Active ingredients: Sofosbuvir
Sovaldi 400 mg film-coated tablets
Why is Sovaldi used? What is it for?
Sovaldi contains the active substance sofosbuvir, which is given to treat hepatitis C virus infection in adults aged 18 years and over.
Hepatitis C is a liver infection caused by a virus. This medicine works by lowering the amount of hepatitis C virus in the body and clearing the virus from the blood after a certain period of time.
Sovaldi must always be taken with other medicines, as it alone has no effect.
It is usually taken with:
- ribavirin, or
- peginterferon alfa and ribavirin
It is very important that you also read the package leaflets of the other medicines you will take together with Sovaldi.
If you have any questions about your medicines, ask your doctor or pharmacist.
Contraindications When Sovaldi should not be used
Do not take Sovaldi
- if you are allergic to sofosbuvir or any of the other ingredients of this medicine
- If this applies to you, tell your doctor immediately.
Precautions for use What you need to know before taking Sovaldi
Sovaldi must always be taken with other medicines (see section 1 above). Talk to your doctor or pharmacist before taking this medicine if:
- have liver problems other than hepatitis C, for example if you are awaiting a liver transplant
- you have hepatitis B, as your doctor may want to monitor you more closely
- have kidney problems. Talk to your doctor or pharmacist if you have severe kidney problems or if you are undergoing kidney dialysis, because the effects of Sovaldi in patients with severe kidney problems have not been fully studied.
Blood analysis
Your doctor will carry out certain blood tests before, during and after treatment with Sovaldi. In this way the doctor can:
- decide which other medicines you should take with Sovaldi and for how long;
- confirm that the treatment was effective and you no longer have the hepatitis C virus.
Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age. The use of Sovaldi in children and adolescents has not yet been studied.
Interactions Which drugs or foods can modify the Sovaldi effect
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including herbal medicines and medicines obtained without a prescription.
In particular, do not take Sovaldi if you are taking any of the following medicines:
- rifampicin (antibiotic used to treat infections such as tuberculosis);
- St. John's Wort (Hypericum perforatum, a herbal medicine used to treat depression);
- carbamazepine and phenytoin (medicines used to treat epilepsy and prevent seizures) as these medicines may reduce the effectiveness of Sovaldi.
If you have any further questions, ask your doctor or pharmacist.
Warnings It is important to know that:
Pregnancy and contraception
Pregnancy should be avoided due to the use of Sovaldi together with ribavirin. Ribavirin can be very harmful to an unborn baby. You and your partner must take special precautions in sexual activity if there is any possibility of pregnancy.
- Sovaldi is normally used with ribavirin. Ribavirin can harm an unborn baby. It is therefore very important that you (or your partner) avoid becoming pregnant during treatment.
- You or your partner must use effective contraception during and after treatment. It is very important that you read the "Pregnancy" section of the ribavirin package leaflet very carefully. Ask your doctor which effective method of contraception is suitable for you.
- If you or your partner become pregnant during treatment with Sovaldi or in the months following, you should contact your doctor immediately.
Feeding time
You should not breast-feed while being treated with Sovaldi. It is not known whether sofosbuvir, the active substance in Sovaldi, passes into breast milk.
Driving and using machines
While taking Sovaldi together with other medicines to treat hepatitis C infection, patients experienced tiredness, dizziness, blurred vision and reduced attention. If you get any of these side effects, do not drive or use any tools or machines.
Dose, Method and Time of Administration How to use Sovaldi: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Recommended dose
The recommended dose is one tablet once a day, with food. Your doctor will tell you how long to take Sovaldi.
Swallow the tablet whole, without chewing, breaking or crushing it as it tastes very bitter. Tell your doctor or pharmacist if you have difficulty swallowing tablets.
Sovaldi must always be taken together with other medicines used to treat hepatitis C.
If you vomit within 2 hours of taking Sovaldi, take another tablet. If you vomit after 2 hours of taking, you should not take another tablet until your next dose at the appointed time.
Overdose What to do if you have taken too much Sovaldi
If you take more Sovaldi than you should
If you accidentally take more than the recommended dose, consult your doctor or the nearest emergency department immediately. Take the bottle containing the tablets with you so that you can easily explain what you have taken.
If you forget to take Sovaldi
It is important not to forget any dose of this medicine.
If you miss a dose:
- and if you notice within 18 hours of the time you usually take Sovaldi, you must take the tablet as soon as possible. Then take your next dose at the usual time.
- and if you notice 18 or more hours after the time you usually take Sovaldi, wait and take your next dose at the usual time. Do not take a double dose (two doses in close proximity to each other).
Do not stop taking Sovaldi
Do not stop taking this medicine unless your doctor tells you to. It is very important to complete the entire treatment to give the medicines a chance to fight the hepatitis C virus infection.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Sovaldi
Like all medicines, this medicine can cause side effects, although not everybody gets them. When taking Sovaldi with ribavirin or peginterferon alfa and ribavirin you may experience one or more of the following side effects:
Very common side effects
(may affect more than 1 in 10 people)
- fever, chills, flu-like symptoms
- diarrhea, nausea, vomiting
- difficulty sleeping (insomnia)
- feeling tired and irritated
- headache
- rash, itching
- loss of appetite
- feeling dizzy
- muscle aches and pains, joint pain
- breathlessness, cough Blood tests may show:
- a low red blood cell count (anemia); the signs may include feeling tired, headache, shortness of breath during physical exertion
- a low white blood cell count (neutropenia); The signs may include more infections with fever and chills or sore throat or mouth ulcers
- a low platelet count
- liver changes (shown by higher amounts of a substance called bilirubin in the blood)
Common side effects
(may affect up to 1 in 10 people)
- mood changes, depressed mood, feeling anxious and feeling agitated
- blurred vision
- severe headache (migraine), memory loss, loss of concentration
- weight loss
- shortness of breath during physical exertion
- stomach pain, constipation, dry mouth, indigestion, acid reflux
- hair loss and hair thinning
- dry skin
- back pain, muscle spasms
- chest pain, feeling of weakness
- cold (nasopharyngitis)
- If any of the side effects get serious, tell your doctor.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Sovaldi contains
- The active ingredient is sofosbuvir. Each film-coated tablet contains 400 mg of sofosbuvir.
- The other components are
- Core of the tablet: mannitol, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate.
- Coating film: polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, yellow iron oxide.
Description of Sovaldi's appearance and contents of the pack
The film-coated tablets are yellow, capsule-shaped tablets debossed with "GSI" on one side and "7977" on the other.
Each bottle contains the silica gel drying agent, which must remain in the bottle to protect the tablets. The silica gel drying agent is contained in a sachet or separate container and should not be swallowed.
The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets and 84 (3 bottles of 28) film-coated tablets. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SOVALDI 400 MG TABLETS COATED WITH FILM
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 400 mg of sofosbuvir.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Capsule-shaped, yellow film-coated tablet, 20 mm x 9 mm in size, debossed with "GSI" on one side and "7977" on the other side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Sovaldi is indicated in combination with other medicines for the treatment of chronic hepatitis C (chronic hepatitis C, CHC) in adults (see sections 4.2, 4.4 and 5.1).
