MyHep

Sofosbuvir

Each film-coated tablet contains 400 mg of sofosbuvir.
Excipients/Inactive Ingredients: Tablet core: Mannitol, Microcrystalline cellulose, Croscarmellose Sodium, Colloidal Silicon Dioxide, Magnesium Stearate. Film-coating: Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc, Iron Oxide Red, Iron Oxide yellow, Ferrosoferric oxide.

Pharmacotherapeutic group: Direct-acting antiviral. ATC code: J05AX15.
Pharmacology: Pharmacodynamics: Mechanism of action: Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC₅₀ ) value ranging from 0.7 to 2.6 µM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Effect of baseline HCV polymorphisms on treatment outcome: Baseline NS5B sequences were obtained for 1,292 subjects from Phase 3 studies by population sequencing and the S282T substitution was not detected in any subject with available baseline sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any HCV NS5B variant at baseline and treatment outcome.
Cross-resistance: HCV replicons expressing the sofosbuvir-associated resistance substitution 5282T were fully susceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.
Pharmacokinetics: Sofosbuvir is a nucleotide prodrug that is extensively metabolised. The active metabolite is formed in hepatocytes and not observed in plasma. The predominant (>90%) metabolite, GS- 331007, is inactive. It is formed through sequential and parallel pathways to the formation of active metabolite.
Absorption: The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Following oral administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed ~0.5-5 hour post-dose, regardless of dose level. Steady-state AUC0-24 for sofosbuvir was 1,053 ng·h/mL.
Effects of food: Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardised high fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was increased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007 was not altered in the presence of a high-fat meal.
Distribution: Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide (OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion, GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3, OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Sofosbuvir is approximately 85% bound to human plasma proteins (ex vivo data) and the binding is independent of drug concentration over the range of 1 µg/mL to 20 µg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [¹⁴C]-sofosbuvir in healthy subjects, the blood to plasma ratio of ¹⁴C-radioactivity was approximately 0.7.
Biotransformation: Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes.
Elimination: Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was approximately 80%, 14%, and 2.5% recovered in urine, faeces, and expired air, respectively. The majority of the sofosbuvir dose recovered in urine was GS-331007. This data indicate that renal clearance is the major elimination pathway for GS-331007 with a large part actively secreted. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 hours.
Linearity/non-linearity: The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.
Pharmacokinetics in special populations: Gender and race: No clinically relevant pharmacokinetic differences due to gender or race have been identified for sofosbuvir and GS-331007.
Elderly: Population pharmacokinetic analysis in HCV infected subjects showed that within the age range (19 to 75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. Clinical studies of sofosbuvir included 65 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups.
Renal Impairment: The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥50 and <80 mL/min/1.73 m²), moderate (eGFR ≥30 and <50 mL/min/1.73 m²), severe renal impairment (eGFR <30 mL/min/1.73 m²) and subjects with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73 m²), the sofosbuvir AUC_0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC_0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir AUC_0-inf was 28% higher when sofosbuvir was dosed 1 hour before haemodialysis compared with 60% higher when sofosbuvir was dosed 1 hour after haemodialysis. The AUC_0-inf of GS-331007 in subjects with ESRD could not be reliably determined. However, data indicate at least 10-fold and 20-fold higher exposure to GS-331007 in ESRD compared to normal subjects when Sofosbuvir 400 mg film-coated tablets was administered 1 hour before or 1 hour after haemodialysis, respectively.
Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety of Sofosbuvir 400 mg film-coated tablets has not been assessed in patients with severe renal impairment or ESRD (see Precautions).
Hepatic impairment: The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV infected subjects with moderate and severe hepatic impairment (CPT class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC_0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC_0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment (see Dosage & Administration).
Paediatric population: The pharmacokinetics of sofosbuvir and GS-331007 in paediatric subjects have not been established (see Dosage & Administration).
Pharmacokinetic/pharmacodynamic relationship(s): Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir as well as GS 331007. However, neither of these entities has been evidenced to be a general surrogate marker for efficacy (SVR12) at the therapeutic 400 mg dose.
Toxicology: Preclinical safety data: In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 30 times (mouse) and 15 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behavior, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 9 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite ranged from 8 to 28 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.

Sofosbuvir is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a combination with Ribavirin or in combination with Pegylated interferon and Ribavirin.
Sofosbuvir efficacy has been established in patients with HCV genotype 1 (naive), genotype 2 or 3 infection including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection.
The following points should be considered when initiating treatment with Sofosbuvir: Monotherapy of Sofosbuvir is not recommended for treatment of CHC; Treatment regimen and duration are dependent on both viral genotype and patient population; Treatment response varies based on baseline host and viral factors.

