- 1 [highlight]Important to know about Sovaldi Tablets ?[/highlight]
- 2 [highlight]Sovaldi Tablets indication and Uses[/highlight]
- 3 [highlight]Sovaldi Tablets Dosage[/highlight]
- 4 [highlight]How it works Sovaldi Tablets[/highlight]
- 5 [highlight]Sovaldi Tablets Side Effects[/highlight]
- 6 Sovaldi Tablets Interactions
- 7 [highlight]Sovaldi Tablets Warnings and Precautions[/highlight]
- 8 [highlight]Drive and use machines[/highlight]
- 9 [highlight]Sovaldi Tablets and Pregnancy / Breastfeeding / Fertility[/highlight]
- 10 [highlight]What should I do if I miss a dose?[/highlight]
- 11 [highlight]What happens if I overdose from Sovaldi Tablets ?[/highlight]
- 12 [highlight]What is Forms and Composition Sovaldi Tablets ?[/highlight]
[highlight]Important to know about Sovaldi Tablets ?[/highlight]
- Sofosbuvir inhibits the growth of the hepatitis C virus.
- In chronic hepatitis C (liver inflammation).
- It takes several months until your symptoms decrease, such as fatigue and abdominal complaints.
- A course usually lasts 12 to 24 weeks, sometimes longer. Complete the entire course, even if your symptoms have already disappeared. Consult with your doctor if you find it difficult to maintain the treatment. For example because of the side effects.
- Side effects include: headache, fatigue and skin rash. If you also take other medicines for hepatitis C, you may get more side effects. Click on this site for these substances.
- There are many interactions with other means. Have your pharmacist check whether you can use it safely with your other medicines.
[highlight]Sovaldi Tablets indication and Uses[/highlight]
Sovaldi Tablets is indicated, in combination with other medicines, for the treatment of chronic hepatitis C (CCH) in adults (see sections Posology and method of administration , Warnings and precautions for use, andPharmacodynamic properties ).
For activity based on hepatitis C virus (HCV) genotype, see Warnings and Precautions andPharmacodynamic Properties sections .
[highlight]Sovaldi Tablets Dosage[/highlight]
Treatment with Sovaldi Tablets should be initiated and monitored by a physician experienced in the management of patients with HCC.
- The recommended dose is one 400 mg tablet once a day, orally, with food.
- Sovaldi Tablets should be used in combination with other medicines.
- Sovaldi Tablets is not recommended as monotherapy.
See also the Summary of Product Characteristics of Drugs Used in Combination with Sovaldi Tablets .
The co-administered drug (s) and duration of treatment recommended for combination therapy with Sovaldi Tablets are shown in Table 1.
[highlight]How it works Sovaldi Tablets[/highlight]
Pharmacotherapeutic group: Direct-acting antiviral; ATC Code: J05AX15
Sofosbuvir is a pan-genotypic inhibitor of NS5B RNA-dependent RNA polymerase
HCV, which is essential for the replication of the virus. Sofosbuvir is the pro-drug of a nucleotide that undergoes intracellular metabolism to form an analogue of uridine triphosphate
(GT-461203) pharmacologically active, which can be incorporated into the viral RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical test, GS-461203 inhibited the recombinant HCV NS5B polymerase activity of genotypes 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC 50 ) ranging from 0.7 to 2.6 microM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA- and RNA polymerases, nor is it an inhibitor of mitochondrial RNA polymerase.
In the HCV replicon assay, the effective concentration (EC 50 ) values of sofosbuvir against full-length replicons of genotypes 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, and the EC 50 values of sofosbuvir against chimeric 1b replicons encoding the NS5B polymerase of genotype 2b, 5a or 6a, ranged from 0.014 to 0.015 μM. The mean EC 50 ( ET) of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67), 0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and 0.085 ± 0.034 μM for genotype 3a (n = 106). In these tests, the in vitro antiviral activity of sofosbuvir with less frequent genotypes 4, 5 and 6 was similar to that observed for genotypes 1, 2 and 3.
The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir.