For specific activity for the hepatitis C virus (HCV) genotype, see sections 4.4 and 5.1.
04.2 Posology and method of administration
Sovaldi treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
Dosage
The recommended dose is one 400 mg tablet orally once daily to be taken with food (see section 5.2).
Sovaldi must be used in combination with other medicines. Sovaldi monotherapy is not recommended (see section 5.1). Please also refer to the Summary of Product Characteristics for medicinal products used in combination with Sovaldi. The recommended medicinal product (s) to be administered together with Sovaldi and the duration of treatment for the combination therapy are shown in Table 1.
Table 1: Recommended medicinal product (s) to be administered together with Sovaldi and duration of treatment for the combination therapy
* Includes patients co-infected with human immunodeficiency virus (HIV).
a For previously treated genotype 1 HCV infected patients, there are no data on the combination of Sovaldi, ribavirin and peginterferon alfa (see section 4.4).
b Consideration should be given to extending the duration of therapy beyond 12 weeks and up to 24 weeks, especially for subgroups with one or more factors historically associated with low response rates to interferon-based therapies (e.g. advanced fibrosis / cirrhosis, elevated basal viral concentrations, black ethnicity, non-CC IL28B genotype, prior lack of response to peginterferon alfa and ribavirin therapy).
c See Special Patient Populations: Patients awaiting liver transplantation.
The dose of ribavirin, used in combination with Sovaldi, is based on body weight (orally, divided into two doses, with food.
For concomitant administration with other HCV direct acting antivirals, see section 4.4.
Dose modifications
No dose reduction of Sovaldi is recommended.
If sofosbuvir is used in combination with peginterferon alfa and a patient experiences a serious adverse reaction potentially related to this drug, the dose of peginterferon alfa should be reduced or administration discontinued. For further information on dose reduction and / or discontinuation of peginterferon alfa administration please refer to the Summary of Product Characteristics for peginterferon alfa.
If a patient experiences a serious adverse reaction potentially related to ribavirin, the dose of ribavirin should be changed or administration discontinued, if necessary, until the adverse reaction has resolved or is less severe. Table 2 provides advice on dose modifications and dose interruptions based on the patient's hemoglobin concentration and cardiac function.
Table 2: Advice on dose modifications of ribavirin when administered in combination with Sovaldi
Once ribavirin has been discontinued due to a laboratory abnormality or clinical manifestation, an attempt may be made to resume ribavirin at 600 mg per day and then to increase the dose to 800 mg per day. however, it is recommended that the ribavirin dose be increased to its original value (1,000 mg-1,200 mg per day).
Discontinuation of administration
If treatment with other medicinal products used in combination with Sovaldi is permanently discontinued, the administration of Sovaldi must also be discontinued (see section 4.4).
Special patient populations
Senior citizens
Dose adjustment in elderly patients is not warranted (see section 5.2).
Renal impairment
No dose adjustment is required for Sovaldi in patients with mild or moderate renal impairment. The safety and appropriate dose of Sovaldi have not been established in patients with severe renal impairment (estimated glomerular filtration rate [estimated glomerular filtration rate, eGFR] 2) or end-stage renal disease (end stage renal disease, ESRD) requiring hemodialysis (see section 5.2).
Hepatic impairment
In patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) no dose adjustment is required for Sovaldi (see section 5.2). The safety and efficacy of Sovaldi in patients with decompensated cirrhosis have not been established.
Patients awaiting liver transplant
The duration of Sovaldi administration in patients awaiting liver transplantation should be determined based on an assessment of the potential benefits and risks for the individual patient (see section 5.1).
Liver transplant recipients
Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. A starting dose of ribavirin of 400 mg administered orally, divided into two doses, with food is recommended. If the starting dose of ribavirin is well tolerated, the dose can be gradually increased to a maximum of 1,000-1,200 mg per day (1,000 mg for patients weighing less than 75 kg and 1,200 mg for patients weighing less than 75 kg and 1,200 mg for patients weighing less than 75 kg). to 75 kg). If the starting dose of ribavirin is not well tolerated, the dose should be reduced as clinically indicated based on hemoglobin levels (see section 5.1).
Pediatric population
The safety and efficacy of Sovaldi in children and adolescents aged less than 18 years have not yet been established. There are no data available.
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, as the active ingredient has a bitter taste. The tablet should be taken with food (see section 5.2).
Patients should be advised that if they vomit within 2 hours of taking a new tablet. If they vomit more than 2 hours after taking no additional dose is required. These recommendations are based on the absorption kinetics of sofosbuvir and GS-331007, which suggests that the majority of the dose is absorbed within 2 hours of dosing.
If a dose is missed and this occurs within 18 hours of the normal intake time, patients should be advised to take the tablet as soon as possible; the next dose should then be taken at the usual time. If this occurs after more than 18 hours, patients should be advised to wait and take the next dose at the usual time. Patients should be advised not to take a double dose.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
General warnings
Sovaldi is not indicated as monotherapy and should be prescribed in combination with other medicinal products for the treatment of hepatitis C virus infection. If treatment with other medicinal products used in combination with Sovaldi is permanently discontinued, the administration of Sovaldi should also be interrupted (see section 4.2). Consult the Summary of Product Characteristics of the jointly prescribed medicinal products before initiating therapy with Sovaldi.
Severe bradycardia and heart block
Cases of severe bradycardia and heart block have been observed when Sovaldi is used in combination with Daklinza and amiodarone concomitantly, with or without other heart rate lowering drugs. The mechanism has not been established.
Concomitant use of amiodarone has been limited by the clinical development of sofosbuvir plus direct acting antivirals (DAA). Cases can be fatal, therefore in patients treated with Sovaldi + Daklinza amiodarone should only be used when alternative antiarrhythmic therapies are not available. tolerated or contraindicated.
If concomitant use of amiodarone is considered necessary, it is recommended that patients be carefully monitored upon initiation of Sovaldi + Daklinza therapy. Patients identified as being at high risk for bradyarrhythmia should be monitored continuously for 48 hours in an appropriate clinical setting.
Due to the long half-life of amiodarone, adequate monitoring should also be envisaged for patients who have discontinued amiodarone treatment in the past few months and should start treatment with Sovaldi in combination with Daklinza.
All patients treated with Sovaldi + Daklinza in combination with amiodarone, with or without other drugs that reduce heart rate, should also be warned of symptoms of bradycardia and heart block and advised to seek urgent medical attention if they appear.
Previously treated patients with genotype 1, 4, 5 and 6 HCV infection
Sovaldi has not been studied in a phase 3 study in previously treated patients with genotype 1, 4, 5 and 6 HCV infection. The optimal duration of treatment in this population has therefore not been established (see also sections 4.2 and 5.1). .
Consideration should be given to treating these patients and extending the duration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks, especially for subgroups with one or more factors historically associated with low rates of response to interferon-based therapies (advanced fibrosis / cirrhosis, elevated basal viral concentrations, black ethnicity, non-CC IL28B genotype).
Treatment of patients with genotype 5 or 6 HCV infection
Clinical data to support the use of Sovaldi in patients with genotype 5 and 6 HCV infection are very limited (see section 5.1).
Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection
Interferon-free Sovaldi regimens for genotype 1, 4, 5 and 6 HCV infected patients have not been evaluated in phase 3 studies (see section 5.1). The optimal regimen and duration of treatment have not been established. These regimens should only be used for patients who are intolerant or ineligible for interferon therapy and who need to be treated urgently.
Administration in combination with other antivirals with direct action against HCV
Sovaldi should only be given in combination with other direct acting antiviral medicinal products if the benefits are considered to outweigh the risks based on the available data. There are no data to support the administration of Sovaldi in combination with telaprevir or boceprevir. Such co-administration is not recommended (see also section 4.5).
Pregnancy and concomitant use of ribavirin
When Sovaldi is used in combination with ribavirin or peginterferon alfa / ribavirin, women of childbearing potential or their male partners should use effective contraception during treatment and for the post-treatment period recommended in the Summary of Product Characteristics of ribavirin. . See the Summary of Product Characteristics for ribavirin for further information.
Use with powerful P-gp inductors
Medicines that are potent inducers of P-glycoprotein (P-gp) in the intestine (eg rifampicin, St. John's wort [Hypericum perforatum], carbamazepine and phenytoin) can significantly reduce the plasma concentration of sofosbuvir, resulting in a reduced therapeutic effect of Sovaldi. These medicinal products must not be used with Sovaldi (see section 4.5).
Renal impairment
The safety of Sovaldi has not been established in subjects with severe renal impairment (eGFR 2) or ESRD requiring hemodialysis. The appropriate dose has also not been established. When Sovaldi is used in combination with ribavirin or peginterferon alfa / ribavirin, refer also to the Summary of Product Characteristics of ribavirin for patients with creatinine clearance (CrCl)
HCV / HBV (hepatitis B virus) co-infection
There are no data on the use of Sovaldi in HCV / HBV co-infected patients.
Pediatric population
Sovaldi is not recommended for use in children and adolescents below 18 years of age because safety and efficacy have not been established in this population.
04.5 Interactions with other medicinal products and other forms of interaction
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and undergoes extensive hepatic first pass metabolism and extensive intestinal metabolism. The intracellular hydrolytic cleavage of the prodrug catalyzed by enzymes such as carboxylesterase 1 and the sequential steps of phosphorylation catalyzed by nucleotide kinases result in the formation of the triphosphate analogue of the nucleoside uridine, which is pharmacologically active. The main circulating inactive metabolite, GS-331007, responsible for over 90% of the systemic exposure to the drug is formed through sequential and parallel pathways to the formation of the active metabolite. The parent molecule sofosbuvir accounts for approximately 4% of systemic drug exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for pharmacokinetic analysis.
Sofosbuvir is a substrate of the drug transporter P-gp and breast cancer resistance protein (breast cancer resistance protein, BCRP), as opposed to GS-331007. Medicinal products that are potent inducers of P-gp in the intestine (eg rifampicin, St. John's wort, carbamazepine and phenytoin) may reduce the plasma concentration of sofosbuvir, resulting in a reduced therapeutic effect of Sovaldi, and therefore should not be used with Sovaldi ( see section 4.4) Administration of Sovaldi in combination with medicinal products that inhibit P-gp and / or BCRP may increase the plasma concentration of sofosbuvir without increasing the plasma concentration of GS-331007; therefore, Sovaldi can be administered in combination with inhibitors of P-gp and / or BCRP. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and therefore an increase in exposure to drugs that are substrates of these transporters is not expected.
Intracellular metabolic activation of sofosbuvir is mediated by hydrolase and nucleotide phosphorylation pathways, which generally have low affinity and high capacity, for which influence by co-administered medicinal products is unlikely (see section 5.2).
Other interactions
The drug interactions of Sovaldi with medicinal products that can be co-administered are summarized in Table 3 (where the confidence interval (confidence interval, CI) at 90% of the ratio of the geometric mean of the least squares (geometric least-squares mean, GLSM) remained within "↔" or was above "↑" or below "↓" of the established equivalence limits). The table is not exhaustive.
Table 3: Interactions between Sovaldi and other medicinal products
NA = not available / not relevant
a Mean ratio (90% CI) of drug pharmacokinetics administered with / without sofosbuvir and mean ratio of sofosbuvir and GS-331007 with / without a co-administered drug. No effect = 1.00
b All interaction studies were conducted in healthy volunteers
c Comparison based on historical control
d Administered as Atripla
e Bioequivalence limit 80% -125%
f Equivalence limit 70% -143%
Medicinal products that are potent inducers of P-gp in the intestine (rifampicin, St. John's wort, carbamazepine and phenytoin) can significantly reduce the plasma concentration of sofosbuvir, resulting in a reduced therapeutic effect. For this reason, sofosbuvir should not be co-administered with known inducers. of the P-gp.
04.6 Pregnancy and lactation
Women of childbearing age / contraception in men and women
When Sovaldi is used in combination with ribavirin or peginterferon alfa / ribavirin, extreme caution should be used to avoid pregnancy in female patients and in the partners of male patients. Significant teratogenic and / or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see section 4.4). Women of childbearing potential or their male partners should use effective contraception during treatment and for the post-treatment period as recommended in the Summary of Product Characteristics for ribavirin. See the Summary of Product Characteristics for ribavirin for further information.
Pregnancy
Data from the use of sofosbuvir in pregnant women do not exist or are limited (less than 300 exposed pregnancies).
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on fetal development were observed in rats and rabbits at the highest doses tested. However, it was not possible to accurately estimate the exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).
As a precaution, it is preferable to avoid the use of Sovaldi during pregnancy.
However, when using ribavirin in combination with sofosbuvir, the contraindications related to the use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin).
Feeding time
It is unknown whether sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals have shown excretion of the metabolites in milk (for details see section 5.3).
A risk to the newborns / infants cannot be excluded. Therefore, Sovaldi should not be used during breastfeeding.
Fertility
There are no data on the effect of Sovaldi on fertility in humans. Animal studies do not indicate harmful effects on fertility.
04.7 Effects on ability to drive and use machines
Sovaldi moderately affects the ability to drive or use machines. Patients should be informed that fatigue, disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8).
04.8 Undesirable effects
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 for treatment with ribavirin and peginterferon alfa, without the frequency or severity of the reactions adverse drug reactions were increased.
Assessment of adverse reactions is based on pooled data from five phase 3 clinical trials (both controlled and uncontrolled).
The percentage of subjects who permanently discontinued treatment due to adverse reactions was 1.4% for subjects who received a placebo, 0.5% for subjects who received sofosbuvir + ribavirin for 12 weeks, 0% for subjects who received sofosbuvir + ribavirin for 16 weeks, 11.1% for subjects who received peginterferon alfa + ribavirin for 24 weeks and 2.4% for subjects who received sofosbuvir + peginterferon alfa + ribavirin for 12 weeks .
Table of adverse reactions
Sovaldi has mainly been studied in combination with ribavirin, with or without peginterferon alfa. No specific adverse drug reactions for sofosbuvir were found in this context. The most frequently reported adverse drug reactions in subjects receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa are fatigue, headache, nausea and insomnia.