Sofosbuvir 400 mg film-coated tablets treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
The recommended dose is one 400 mg tablet, taken orally, once daily with or without food. Sofosbuvir should be used in combination with other medicinal products. Monotherapy of Sofosbuvir is not recommended. The recommended regimen and treatment duration for Sofosbuvir combination therapy are provided in Table 1. (See Table 1.)


Click on icon to see table/diagram/image


Patients with Genotype 1 HCV Who are Ineligible to Receive an Interferon-Based Regimen: Sofosbuvir in combination with ribavirin for 24 weeks can be considered as a therapeutic option for patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.
Dose modification: Dose reduction of Sofosbuvir 400 mg film-coated tablets is not recommended.
If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse reaction potentially related to this drug, the peginterferon alfa dose should be reduced or discontinued. Refer to the peginterferon alfa Summary of Product Characteristics for additional information about how to reduce and/or discontinue the peginterferon alfa dose.
If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status. (See Table 2.)


Click on icon to see table/diagram/image


Once ribavirin has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin be increased to the original assigned dose (1,000 mg to 1,200 mg daily).
Discontinuation of dosing: If the other medicinal products used in combination with Sofosbuvir 400 mg film-coated tablets are permanently discontinued, Sofosbuvir 400 mg film-coated tablets should also be discontinued (see Precautions).
Special population: No dose adjustment is warranted for elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment of Sofosbuvir 400 mg film-coated tablets is required for patients with mild or moderate renal impairment. The safety and appropriate dose of Sofosbuvir 400 mg film­-coated tablets have not been established in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) or end stage renal disease (ESRD) requiring haemodialysis.
Hepatic impairment: No dose adjustment of Sofosbuvir 400 mg film-coated tablets is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class. A, B or C). The safety and efficacy of Sofosbuvir 400 mg film-coated tablets have not been established in patients with decompensated cirrhosis.
Patients awaiting liver transplantation: The duration of administration of Sofosbuvir 400 mg film-coated tablets in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient (see Pharmacology: Pharmacodynamics under Actions).
Paediatric population: The safety and efficacy of Sofosbuvir 400 mg film-coated tablets in children and adolescents aged <18 years have not yet been established. No data are available.
Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation: Administer Sofosbuvir in combination with ribavirin for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection.
Method of administration: The film-coated tablet is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed, due to the bitter taste of the active substance. The tablet should be taken with food (see Pharmacology: Pharmacokinetics under Actions).
Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional tablet should be taken. If vomiting occurs more than 2 hours after dosing, no further dose is needed. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007 suggesting that the majority of the dose is absorbed within 2 hours after dosing.
If a dose is missed and it is within 18 hours of the normal time, patients should be instructed to take the tablet as soon as possible and then patients should take the next dose at the usual time. If it is after 18 hours then patients should be instructed to wait and take the next dose at the usual time. Patients should be instructed not to take a double dose.

The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.
No specific antidote is available for overdose with Sofosbuvir. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sofosbuvir consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed 18% of the administered dose.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
When Sofosbuvir is used in combination with ribavirin or peg-interferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peg-interferon alfa and ribavirin for list of their contraindications.

General: Sofosbuvir is not recommended for administration as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C infection. If the other medicinal products used in combination with Sofosbuvir are permanently discontinued, Sofosbuvir should also be discontinued (see Dosage & Administration). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sofosbuvir.
Severe bradycardia and heart block: Cases of severe bradycardia and heart block have been observed when Sofosbuvir is used in combination with Daclatasvir and concomitant amiodarone with or without other drugs that lower heart rate. The mechanism is not established.
The concomitant use of amiodarone was limited through the clinical development of sofosbuvir plus direct-acting antivirals (DAAs). Cases are potentially life threatening, therefore amiodarone should only be used in patients on Sofosbuvir + Daclatasvir when other alternative anti­ arrhythmic treatments are not tolerated or are contraindicated.
Should concomitant use of amiodarone be considered necessary it is recommended that patients are closely monitored when initiating Sofosbuvir + Daclatasvir. Patients who are identified as being high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting.
Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on Sofosbuvir in combination with Daclatasvir.
All patients receiving Sofosbuvir + Daclatasvir in combination with amiodarone with or without other drugs that lower heart rate should also be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
Treatment-experienced patients with genotype 1 HCV Infection: Sofosbuvir has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1 HCV infection. Thus, the optimal treatment duration in this population has not been established.
Co-administration with other direct-acting antivirals against HCV: Sofosbuvir should only be co-administered with other direct-acting antiviral medicinal products if the benefit is considered to outweigh the risks based upon available data. There are no data to support the co-administration of Sofosbuvir and telaprevir or boceprevir. Such co-administration is not recommended (see also Interactions).
Risks associated with Combination Treatment: Because sofosbuvir is used in combination with other antiviral drugs for treatment of HCV infection, consult the prescribing information for these drugs used in combination with sofosbuvir. Warnings and Precautions related to these drugs also apply to their use in sofosbuvir combination treatment.
Pregnancy and concomitant use with ribavirin: When Sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.  
Use with moderate P-gp inducers: Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine and modafinil) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofosbuvir. Co-administration of such medicinal products is not recommended with Sofosbuvir (see Interactions).
Renal impairment: The safety of Sofosbuvir has not been assessed in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m²) or ESRD requiring haemodialysis. Furthermore, the appropriate dose has not been established. When Sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, refer also to the Summary of Product Characteristics for ribavirin for patients with creatinine clearance (CrCI) <50 mL/min (see also Pharmacology: Pharmacokinetics under Actions).
HCV/HBV (hepatitis B virus) co-infection: There are no data on the use of Sofosbuvir in patients with HCV/HBV co-infection.
Effects on ability to drive and use machines: Sofosbuvir has moderate influence on the ability to drive and use machines. Patients should be informed that fatigue and disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see Adverse Reactions).
Paediatric population: Sofosbuvir is not recommended for use in children and adolescents under 18 years of age because the safety and efficacy have not been established in this population.

