvir and NRTIs is not required.Efavirenz. Combined use daclatasvir reduces the concentration in the blood plasma; daclatasvir dose should be increased to 90 mg 1 time per day with concomitant use of efavirenz or other moderate inducers CYP3A4 .Etravirine, nevirapine. Interaction not studied. In view of the induction CY3A4 etravirine and nevirapine is expected to decrease daclatasvir plasma concentrations. Due to insufficient data combined use daclatasvir and etravirine or nevirapine is not recommended.Rilpivirine. Interaction not studied. Expected no clinically significant changes in concentration and daclatasvir rilpivirine plasma. Changing dose daclatasvir and rilpivirine is required.Raltegravir dolutegravir (integrase inhibitors). Interaction not studied. Expected no clinically significant changes in concentration daclatasvir and integrase inhibitors in plasma. Changing dose daclatasvir and integrase inhibitors is not required.Enfuvirtide (fusion inhibitor). Interaction not studied. Expected no clinically significant changes in concentration daclatasvir and enfuvirtide plasma. Changing dose daclatasvir and enfuvirtide is not required.Maraviroc (CCR5-receptor antagonist). Interaction not studied. Expected no clinically significant changes in concentration and daclatasvir maraviroc plasma. Changing dose daclatasvir and maraviroc is not required.Kobitsistat. Interaction not studied. Due to inhibition of CYP3A4 kobitsistatom daclatasvir expected to increase plasma concentrations. Daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use kobitsistata or other potent inhibitors of CYP3A4 .Means suppressing acid productionFamotidine (antagonist of H 2 histamine receptors). There are no clinically significant changes daclatasvir plasma concentrations. Daclatasvir change in dose is required.Omeprazole (proton pump inhibitor). There are no clinically significant changes daclatasvir plasma concentrations. Daclatasvir change in dose is required.antibacterial drugsClarithromycin, telithromycin. Interaction not studied. Due to inhibition of CYP3A4 antibiotics daclatasvir expected to increase plasma concentrations. Daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use of clarithromycin or other potent inhibitors of CYP3A4 .Erythromycin. Interaction not studied. Due to inhibition of CYP3A4 erythromycin daclatasvir expected to increase plasma concentrations. The combined use requires caution.Azithromycin, ciprofloxacin. Interaction not studied. Expected no clinically significant changes daclatasvir concentration of azithromycin and ciprofloxacin in the blood plasma. Changing daclatasvir dose or ciprofloxacin, and azithromycin is not required.anticoagulantsDabigatran etexilate. Interaction not studied. Due to inhibition of P-gp daclatasvir is expected to increase concentrations of dabigatran etexilate in the blood plasma. Recommended thorough security monitoring early application circuits daclatasvir in patients treated with dabigatran etexilate or other substrates of P-gp with a narrow therapeutic range.Warfarin. Interaction not studied. Expected no clinically significant changes in concentration daclatasvir and warfarin in the blood plasma. Changing the dose of warfarin and daclatasvir not required.antidepressantsEscitalopram ( an SSRI ). Expected no clinically significant changes in concentration daclatasvir and escitalopram in plasma. Changing the dose of escitalopram and daclatasvir not required.antifungal drugsKetoconazole 400 mg. Clinically significant increase daclatasvir plasma concentrations due to the suppression of ketoconazole CYP3A and P-gp. Daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use of ketoconazole or other potent inhibitors of CYP3A4 .Itraconazole, posaconazole, voriconazole. Interaction not studied. In view of the inhibition of CYP3A antifungal drugs is expected clinically significant increase daclatasvir plasma concentrations. Daclatasvir dose should be reduced to 1 to 30 mg once a day with concomitant use of ketoconazole or other potent inhibitors of CYP3A4 .Fluconazole. Interaction not studied. In view of the inhibition of CYP3A antifungal drugs is expected moderate increase daclatasvir plasma concentrations, requiring no change in the dose of both drugs . No clinically significant changes in the concentration of Fluconazole is not expected.Cardiovascular drugsDigoxin. It is expected a clinically significant increase in the concentration of digoxin in the blood plasma due to the suppression of P-gp by daclatasvir. Digoxin and other P-gp substrates with a narrow therapeutic range must be used with caution in conjunction with daclatasvir. Should be prescribed the lowest dose of digoxin and monitor the level of digoxin in the blood plasma. To achieve the desired therapeutic effect, the dose titration should use.Diltiazem, nifedipine, amlodipine. Interaction not studied. In view of the inhibition of CYP3A CCB is expected clinically significant increase daclatasvir plasma concentrations. Daclatasvir together with BPC should be used with caution.Verapamil. Interaction not studied. In view of the inhibition of CYP3A and P-gp verapamil is expected clinically significant increase daclatasvir plasma concentrations. Daclatasvir together with verapamil should be used with caution.oral contraceptives35 ug ethinylestradiol 1 time per day norgestimate + 0.18 / 0.215 / 0.25 1 mg once a day for 7 days. There are no clinically significant changes in concentrations of oral contraceptives. Joint application has no clinically significant effect on the pharmacokinetics daclatasvir.30 ug ethinylestradiol 1 time per day plus norethindrone acetate 1.5 mg 1 time per day (vysokodozirovannoe contraceptive). There are no clinically significant changes in oral contraceptives concentrations (as compared to using only low-dose oral contraceptives). Joint application has no clinically significant effect on the pharmacokinetics daclatasvir.ImmunodupressantyCiclosporin 400 mg 1 time per day. There are no clinically significant changes daclatasvir and concentration of cyclosporine in the blood plasma. Changing daclatasvir dose cyclosporine and not required.Tacrolimus 5 mg 1 time per day. There are no clinically significant changes daclatasvir concentration and tacrolimus in the blood plasma. Changing dose daclatasvir and tacrolimus are required.Sirolimus, mycophenolate mofetil. Interaction not studied. Not expected to clinically significant changes in concentrations of immunosuppressant daclatasvir and plasma. Changing dose daclatasvir and immunosuppressants is not required.Lipid-lowering drugsRosuvastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin, pravastatin. Daclatasvir increases the concentration in blood plasma rosuvastatin. For other statin interaction has not been studied, but is expected to increase statin concentrations in plasma due to the inhibition of OATP 1B1 and / or BCRP daclatasvir. Care must be taken when used together daclatasvir and rosuvastatin, or other substrates OATP 1B1, OATP 1B3 and BCRP.narcotic analgesicsBuprenorphine / naloxone from 8/2 to 24/6 mg once a day 1, the individual dose (60 daclatasvir 1 mg once a day). At opioidzavisimyh patients receiving therapy with buprenorphine / naloxone has been detected clinically significant changes in pharmacokinetics daclatasvir ( AUC , C max , C min ). There are no clinically significant changes in concentrations of buprenorphine and norbuprenorfina plasma. Changing dose daclatasvir and buprenorphine are required.Methadone 40-120 mg once daily dose (60 mg daclatasvir 1 time daily). In opioidzavisimyh patients receiving methadone, is not revealed clinically significant changes in concentration daclatasvir and R-methadone in the blood plasma. Changing the dose of methadone and daclatasvir not required.sedativesMidazolam (5 mg dose), triazolam, alprazolam. There are no clinically significant changes in midazolam plasma levels. With regard to triazolam and alprazolam interaction has not been studied, but is not expected to change the concentration of these benzodiazepines in blood plasma. Changing the dose of midazolam and other substrates CYP3A4 is not required. The potential drug interaction of other drugs with daclatasvir Daclatasvir is a substrate of CYP3A . Consequently, moderate or strong inducers of CYP3A can lower plasma levels and therapeutic efficacy daclatasvir. Strong inhibitors of CYP3A (e.g. clarithromycin, itraconazole, ketoconazole, ritonavir) may increase daclatasvir plasma.Daclatasvir potential drug interactions with other drugsDaclatasvir an inhibitor of P-gp, organic anions transport polypeptide (OATP) 1B1 and 1B3 and the protein resistant breast cancer (BCRP). Application daclatasvir may increase systemic exposure drugs that are substrates of P-gp, OATP 1B1 or 1B3 or BCRP, which may lead to prolongation of their therapeutic effects or side effects.Installed or potentially significant drug interactionsClinical guidelines for joint use daclatasvir and other drugs with established or potentially significant drug interactions are shown below (see. "Contra". The letter a marked combination, interact with whom studied in clinical trials).Strong inhibitors of CYP3A . Atazanavir / ritonavir a , clarithromycin, indinavir, itraconazole, ketoconazole, a , nefazodone, nelfinavir, posaconazole, saquinavir, telithromycin, voriconazole - daclatasvir increase the concentration in plasma; daclatasvir recommended dose reduction to 30 mg 1 time per day when used together with potent inhibitors of CYP3A .Moderate inhibitors of CYP3A . Atazanavir, ciprofloxacin, darunavir / ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil - daclatasvir increase the concentration in plasma; recommended monitoring of side effects daclatasvir.Moderate inducers of CYP3A . Bosentan, dexamethasone, efavirenz a , etravirine, modafinil, nafcillin, rifapentine - daclatasvir reduce the concentration in the blood plasma; daclatasvir recommended to increase the dose of 1 to 90 mg once daily when combined with inductors moderate CYP3A .Anticoagulants. Daclatasvir increases the concentration of dabigatran etexilate in the blood plasma; the combined use of dabigatran etexilate with daclatasvir not recommended in patients with renal insufficiency. Specific recommendations are given in the instructions for use of dabigatran.Cardiovascular drugs:- antiarrhythmic drug amiodarone - effects are unknown; the combined use of amiodarone with the combination daclatasvir + sofosbuvir not, as recommended It can lead to severe symptomatic bradycardia. The mechanism of this phenomenon is unknown. If necessary, concomitant use recommended control of cardiac activity (see "Side effects".);- antiarrhythmic drug