The following adverse drug reactions have been reported with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 4). Adverse reactions are listed below by system organ and by frequency. Frequencies are defined as follows: very common (≥1 / 10), common (≥1 / 100,
Table 4: Adverse drug reactions reported with sofosbuvir in combination with ribavirin or with peginterferon alfa and ribavirin.
a SOF = sofosbuvir;
b RBV = ribavirin;
c PEG = peginterferon alfa
Other particular 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 HCV monoinfected subjects treated with sofosbuvir and ribavirin in phase 3 clinical studies (see section 5.1).
Patients awaiting liver transplant
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 section 5.1).
Liver transplant recipients
The safety profile of sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C was similar to that observed in subjects treated with sofosbuvir and ribavirin in phase 3 clinical studies (see section 5.1). In study 0126, reduction in hemoglobin during treatment was very common, with 32.5% of subjects (13/40) having decreased hemoglobin to epoetin and / or a blood product. In 5 subjects (12.5%), study drugs were withheld, changed, or discontinued due to adverse events.
Description of selected adverse reactions
Cardiac arrhythmias
Cases of severe bradycardia and heart block have been observed when Sovaldi is used in combination with Daklinza and concomitantly with amiodarone and / or other drugs that reduce heart rate (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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:
Italian Medicines Agency website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
04.9 Overdose
The highest documented dose of sofosbuvir was a single supratherapeutic dose of 1,200 mg administered to 59 healthy subjects. No adverse effects were observed at this dose level in this study 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 not known.
There is no specific antidote for Sovaldi overdose. In the event of an overdose, the patient should be monitored for signs of toxicity. Treatment of Sovaldi overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical condition. The major circulating metabolite GS-331007 can be successfully removed (53% extraction rate) by hemodialysis. A 4-hour hemodialysis removed 18% of the administered dose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: direct acting antivirals.
ATC code: J05AX15.
Mechanism of action
Sofosbuvir is a pan-genotypic inhibitor of HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug subject to intracellular metabolism, giving rise to the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by NS5B polymerase and act as a chain terminator. In a biochemical test, GS-461203 inhibited the polymerase activity of recombinant NS5B of HCV genotypes 1b, 2a, 3a and 4a with an inhibitory concentration value of 50% (inhibitory concentration, IC50) between 0.7 and 2.6 mcM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases, nor an inhibitor of mitochondrial RNA polymerase.
Antiviral activity
In tests conducted with HCV replicons, the effective concentration values (effective concentration, EC50) of sofosbuvir against whole replicons of genotypes 1a, 1b, 2a, 3a and 4a were respectively 0.04, 0.11, 0.05, 0.05 and 0.04 mcM and the EC50 values of sofosbuvir against chimeric replicons 1b encoding NS5B genotypes 2b, 5a or 6a ranged from 0.014 to 0.015 mcM. Sofosbuvir mean ± SD EC50 against chimeric replicons encoding NS5B sequences of clinical isolates was 0.068 ± 0.024 mcM for genotype 1a (n = 67), 0.11 ± 0.029 mcM for genotype 1b (n = 29), 0.035 ± 0.018 mcM for genotype 2 (n = 15) and 0.085 ± 0.034 mcM for genotype 3a (n = 106). In these tests, antiviral activity in vitro sofosbuvir against less common 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.
Resistence
In cell cultures
HCV replicons with reduced susceptibility to sofosbuvir were selected in cell cultures for several genotypes, including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with primary NS5B substitution S282T in all replicon genotypes tested. Site-specific mutagenesis of S282T substitution in replicons of 8 genotypes conferred a 2-18 fold reduced susceptibility to sofosbuvir and resulted in a reduced viral replication capacity by 89-99% compared to wild-type corresponding. In biochemical analyzes, recombinant NS5B polymerase of genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to wild-type correspondents.
In clinical trials
In a pooled analysis of 991 subjects who received sofosbuvir in phase 3 studies, 226 subjects were eligible for resistance analysis due to virologic failure or early discontinuation of the investigational drug and because they had HCV levels. RNA> 1,000 IU / mL. Post-baseline NS5B sequences were available for 225 of the 226 subjects, and massive sequencing data were obtained for 221 of these subjects (deep sequencing) (test cutoff value of 1%). S282T substitution associated with resistance to sofosbuvir was not detected in any of these subjects by massive sequencing or population sequencing. NS5B S282T substitution was detected in only one subject receiving Sovaldi as monotherapy in a phase 2 study. This subject had less than 1% HCV S282T at baseline and developed S282T replacement (> 99%) 4 weeks after treatment, resulting in a 13.5-fold change of the EC50 value of sofosbuvir and reduction of viral replication capacity. The S282T replacement is back to wild-type in the following 8 weeks and was no longer detectable by massive sequencing 12 weeks after treatment.
In Phase 3 clinical trials, two NS5B substitutions, L159F and V321A, were detected in samples from numerous genotype 3 HCV infected subjects, relapsing after treatment. There was no change in the phenotypic susceptibility to sofosbuvir or ribavirin of the isolates with these substitutions. S282R and L320F substitutions were also detected during treatment by massive sequencing in a transplant recipient with a partial response to treatment. The clinical significance of these findings is unknown.
Effect of baseline HCV polymorphisms on treatment outcome
In 1,292 subjects included in the phase 3 studies, baseline NS5B sequences were obtained by population sequencing and the S282T substitution was not found in any subject in the available baseline sequence. In an analysis to determine the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any variant of HCV NS5B and treatment outcome.
Cross resistance
HCV replicons expressing the sofosbuvir resistance-associated S282T substitution were fully susceptible to other classes of anti-HCV drugs. Sofosbuvir remained active against NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against resistance-associated substitutions to other direct acting antivirals with different mechanisms of action, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.
Clinical efficacy and safety
The efficacy of sofosbuvir was determined in five Phase 3 studies in a total of 1,568 subjects with genotype 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve subjects with genotype 1 chronic hepatitis C, 4, 5 or 6 in combination with peginterferon alfa 2a and ribavirin and the other four studies were conducted in subjects with chronic hepatitis C of genotype 2 or 3 in combination with ribavirin, of which one in treatment-naïve subjects, one in intolerant subjects , ineligible or not consenting to treatment with interferon, one in subjects previously treated with an interferon-based regimen and one in all subjects, regardless of their previous treatment or their ability to receive interferon-based treatment. patients included in these studies had compensated liver diseases, including cirrhosis Sofosbuvir was administered at a dose of 400 mg once daily.The ribavirin dose was 1,000-1,200 mg per day based on body weight, given in two divided doses, and the dose of peginterferon alfa 2a, where applicable, was 180 mcg per week. In each study, the duration of treatment was predetermined and not dependent on the subjects' HCV RNA levels (no response-dependent algorithm).
Plasma HCV RNA values were measured in clinical studies with the COBAS TaqMan HCV test (version 2.0), used with the High Pure System. The test had a lower limit of quantification (lower limit of quantification, LLOQ) of 25 IU / mL. In all studies, the sustained virological response (sustained virologic response, SVR) was the primary endpoint for determining the HCV cure rate, and was defined as HCV RNA levels below the LLOQ 12 weeks after the end of treatment (SVR12).