In cell cultures
Low-sensitivity HCV replicons to sofosbuvir were selected in cell cultures for multiple genotypes, including 1b, 2a, 2b, 3a, 4a, 5a and 6a. The decrease in sofosbuvir sensitivity was associated with S282T primary substitution in NS5B, in all analyzed replicon genotypes. Site-directed mutagenesis of S282T substitution in replicons of 8 genotypes conferred sofosbuvir sensitivity 2-18 fold and reduced viral replication capacity from 89% to 99% relative to the corresponding wild type. In biochemical tests, the recombinant NS5B polymerase of genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced sensitivity to GS-461203 relative to the respective wild types.
In clinical studies
In a cumulative analysis of 991 subjects who received sofosbuvir in phase 3 studies, 226 subjects underwent a resistance analysis because of virologic failure or premature discontinuation of treatment. study and because they had a viral RNA level> 1000 IU / mL. Post-inclusion NS5B sequences were available for 225 of the 226 subjects, with sensitive sequencing (deep-sequencing, 1% test threshold) data for 221 of these subjects. The resistance substitution associated with sofosbuvir, S282T, was not detected in any of these subjects by deep-sequencing or population sequencing. The S282T substitution in NS5B was detected in a single subject receiving Sovaldi Tablets monotherapy in a phase 2 study.
At 4 weeks post-treatment, 99% of his viruses carried the S282T mutation, resulting in a 13.5- fold change in EC 50 and reduced viral replication capacity. In the
After 8 weeks, the S282T substitution disappeared in favor of the wild type and was no longer detectable by deep-sequencing 12 weeks post-treatment.
In the Phase 3 studies, two NS5B, L159F and V321A substitutions were detected in post-treatment relapse samples in many HCV genotype 3 subjects. No change in susceptibility to sofosbuvir or ribavirin Isolates from subjects with these substitutions were detected. In addition, the S282R and L320F substitutions were detected under sensitive sequencing (deep-sequencing) treatment in a transplant-awaiting subject who had a partial response to treatment. The clinical significance of these results is not known.
Effect of initial HCV polymorphisms on treatment response
Inclusion NS5B sequences were obtained for 1,292 subjects in phase 3 studies, by population sequencing, and S282T substitution was not detected in any subjects for whom reference sequences were available. In an analysis evaluating the effect of initial polymorphisms on treatment response, no statistically significant association was found between the presence of an HCV NS5B variant at baseline and response to treatment.
HCV replicons expressing the S282T substitution associated with sofosbuvir resistance were fully sensitive to other classes of anti-HCV agents. Sofosbuvir retained its activity against L159F and L320F substitutions in NS5B, associated with resistance to other nucleoside analogues. Sofosbuvir has been fully active against substitutions associated with
resistance to other direct acting antivirals with different mechanisms of action, such as non-nucleoside NS5B inhibitors, NS3 protease inhibitors and NS5A inhibitors.
Efficacy and clinical safety
The efficacy of sofosbuvir was evaluated in five phase 3 studies in a total of 1,568 HCV genotype 1 to 6 subjects. A study was conducted in treatment-naive patients infected with genotype HCV 1, 4, 5 or 6 in combination with peginterferon alfa 2a and ribavirin, and the other four studies were conducted in HCV-infected subjects with genotype 2 or 3 in combination with ribavirin, including one in naïve subjects any treatment, one in intolerant subjects, ineligible for interferon or refusing interferon, one in subjects who have already been treated with interferon, and one in any type of subjects, regardless of their therapeutic history or their ability to receive interferon treatment. In these studies, subjects had compensated liver disease, including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The dose of ribavirin was based on weight, 1000-1200 mg / day in two divided doses and the dose of peginterferon alfa 2a, if present, was 180 μg weekly. The duration of treatment was fixed in each study and was not guided by the subjects’ HCV plasma RNA levels (no answer-driven algorithm).
Plasma levels of HCV RNA were measured during clinical trials using the COBAS TaqMan VHC Test (version 2.0) for use with the High Pure system. The assay had a lower limit of quantification (LIQ) of 25 IU / mL. Sustained virologic response (SVR) was the primary endpoint for determining the rate of cure for HCV in all studies, defined by an HCV RNA lower than the LIQ 12 weeks after the end of treatment (SVR12).