Women of childbearing potential/contraception in males and females: When Sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see Precautions). Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
Pregnancy: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see Pharmacology: Toxicology: Preclinical safety data under Actions).
As a precautionary measure, it is preferable to avoid the use of Sofosbuvir during pregnancy.
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin).
Breast-feeding: It is unknown whether sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals has shown excretion of metabolites in milk (for details see Pharmacology: Toxicology: Preclinical safety data under Actions).
A risk to newborns/infants cannot be excluded. Therefore, Sofosbuvir should not be used during breast-feeding.
Fertility: No human data on the effect of Sofosbuvir on fertility are available. Animal studies do not indicate harmful effects on fertility.

Summary of the safety profile: During treatment with sofosbuvir in combination with ribavirin or with peginterferon alfa and ribavirin, the most frequently reported adverse drug reactions were consistent with the expected safety profile of ribavirin and peginterferon alfa treatment, without increasing the frequency or severity of the expected adverse drug reactions.
Tabulated summary of adverse reactions: Sofosbuvir has mainly been studied in combination with ribavirin, with or without peginterferon alfa. In this context, no adverse drug reactions specific to sofosbuvir have been identified. The most common adverse drug reactions occurring in subjects receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.
The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (see Table 3). The adverse reactions are listed by body system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to  <1/1,000) or very rare (<1/10,000).


Click on icon to see table/diagram/image


Other special population(s): HIV/HCV co-infection: The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected subjects was similar to that observed in mono-infected HCV subjects treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see Pharmacology: Pharmacodynamics under Actions).
Patients awaiting liver transplantation: The safety profile of sofosbuvir and ribavirin in HCV infected subjects prior to liver transplantation was similar to that observed in subjects treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see Pharmacology: Pharmacodynamics under Actions).
Description of selected adverse reactions: Cardiac arrhythmias: Cases of severe bradycardia and heart block have been observed when Sofosbuvir is used in combination with Daclatasvir and concomitant amiodarone and/or other drugs that lower heart rate (see Precautions and Interactions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Sofosbuvir is a nucleotide prodrug. After oral administration of Sofosbuvir, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see Pharmacology: Pharmacokinetics under Actions). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not.
Medicinal products that are potent P-gp inducers in the intestine (rifampicin, rifabutin, St. John's wort, carbamazepine, phenobarbital and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofosbuvir and thus are contraindicated with Sofosbuvir (see Contraindications). Medicinal products that are moderate P-gp inducers in the intestine (e.g. oxcarbazepine and modafinil) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofosbuvir. Co-administration with such medicinal products is not recommended with Sofosbuvir (see Precautions). Co-administration of Sofosbuvir with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sofosbuvir may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see Pharmacology: Pharmacokinetics under Actions).
Other interactions: Drug interaction information for Sofosbuvir with potential concomitant medicinal products is summarised in Table 4 (where 90% confidence interval (Cl) of the geometric least-squares mean (GLSM) ratio were within "↔", extended above "↑", or extended below "↓" the predetermined equivalence boundaries). The table is not all-inclusive. (See Table 4.)


Click on icon to see table/diagram/image




Click on icon to see table/diagram/image




Click on icon to see table/diagram/image

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

Do not store above 30°C. Store in the original container.
Shelf-life: 24 Months.

Antivirals

J05AP08 - sofosbuvir ; Belongs to the class of antivirals for treatment of HCV infections. Used in the treatment of hepatitis C viral infections.

G