Clinical studies in subjects with chronic hepatitis C of genotype 1, 4, 5 and 6
Treatment-naïve subjects - NEUTRINE (study 110)
NEUTRINO was an open-label, single-arm study evaluating a 12-week treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection. .
Treated subjects (n = 327) had a median age of 54 years (range: 19 to 70); 64% of subjects were male; 79% were white, 17% black; 14% were of Hispanic or Latin American descent; mean body mass index was 29 kg / m2 (range: 18 to 56 kg / m2); 78% had baseline HCV RNA levels greater than 6 log10 IU / mL; 17% had cirrhosis; 89% had genotype 1 HCV and 11% had genotype 4, 5, or 6 HCV. Table 5 reports response rates for the sofosbuvir + peginterferon alfa + ribavirin treatment group.
Table 5: Response rates in the NEUTRINO study
a The denominator for relapse is the number of subjects with HCV RNA
b "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
Response rates for selected subgroups are shown in Table 6.
Table 6: SVR12 percentages for selected subgroups in NEUTRINO
SVR12 rates were similarly elevated in subjects with IL28B C / C allele [94/95 (99%)] and non-C / C (C / T or T / T) allele [202/232 (87%)] at baseline.
27/28 patients with genotype 4 HCV infection achieved SVR12. Only one genotype 5 HCV infected subject and all 6 genotype 6 HCV infected subjects in this study achieved SVR12.
Clinical studies in subjects with chronic hepatitis C of genotype 2 and 3
Treatment-naïve adults - FISSION (study 1231)
FISSION was a randomized, open-label, active-controlled study evaluating a 12-week treatment with sofosbuvir and ribavirin compared to a 24-week treatment with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with HCV genotype 2 or 3. The doses of ribavirin used in the sofosbuvir + ribavirin and peginterferon alfa 2a + ribavirin arms were 1,000-1,200 mg / day based on body weight and 800 mg / day regardless of body weight, respectively. Subjects were randomized 1: 1 and stratified by cirrhosis (presence versus absence), to the HCV genotype (2 versus 3) and baseline HCV RNA level (versus ≥6 log10 IU / mL). Subjects with genotype 2 or 3 HCV were enrolled at a ratio of approximately 1: 3.
Treated subjects (n = 499) had a median age of 50 years (range: 19 to 77); 66% of subjects were male; 87% were white, 3% black ; 14% were of Hispanic or Latin American descent; mean body mass index was 28 kg / m2 (range: 17 to 52 kg / m2); 57% had baseline HCV RNA levels greater than 6 log10 IU / mL; 20% had cirrhosis; 72% had genotype 3 HCV. Table 7 reports response rates for the sofosbuvir + ribavirin and peginterferon alfa + ribavirin treatment groups.
Table 7: Response rates in the FISSION study
a The efficacy analysis includes 3 subjects with recombinant genotype 2/1 HCV infection.
b The denominator for relapse is the number of subjects with HCV RNA
c "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
The difference in overall SVR12 percentages between the sofosbuvir + ribavirin and peginterferon alfa + ribavirin treatment groups was 0.3% (95% confidence interval: -7.5% to 8.0%) and the study met the predefined non-inferiority criterion.
Response rates for subjects with cirrhosis at baseline are shown in Table 8 by HCV genotype.
Table 8: SVR12 rates by cirrhosis and genotype in the FISSION study
Genotype 3to. The efficacy analysis includes 3 subjects with recombinant genotype 2/1 HCV infection.
Adults intolerant, ineligible or unwilling to interferon treatment - POSITRON (study 107)
POSITRON was a randomized, double-blind, placebo-controlled trial evaluating 12 weeks of treatment with sofosbuvir and ribavirin (n = 207) compared to placebo (n = 71) in intolerant, ineligible or not consenting to treatment with interferon. Subjects were randomized with a 3: 1 ratio and stratified by cirrhosis (presence versus absence).
Treated subjects (n = 278) had a median age of 54 years (range: 21 to 75); 54% of subjects were male; 91% were white, 5% black; 11% were of Hispanic or Latin American descent; mean body mass index was 28 kg / m2 (range: 18 to 53 kg / m2); 70% had baseline HCV RNA levels greater than 6 log10 IU / mL; 16% had cirrhosis; 49% had genotype 3 HCV. The percentage of subjects intolerant, ineligible or unwilling to interferon treatment was 9%, 44% and 47%, respectively. Most subjects had never been treated for "HCV (81.3%). Table 9 reports response rates for the sofosbuvir + ribavirin and placebo treatment groups.
Table 9: Response rates in the POSITRON study
a The denominator for relapse is the number of subjects with HCV RNA
b "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
The percentage of SVR12 in the sofosbuvir + ribavirin group was statistically significant compared to placebo (p
Table 10 reports the subgroup analysis by genotype based on cirrhosis and treatment with interferon in ineligible, intolerant, non-consenting subjects.
Table 10: SVR12 percentages by genotype-selected subgroups in the POSITRON study
Previously treated adults - FUSION (study 108)
FUSION was a randomized, double-blind study in which 12 or 16-week treatment with sofosbuvir and ribavirin was evaluated in subjects who did not achieve SVR with prior interferon-based treatment (patients with relapse or non-responders). ). Subjects were randomized with a 1: 1 ratio and stratified by cirrhosis (presence versus absence) and the HCV genotype (2 versus 3).
Treated subjects (n = 201) had a median age of 56 years (range: 24 to 70); 70% of subjects were male; 87% were white, 3% black ; 9% were of Hispanic or Latin American descent; mean body mass index was 29 kg / m2 (range: 19 to 44 kg / m2); 73% had baseline HCV RNA levels greater than 6 log10 IU / mL; 34% had cirrhosis; 63% had HCV genotype 3; 75% had already relapsed.Table 11 reports response rates for the sofosbuvir + ribavirin treatment groups for 12 weeks and 16 weeks.
Table 11: Response rates in the FUSION study
a The efficacy analysis includes 6 subjects with recombinant genotype 2/1 HCV infection.
b The denominator for relapse is the number of subjects with HCV RNA
c "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
Table 12 reports the subgroup analysis by genotype in terms of cirrhosis and response to previous anti-HCV treatment.
Table 12: SVR12 percentages by genotype-selected subgroups in the FUSION study
Treatment-naïve and previously treated adults - VALENCE (study 133)
VALENCE was a Phase 3 study evaluating sofosbuvir in combination with weight-based ribavirin for the treatment of genotype 2 or 3 HCV infection in treatment-naïve subjects or in subjects who did not achieve a SVR with prior interferon-based treatment, including subjects with compensated cirrhosis. The study involved a direct comparison of sofosbuvir and ribavirin versus placebo for 12 weeks. Based on the emerging data, however, the study was no longer performed in a blinded manner. and all subjects with HCV genotype 2 continued to receive sofosbuvir and ribavirin for 12 weeks, while the treatment of subjects with HCV genotype 3 was extended to 24 weeks. Eleven subjects with HCV genotype 3 had already completed treatment with 12 weeks with sofosbuvir and ribavirin at the time of the change.