Clinical Studies in Subjects With Chronic Hepatitis C Genotype 1, 4, 5 or 6 Treatment-naive Subjects – NEUTRINO (Study 110)
NEUTRINO was an open-label, one-arm study evaluating 12-week treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in HCV-infected subjects with genotype 1, 4, 5 or 6, naive any treatment.
[highlight]Sovaldi Tablets Side Effects[/highlight]
In addition to the desired effect, this can cause drug side effects.
Sofosbuvir is always used in combination with other medicines for hepatitis C. As with peginterferon alfa, ribavirin, simeprevir or daclatasvir. The combination usually has more side effects than sofosbuvir alone. Check out the side effects of these drugs on this site.
The most important side effects of sofosbuvir are the following.
Sometimes (from 10 to 30 people in 100)
- Headache , fatigue.
Rarely (from 1 to 10 in 100 people)
- Skin rash . Contact your doctor if you notice this.
Consult your doctor if you suffer too much from one of the above mentioned side effects or if you experience other side effects that you are worried about.
Sovaldi Tablets Interactions
Sofosbuvir is a pro-nucleotide drug. After oral administration of Sovaldi Tablets , sofosbuvir is rapidly absorbed and undergoes significant hepatic first pass and intestinal metabolism. Intracellular hydrolytic cleavage of the pro-drug catalyzed by enzymes such as carboxylesterase 1 and subsequent phosphorylation steps catalyzed by nucleotide kinases lead to the formation of the nucleotide analog of uridine triphosphate, which is pharmacologically active. The principal inactive circulating metabolite, GS-331007, which accounts for more than 90% of systemic exposure to compounds derived from sofosbuvir, is formed by a series of reactions parallel to the formation of the active metabolite. The parent molecule (sofosbuvir) represents about 4% of thePharmacokinetic properties ).
In clinical pharmacology studies, both sofosbuvir and GS-331007 have been analyzed for pharmacokinetics.
Sofosbuvir is a substrate of the P-gp drug carrier and Breast Cancer Resistance Protein (BCRP) , while GS-331007 is not.
Drugs that are potent inducers of P-gp in the gut (rifampicin, rifabutin, St. John’s wort, lacarbamazepine, phenobarbital and phenytoin) can significantly decrease plasma concentrations of sofosbuvir, reducing the therapeutic effect of Sovaldi Tablets and they are therefore contraindicated with Sovaldi Tablets (see Contraindications section). Drugs that are moderate inducers of P-gp in the intestine (such as oxcarbazepine and modafinil) may decrease plasma concentrations of sofosbuvir, reducing the therapeutic effect of Sovaldi Tablets . Co-administration of this type of medication with Sovaldi Tablets is not recommended (see Warnings and precautions for use section).). Co-administration of Sovaldi Tablets with drugs that inhibit P-gp and / or BCRP may increase the plasma concentration of sofosbuvir without increasing that of GS-331007. Therefore, Sovaldi Tablets can be co-administered with inhibitors of P-gp and / or BCRP. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP, and therefore should not increase the exposure to drugs that are substrates of these transporters.
The intracellular metabolic activation of sofosbuvir is mediated by the generally low-affinity, high-capacity nucleotide hydrolase and phosphorylation pathways, over which co-medications are unlikely to have an effect (see
section Pharmacokinetic properties ).
Patients treated with vitamin K antagonists
Because hepatic function may change during treatment with Sovaldi Tablets , close monitoring of International Standard Report (INR) values is recommended.
[highlight]Sovaldi Tablets Warnings and Precautions[/highlight]
Sovaldi Tablets is not recommended as monotherapy and should be prescribed in combination with other drugs for the treatment of HCV infection. In case of definitive discontinuation of other medicinal products used in combination with Sovaldi Tablets , Sovaldi Tablets should also be discontinued (see Dosage and method of administration section). Refer to the Summary of Product Characteristics of Prescribed Drugs in Combination with Sovaldi Tablets before starting Sovaldi Tablets treatment.