digoxin - daclatasvir increases the concentration of digoxin in the blood plasma. Patients already receiving daclatasvir, the appointment of digoxin should use the lowest dose of digoxin, monitor digoxin concentrations and adjust the dose of digoxin, while maintaining control of its concentration in the blood, if necessary. Patients already receiving digoxin, before application daclatasvir measure the serum concentration of digoxin, reduce it by reducing the dose of digoxin by approximately 30-50% or by changing the interval between doses, and continue to monitor the concentration of digoxin in plasma.Lipid-lowering agents. Daclatasvir increases the concentration in the blood plasma inhibitors GMG CoA reductase atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin a and simvastatin; requires monitoring of side effects associated with the use of an inhibitor of GMG CoA reductase as myopathy.Drugs for which there is no clinically significant interaction with daclatasvir According to the results of clinical studies of drug interactions, no clinically significant changes in exposure cyclosporin, escitalopram, ethinyl estradiol / norgestimate, methadone, midazolam, tacrolimus or the combined use of tenofovir daclatasvir. There were no clinically significant changes in exposure daclatasvir while the use of cyclosporine, escitalopram, famotidnom, omeprazole, sofosbuvir, tacrolimus, or tenofovir. Not considered clinically significant drug interactions daclatasvir or in conjunction with peginterferon applied, ribavirin or antacids.

Overdose Overdosage symptoms is not described.In Phase 1 clinical trials at application daclatasvir healthy volunteers at doses up to 100 mg for up to 10 days duration time period or a single dose up to 200 mg of an unexpected adverse reactions were noted. Antidote to daclatasvir absent. Daclatasvir Treatment of overdose should include general supportive measures, including monitoring of vital signs and observation of clinical status. Due to the high binding daclatasvir plasma proteins dialysis is not recommended in overdose.RxList.comUnknown antidote to overdose daclatasvir. Daclatasvir treatment of overdose should consist of general supportive measures, including monitoring of vital signs and observation of clinical status. Due to the high plasma protein binding (> 99%) it is unlikely that dialysis significantly reduce plasma concentration daclatasvir.

route of administration Inside.

Precautions Daclatasvir substance Daclatasvir should not be used as monotherapy.Of the more than 2000 patients enrolled in clinical trials of combination therapy daclatasvir, 372 patients had compensated cirrhosis (Class A according to Child-Pugh). Differences in safety and efficacy of therapy in patients with compensated cirrhosis and patients without cirrhosis were observed. Safety and effectiveness of daсlatasvir in patients with uncompensated cirrhosis has not been established. Not required dose change daclatasvir in patients with mild (Class A according to Child-Pugh), moderate (Class B of Child-Pugh) or severe (grade C in Child-Pugh) liver dysfunction.The safety and efficacy of combination therapy daclatasvir in patients with liver transplant has not been established. There is limited experience daclatasvir after liver transplantation.Daclatasvir influence on QTc interval was evaluated in a randomized, placebo-controlled study in healthy volunteers. Daclatasvir Single doses of 60 mg and 180 did not have a clinically meaningful effect on interval QTc, Frederick adjusted by formula (QTcF). There was no significant relationship between elevated concentrations daclatasvir in plasma and changes in QTc. Thus a single dose of 180 mg daсlatasvira corresponds to the maximum expected concentration in blood plasma in clinical use.Not examined the use daclatasvir for the treatment of chronic hepatitis C in patients co-infected with hepatitis B or HIV .Daclatasvir formulation contains lactose: in Table 1. 60 mg (daily dose) contained 115.50 mg of lactose.It is necessary to use adequate contraception during 5 weeks after completion of therapy daclatasvir.Effects on ability to drive vehicles, machinery. Studies of the possible effect on the ability to use daсlatasvira VEHICLES control and work carried out with no mechanisms. If a patient experiences dizziness, impaired attention, blurred / decreased visual acuity (these adverse events have been reported with the use of the treatment regimen with peginterferon alpha), which may affect the ability to concentrate, he should refrain from driving vehicles and mechanisms.Before the appointment of therapy daclatasvir and during it is necessary to consider the possibility of drug interactions, check the function of related drugs and to monitor adverse reactions associated with concomitant drugs .RxList.comThe risk of side reactions or loss of virological response resulting drug interactionsCombined application daсlatasvira and other drugs can lead to a known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect daсlatasvira and possible development of resistance, the need to adjust the dose of concomitant drugs or daсlatasvira, possible development of clinically significant adverse reactions due to increased exposure concomitant drug or daсlatasvira (cm. "Interaction").

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