Treated subjects (n = 419) had a median age of 51 years (range: 19 to 74); 60% of subjects were male; median body mass index was 25 kg / m2 (range: from 17 to 44 kg / m2); the mean baseline HCV RNA level was 6.4 log10 IU / mL; 21% had cirrhosis; 78% had genotype 3 HCV; 65% had already reported a relapse. Table 13 reports response rates for the sofosbuvir + ribavirin treatment groups for 12 weeks and 24 weeks.
Subjects who received a placebo were not included in the tables, as none of them achieved SVR12.
Table 13: Response rates in the VALENCE study
a The denominator for relapse is the number of subjects with HCV RNA
b "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
Table 14 reports the subgroup analysis by genotype in terms of cirrhosis and exposure to previous anti-HCV treatment.
Table 14: SVR12 percentages by genotype-selected subgroups in the VALENCE study
SVR12-SVR24 concordance
The concordance between SVR12 and SVR24 (SVR 24 weeks after the end of treatment) after therapy with sofosbuvir in combination with ribavirin or ribavirin and pegylated interferon shows a positive predictive value of 99% and a negative predictive value of 99%.
Clinical efficacy and safety in special populations
Patients with HCV / HIV co-infection - PHOTON-1 (study 123)
Sofosbuvir was evaluated in an open-label clinical study to determine the clinical efficacy and safety of 12 or 24 weeks of treatment with sofosbuvir and ribavirin in subjects with genotype 1, 2 or 3 chronic hepatitis C and co-infected with HIV-1. Subjects with genotype 2 and 3 were treatment-naïve or previously treated, while subjects with genotype 1 were prior treatment-naïve. Treatment duration was 12 weeks in treatment-naïve subjects infected with HIV-1. HCV genotype 2 or 3, and 24 weeks in previously treated subjects, infected with HCV genotype 3, as well as in subjects with HCV genotype 1 infection. Subjects received 400 mg sofosbuvir and ribavirin daily based on body weight (1,000 mg for subjects weighing less than 75 kg or 1,200 mg for subjects weighing 75 kg or more). Subjects were not on antiretroviral therapy and had cell counts and CD4 + greater than 500 cells / mm3, or had virologic suppression of HIV-1 and a CD4 + cell count greater than 200 cells / mm3. Ninety-five percent of patients were receiving antiretroviral therapy at study enrollment. Preliminary SVR12 data are available for 210 subjects.
Table 15 presents response rates by genotype and exposure to previous anti-HCV treatment.
Table 15: Response rates in the PHOTON-1 study
a The denominator for relapse is the number of subjects with HCV RNA
b "Other" includes subjects who did not achieve SVR12 and did not meet virologic failure criteria (eg lost to follow-up).
Table 16 reports the subgroup analysis by genotype in terms of cirrhosis.
Table 16: SVR12 percentages by genotype-selected subgroups in PHOTON-1 study
NT = treatment naive; PT = previously treated.
Patients awaiting liver transplant - Study 2025
Sofosbuvir has been studied in HCV-infected subjects awaiting liver transplantation in an open-label clinical study to determine the safety and efficacy of sofosbuvir and ribavirin administered before transplantation to prevent post-transplant HCV re-infection. The primary endpoint of the study was post-transplant virologic response (post-transplant virologic response, pTVR, HCV RNA Table 17: Post-transplant virological response in subjects with HCV RNA a The subjects that can be assessed are, by definition, those who have reached the observation interval specified at the time of the preliminary analysis. b pTVR: post-transplant virological response (HCV RNA
In patients who discontinued therapy after 24 weeks, according to the protocol, the relapse rate was 11/15. Liver transplant recipients - Study 0126 Sofosbuvir was studied in an open-label clinical study to determine the safety and efficacy of 24 weeks of treatment with sofosbuvir and ribavirin in liver transplant recipients with chronic hepatitis C.Eligible subjects were 18 years of age or older and had undergone liver transplantation 6 to 150 months prior to screening. Subjects had HCV RNA ≥104 IU / mL at screening and documented evidence of chronic HCV infection prior to transplantation. The starting dose of ribavirin was 400 mg, divided into two daily doses. If subjects maintained hemoglobin levels ≥12 g / dL, ribavirin dose was increased at weeks 2, 4, and up to 4-week intervals until the appropriate dose based on body weight (1,000 mg per day in subjects of weight less than 75 kg, 1,200 mg per day in subjects weighing 75 kg or more). The median dose of ribavirin was 600 mg-800 mg daily at weeks 4-24. Forty subjects were enrolled (33 with genotype 1 HCV infection, 6 with genotype 3 HCV infection and 1 with genotype 4 HCV infection), in 35 of whom prior interferon-based therapy had failed while 16 of they were suffering from cirrhosis. Twenty-eight of 40 subjects (70%) achieved SVR12: 22/33 (73%) with genotype 1 HCV infection, 6/6 (100%) with genotype 3 and 0/1 HCV infection (0%) infected with HCV genotype 4. All subjects who achieved SVR12 achieved SVR24 and SVR48. Overview of outcomes by treatment regimen and treatment duration, comparison between studies The following tables (Table 18 to Table 21) present dosing data from Phase 2 and Phase 3 studies to help clinicians determine the best regimen for individual patients. Table 18: Results by therapeutic regimen and treatment duration, comparison between studies in genotype 1 HCV infection n = number of subjects with SVR12 response; N = total number of subjects per group. a For previously treated patients with HCV genotype 1 infection, there are no data on the combination of sofosbuvir, peginterferon alfa and ribavirin. Consideration should be given to treating these patients and extending the duration of therapy with sofosbuvir. peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks, especially for subgroups with one or more factors historically associated with low response rates to interferon-based therapies (prior lack of response to peginterferon alfa and ribavirin therapy, fibrosis / advanced cirrhosis, elevated basal viral concentrations, black ethnicity, non-CC IL28B genotype). b Exploratory or Phase 2 studies. Results should be interpreted with caution, as subject numbers are small and SVR rates can be influenced by patient choice. c Summary data from both studies. Table 19: Results by therapeutic regimen and treatment duration, comparison between studies in genotype 2 HCV infection n = number of subjects with SVR12 response; N = total number of subjects per group. a These data are preliminary. b Exploratory or phase 2 studies. Results should be interpreted with caution, as the number of subjects is small and SVR rates can be influenced by patient choice. In the ELECTRON study (N = 11), the duration of treatment with peginterferon alfa in combination with sofosbuvir + ribavirin ranged from 4 to 12 weeks. c In these two studies, all patients were not cirrhotic. Table 20: Results by therapeutic regimen and treatment duration, comparison between studies in genotype 3 HCV infection n = number of