Severe Bradycardia and Conduction Disorders
Cases of severe bradycardia and conduction disturbances have been observed with sofosbuvir in combination with another direct-acting antiviral (DAA, including daclatasvir, simeprevir and ledipasvir) when co-administered with amiodarone with or without other medicines that lower the heart rate. The mechanism is not established.
The concomitant use of amiodarone has been limited in the clinical development of sofosbuvir in combination with DAAs. Some cases have been life-threatening. Therefore, amiodarone should be used in patients treated with Sovaldi Tablets and another DAA only in the case of intolerance or contraindication to other anti-arrhythmic therapies. Patients also taking beta-blockers, or with underlying cardiac comorbidities and / or advanced liver disease may be at increased risk of symptomatic bradycardia when co-administered with amiodarone.
If concomitant use of amiodarone is considered necessary, close monitoring of patients should be considered when initiating Sovaldi Tablets therapy in combination with another DAA. Patients identified as being at high risk for bradyarrhythmia should be monitored continuously for 48 hours in a suitable hospital setting.
Given the long half-life of amiodarone, appropriate monitoring should also be performed in patients who have discontinued amiodarone in the last few months and need to start treatment with Sovaldi Tablets in combination with another DAA.
All patients treated with Sovaldi Tablets in combination with another DAA receiving amiodarone with or without other bradycardic medicinal products should also be advised of the symptoms of bradycardia and conduction disturbances, and should be informed of the need to consult a patient. emergency doctor if they experience these symptoms.
Patients with HCV genotype 1, 4, 5 or 6 and previously treated Sovaldi Tablets has not been studied in a phase 3 study in patients with
HCV infection genotype 1, 4, 5 or 6 and previously treated. Therefore, the optimal duration of treatment has not been established in this population (see also section Posology and method of administration and Pharmacodynamic properties ).
An extension of the duration of treatment with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks, and up to 24 weeks, should be considered especially for subgroups that have one or more factor (s) that have already been associated with lower response rates to interferon-based therapies (eg advanced fibrosis / cirrhosis, high initial viral loads, African origin, IL28B non-CC genotype).
Patients with genotype 5 or 6 HCV infection
The clinical data underlying the use of Sovaldi Tablets in patients with genotype 5 or 6 HCV infection are very limited (see section 5.1 ).
Interferon-Free Treatment for HCV Genotype 1, 4, 5 or 6 Infection
Sovaldi Tablets -based therapies without interferon in patients with genotype 1, 4, 5 or 6 HCV infection have not been studied in phase 3 (see section 5.1 ). Optimal treatment and duration of treatment have not been established. This type of treatment should only be used for patients who are intolerant or ineligible for treatment with interferon and who need to be treated urgently.
Co-administration with other anti-HCV antiviral agents
Sovaldi Tablets should be co-administered with other direct-acting antiviral medicines only if it is estimated that, based on available data, the benefit outweighs the risks. There is no evidence to support concomitant use of Sovaldi Tablets with telaprevir or boceprevir. Such co-administration is not recommended (see also section Interactions with other medicinal products and other forms of interaction ).
Concomitant use with ribavirin during pregnancy
When Sovaldi Tablets is used in combination with ribavirin or peginterferon alfa plus ribavirin, women of childbearing potential or their male partner should use an effective method of contraception during treatment and for some time after the end of treatment. as recommended in the Summary of Product Characteristics of Ribavirin. See the Summary of Product Characteristics of Ribavirin for more information.
Use with moderate inducers of P-gp
Medications that are moderate inducers of P-gp in the intestine (such as oxcarbazepine and modafinil) may decrease plasma concentrations of sofosbuvir, reducing the therapeutic effect of Sovaldi Tablets . Co-administration of this type of medication with Sovaldi Tablets is not recommended (see section Interactions with other medicinal products and other forms of interaction ).
The safety of Sovaldi Tablets has not been evaluated in subjects with severe renal impairment (eGFR <30 mL / min / 1.73 m 2 ) or an IRT requiring hemodialysis. In addition, the appropriate dose has not been established. When Sovaldi Tablets is used in combination with ribavirin or peginterferon alfa plus ribavirin, also refer to the Summary of Product Characteristics of Ribavirin for Patients With Crystalline Clearance (CrCl) <50 mL / min (see also section 4.4).
section Pharmacokinetic properties ).