subjects with SVR12 response; N = total number of subjects per group. a These data are preliminary. b Exploratory or Phase 2 studies. Results should be interpreted with caution, as subject numbers are small and SVR rates can be influenced by patient choice. In the ELECTRON study (N = 11), the duration of treatment with peginterferon alfa in combination with sofosbuvir + ribavirin ranged from 4 to 12 weeks. c. In these two studies, all patients were not cirrhotic. Table 21: Results by therapeutic regimen and treatment duration, comparison of studies in genotype 4, 5 or 6 HCV infection n = number of subjects with SVR12 response; N = total number of subjects per group. Pediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with sofosbuvir in one or more subsets of the pediatric populations for the treatment of chronic hepatitis C (see section 4.2 for information on pediatric use). Sofosbuvir is a nucleotide prodrug which is extensively metabolised. The active metabolite is formed in hepatocytes and is not observed in plasma. The major (> 90%) metabolite, GS-331007, is inactive and is formed via sequential and parallel pathways to the formation of the active metabolite. Absorption The pharmacokinetic properties of sofosbuvir and the major circulating metabolite GS-331007 were determined in healthy adult subjects and in subjects with chronic hepatitis C. After oral administration, sofosbuvir was rapidly absorbed and peak plasma concentrations were observed ≈0.5-2 hours after administration, regardless of the dose level. The peak plasma concentration of GS-331007 was observed 2 to 4 hours after administration. Based on the population pharmacokinetic analysis of genotype 1 to 6 HCV infected subjects (n = 986), the steady-state AUC0-24 of sofosbuvir and GS-331007 was 1,010 ng • h / mL and 7,200 ng • h / mL. Compared to healthy subjects (n = 284), the AUC0-24 of sofosbuvir and GS-331007 in HCV-infected subjects was 57% higher and 39% lower, respectively. Effects of food intake Compared to fasting, administration of a single dose of sofosbuvir with a standardized high-fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir increased approximately 1.8-fold, with a limited effect on peak concentration. Exposure to GS-331007 was not changed in the presence of a high-fat meal. Distribution Sofosbuvir is not a substrate for hepatic uptake transporters, the organic anion transporting polypeptide (organic anion-transporting polypetide, OATP) 1B1 or 1B3 and the organic cation transporter (organic cation transporter, OCT) 1. Although subject to active tubular secretion, GS-331007 is not a substrate of renal transporters such as organic anion transporter (organic anion transporter, OAT) 1 or 3, OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of the 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 (data ex vivo) and binding is independent of drug concentration in the range of 1 mcg / mL to 20 mcg / mL. Protein binding of GS-331007 in human plasma was minimal. 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 includes sequential hydrolysis of the carboxylic ester residue, catalyzed by the human enzymes cathepsin A (CatA) or carboxylesterase 1 (CES1). and the cleavage of phosphoramidate by the HINT1 protein (histidine triad nucleotide-binding protein 1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation induces the formation of the nucleoside metabolite GS-331007, which cannot be effectively re-phosphorylated and has no anti-HCV activity. in vitro. Sofosbuvir and GS-331007 are not substrates or inhibitors of the UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 enzymes. After a single 400 mg oral dose of [14C] -sofosbuvir, sofosbuvir and GS-331007 were responsible, respectively, for approximately 4% and> 90% of drug-related systemic exposure (sum of weight-adjusted AUC of sofosbuvir and its metabolites). Elimination After a single 400 mg oral dose of [14C] -sofosbuvir, the mean total dose recovery was greater than 92% and comprised approximately 80%, 14%, and 2.5%, respectively, recovery in urine. in feces and exhaled air. Most of the sofosbuvir dose recovered in urine was GS-331007 (78%), while 3.5% was recovered as sofosbuvir. These data indicate that renal clearance is the major route of elimination of GS-331007 and that a high percentage is actively secreted. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. Linearity / Non-linearity The dose linearity of sofosbuvir and its major metabolite, GS-331007, was determined in fasted healthy subjects. The AUC of sofosbuvir and GS-331007 are nearly dose proportional in the range of 200 mg to 400 mg. Pharmacokinetic properties in particular populations Gender and ethnicity No clinically relevant pharmacokinetic differences due to gender or ethnicity were found for sofosbuvir and GS-331007. Senior citizens Population pharmacokinetic analysis in HCV infected subjects showed that, in the age group analyzed (19-75 years), age had no clinically relevant effect on sofosbuvir and GS-331007 exposure. Clinical studies conducted with sofosbuvir included 65 subjects aged 65 and over. Response rates observed in subjects over 65 years of age were similar to those of younger subjects in all treatment groups. Renal impairment Sofosbuvir pharmacokinetics were studied in HCV negative subjects with mild (eGFR ≥50 and 2), moderate (eGFR ≥30 and 2) and severe (eGFR 2) renal impairment and in subjects with ESRD and need for hemodialysis after a single dose. from 400 mg of sofosbuvir. Compared to subjects with normal renal function (eGFR> 80 mL / min / 1.73 m2), sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild renal impairment, respectively. moderate and severe, while the AUC0-inf of GS-331007 was 55%, 88% and 451% higher. In subjects with ESRD, compared to subjects with normal renal function, the AUC0-inf of sofosbuvir was 28% higher when sofosbuvir was administered 1 hour before hemodialysis and 60% higher when sofosbuvir was administered 1 hour. after hemodialysis. It was not possible to reliably determine the AUC0-inf of GS-331007 in subjects with ESRD. However, the data indicate at least 10-fold and 20-fold higher exposure to GS-331007 in subjects with ESRD compared to healthy subjects when Sovaldi was administered 1 hour before or 1 hour after hemodialysis, respectively. By hemodialysis it is possible to successfully remove (53% extraction rate) the major circulating metabolite GS-331007. A 4-hour "hemodialysis" removed approximately 18% of the administered dose. No dose adjustment is required in patients with mild or moderate renal impairment. The safety of Sovaldi has not been established in patients with severe renal impairment or ESRD (see section 4.4). Hepatic impairment Sofosbuvir pharmacokinetics were studied following administration of 400 mg sofosbuvir for 7 days in patients with HCV infection and moderate or severe hepatic impairment (CPT class B and C). Compared to subjects with normal hepatic function, sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, respectively, while GS-331007 AUC0-24 was higher than 18% and 9%. Population pharmacokinetic analysis in HCV infected subjects showed that cirrhosis had no clinically relevant effect on sofosbuvir and GS-331007 exposure. No dose adjustment is recommended in patients with mild, moderate or severe hepatic impairment (see section 4.2). Pediatric population The pharmacokinetics of sofosbuvir and GS-331007 in pediatric patients have not been established (see section 4.2). Pharmacokinetic (which) / pharmacodynamic (which) relationship Efficacy, in terms of rapid virological response, has been shown to correlate with exposure to sofosbuvir as well as GS-331007. However, these entities have not been shown to be general surrogate markers of efficacy (SVR12) at the therapeutic dose of 400 mg. In repeat-dose toxicology studies in rats and dogs, high doses of a 1: 1 diastereoisomeric mixture caused adverse hepatic (dog) and cardiac (rat) effects and gastrointestinal reactions (dog). Sofosbuvir exposure could not be detected in rodent studies probably due to the 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. Hepatic and cardiac findings were not 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 series of tests in vitro or in vivo including bacterial mutagenicity, chromosomal aberration with human peripheral blood lymphocytes and mouse micronucleus test in vivo. Carcinogenicity studies in mice and rats indicate no carcinogenic potential of sofosbuvir administered at doses up to 600 mg / kg / day in mice and 750 mg / kg / day in rats. The 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 effect on embryo-fetal viability or fertility in rats and was not teratogenic in developmental studies in rats and rabbits. No adverse effects on behavior, reproduction or development of offspring were reported in the rat. In rabbit studies, sofosbuvir exposure was 9 times the expected clinical exposure. Exposure to sofosbuvir could not be determined in rat studies but exposure margins based on the major human metabolite ranged from 8 to 28 times the clinical exposure at 400 mg sofosbuvir. Sofosbuvir-derived material was transferred across the placenta in pregnant rats and into the milk of lactating rats. Core of the tablet Mannitol (E421) Microcrystalline cellulose (E460 (i)) Croscarmellose sodium Colloidal anhydrous silica (E551) Magnesium stearate (E470b) Coating film Polyvinyl alcohol (E1203) Titanium dioxide (E171) Macrogol 3350 (E1521) Talc (E553b) Yellow iron oxide (E172) Not relevant. 3 years. This medicine does not require any special storage conditions. Sovaldi tablets are available in high-density polyethylene (HDPE) bottles with child resistant closure, containing 28 film-coated tablets with silica gel drying agent and polyester spiral. The following pack sizes are available: outer cartons containing 1 bottle of 28 film-coated tablets and outer cartons containing 84 (3 bottles of 28) film-coated tablets. Not all pack sizes may be marketed. Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations. Gilead Sciences International Ltd. Cambridge CB21 6GT UK EU / 1/13/894/001 043196017 EU / 1/13/894/002 043196029 Date of first authorization: 16 January 2014 10/2015
Post-transplant week 12 (pTVR) b
Virological response in evaluable subjects 23/37 (62%)
Patient population (Study number / name) Scheme / Duration Subgroup Percentages of SVR12 (n / N) Treatment Naïve (NEUTRINE) SOF + PEG + RBV 12 weeks Global 90% (262/292) Genotype 1a 92% (206/225) Genotype 1b 83% (55/66) Not cirrhotic 93% (253/273) Cirrhotic 80% (43/54) Treatment-naïve and HIV co-infected (PHOTON-1) SOF + RBV 24 weeks Global 76% (87/114) Genotype 1a 82% (74/90) Genotype 1b 54% (13/24) Not cirrhotic 77% (84/109) Cirrhotic 60% (3/5) Treatment naïve (QUANTUMbe 11-1-0258b) SOF + RBV 24 weeks Globalec 65% (104/159) Genotype 1ac 69% (84/121) Genotype 1bc 53% (20/38) Not cirroticic 68% (100/148)
Cirroticic 36% (4/11)
Patient population (Study number / name) Scheme / Duration Subgroup Percentages of SVR12 (n / N) Treatment Naïve (FISSION) SOF + RBV 12 weeks Global 95% (69/73) Not cirrhotic 97% (59/61) Cirrhotic 83% (10/12) Intolerant, ineligible or unwilling to treatment with interferon (POSITRON) SOF + RBV 12 weeks Global 93% (101/109) Not cirrhotic 92% (85/92) Cirrhotic 94% (16/17) Previously treated (FUSION) SOF + RBV 12 weeks Global 82% (32/39) Not cirrhotic 90% (26/29) Cirrhotic 60% (6/10) Treatment Naïve (VALENCE) SOF + RBV 12 weeks Global 97% (31/32) Not cirrhotic 97% (29/30) Cirrhotic 100% (2/2) Previously treated (VALENCE) SOF + RBV 12 weeks Global 90% (37/41) Not cirrhotic 91% (30/33) Cirrhotic 88% (7/8) Previously treated (FUSION) SOF + RBV 16 weeks Global 89% (31/35) Not cirrhotic 92% (24/26) Cirrhotic 78% (7/9) Treatment-naïve and HIV co-infected (PHOTON-1) SOF + RBV 12 weeks Global 88% (23/26) Not cirrhotic 88% (22/25) Cirrhotic 100% (1/1) Previously treated and HIV co-infected (PHOTON-1) SOF + RBV 24 weeks Globalea 93% (14/15) Not cirrhoticia 92% (12/13) Cirroticia 100% (2/2) Treatment-naïve (ELECTRONbe PROTONb) SOF + PEG + RBV 12 weeks Global 96% (25/26) c Previously treated (LONE STAR-2b) SOF + PEG + RBV 12 weeks Global 96% (22/23) Not cirrhotic 100% (9/9)
Cirrhotic 93% (13/14)
Patient population (Study number / name) Scheme / Duration Subgroup Percentages of SVR12 (n / N) Treatment Naïve (FISSION) SOF + RBV 12 weeks Global 56% (102/183) Not cirrhotic 61% (89/145) Cirrhotic 34% (13/38) Intolerant, ineligible or unwilling to treatment with interferon (POSITRON) SOF + RBV 12 weeks Global 61% (60/98) Not cirrhotic 68% (57/84) Cirrhotic 21% (3/14) Previously treated (FUSION) SOF + RBV 12 weeks Global 30% (19/64) Not cirrhotic 37% (14/38) Cirrhotic 19% (5/26) Previously treated (FUSION) SOF + RBV 16 weeks Global 62% (39/63) Not cirrhotic 63% (25/40) Cirrhotic 61% (14/23) Treatment Naïve (VALENCE) SOF + RBV 24 weeks Global 93% (98/105) Not cirrhotic 94% (86/92) Cirrhotic 92% (12/13) Previously treated (VALENCE) SOF + RBV 24 weeks Global 77% (112/145) Not cirrhotic 85% (85/100) Cirrhotic 60% (27/45) Treatment-naïve and HIV co-infected (PHOTON-1) SOF + RBV 12 weeks Global 67% (28/42) Not cirrhotic 67% (24/36) Cirrhotic 67% (4/6) Previously treated and HIV co-infected (PHOTON-1) SOF + RBV 24 weeks Globalea 92% (12/13) Not cirrhoticia 100% (8/8) Cirroticia 80% (4/5) Treatment-naïve (ELECTRONbe PROTONb) SOF + PEG + RBV 12 weeks Globalec 97% (38/39) Previously treated (LONE STAR-2b) SOF + PEG + RBV 12 weeks Global 83% (20/24) Not cirrhotic 83% (10/12)
Cirrhotic 83% (10/12)
Patient population (Study number / name) Scheme / Duration Subgroup Percentages of SVR12 (n / N) Treatment Naïve (NEUTRINE) SOF + PEG + RBV 12 weeks Global 97% (34/35) Not cirrhotic 100% (33/33)
Cirrhotic 50% (1/2)
05.2 Pharmacokinetic properties
05.3 Preclinical safety data
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
06.2 Incompatibility
06.3 Period of validity
06.4 Special precautions for storage
06.5 Nature of the immediate packaging and contents of the package
06.6 Instructions for use and handling
07.0 MARKETING AUTHORIZATION HOLDER
08.0 MARKETING AUTHORIZATION NUMBER
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
10.0 DATE OF REVISION OF THE TEXT
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