HCV / HBV co-infection (hepatitis B virus)
Cases of hepatitis B virus (HBV) reactivation, some with fatal outcome, have been reported during or after treatment with direct-acting antiviral agents. HBV testing should be performed in all patients prior to initiation of treatment. Patients co-infected with HBV / HCV are at risk for reactivation of HBV and should therefore be monitored and managed according to clinical guidelines.
Sovaldi Tablets is not recommended for use in children and adolescents under 18 years of age as safety and efficacy have not been established in this population.
[highlight]Drive and use machines[/highlight]
Sovaldi Tablets has a moderate influence on the ability to drive and use machines. Patients should be informed that fatigue, attention deficit disorder, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin ( see section 4.8 ).
[highlight]Sovaldi Tablets and Pregnancy / Breastfeeding / Fertility[/highlight]
Women of childbearing age / contraception in men and women
When Sovaldi Tablets is used in combination with ribavirin or peginterferon alfa plus ribavirin, all precautions should be taken to prevent pregnancy in patients and female partners of patients. Significant teratogenic and / or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see sectionWarnings and Precautions section).). Women of childbearing potential and / or their male partner should use an effective method of contraception during treatment and for some time after the end of treatment, as recommended in the Summary of Product Characteristics of Ribavirin. See the Summary of Product Characteristics of Ribavirin for more information.
There are no data or limited data (less than 300 pregnancies) on the use of sofosbuvir in pregnant women.Studies in animals have not shown any direct or indirect harmful effects on reproduction. No effects on fetal development were observed in the rat and rabbit with the highest studied doses. However, it was not possible to fully evaluate margins of exposure with sofosbuvir in rats compared to human exposure at the recommended clinical dose (see section 5.3 ).As a precaution, it is best to avoid the use of Sovaldi Tablets during pregnancy.However, if ribavirin is co-administered with sofosbuvir, contraindications for the use of ribavirin during pregnancy apply (see also Summary of Product Characteristics of Ribavirin).
It is not known whether sofosbuvir and its metabolites are excreted in breast milk.The pharmacokinetic data available in animals have demonstrated the excretion of metabolites in milk (for more details, see Preclinical safety data ).A risk for newborns / infants can not be ruled out. Therefore, Sovaldi Tablets should not be used during breastfeeding.
There are no data on the effect of Sovaldi Tablets on human fertility. Studies in animals have not shown deleterious effects on fertility.
[highlight]What should I do if I miss a dose?[/highlight]
You use this medicine once a day:
Does it take more than 6 hours before you should take the next dose?
- Swallow the forgotten tablet as soon as possible and take the next dose at the usual time.
Does it take less than 6 hours before you should take the next dose?
- Skip the forgotten tablet and take the next dose at the usual time.
[highlight]What happens if I overdose from Sovaldi Tablets ?[/highlight]
The highest documented dose of sofosbuvir was a single supra-therapeutic single dose of 1200 mg sofosbuvir administered to 59 healthy subjects. In this study, no adverse events were observed at this dose and adverse events were similar in frequency and intensity to those reported in the placebo and sofosbuvir 400 mg groups. The effects of higher doses are not known.
There is no specific antidote for overdose of Sovaldi Tablets . If overdose occurs, all symptoms of toxicity will be monitored in the patient. Treatment of Sovaldi Tablets overdose consists of general supportive measures, with monitoring of vital signs and observation of the patient’s clinical condition. Hemodialysis can effectively (53% extraction ratio) eliminate the major circulating metabolite (ie, GS-331007). A 4-hour hemodialysis session eliminated 18% of the administered dose.
[highlight]What is Forms and Composition Sovaldi Tablets ?[/highlight]
400 mg film-coated tablet (20 mm x 9 mm capsule-shaped, imprinted “GSI” on one side and “7977” on the other side, yellow): 28- bottle , with child- resistant closure, with Silicagel as a desiccant and a polyester pad.
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- It treats possible side effects and drug interactions that require attention and its effect on continuous use.
- The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.
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