COMPOSITION AND EXCIPIENTS
Active substance:
Each film coated tablet contains 400 mg of sofosbuvir.
Excipients:
Colloidal silicon dioxide, Croscarmellose sodium, Magnesium Stearate, Mannitol, Microcrystalline cellulose, Polyethylene glycol, Polyvinyl alcohol, Talc, Titanium dioxide, Yellow iron oxide.
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.
PHARMACOKINETIC PROPERTIES
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:
Following oral administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed at ~0.5-2 hour post-dose, regardless of dose level. Peak plasma concentration of GS-331007 was observed between 2 to 4 hours post-dose.
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 approximately 85% bound to human plasma proteins 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.
Biotransformation:
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203.
Elimination:
Following a single 400 mg oral dose of sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of 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 (78%) while 3.5% was recovered as sofosbuvir. 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 and 27 hours respectively.
Incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.
INDICATIONS
Sofosbuvir is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults and paediatric patients aged 3 years and above.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Medicinal products that are strong P-glycoprotein (P-gp) inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John’s wort) Co-administration will significantly decrease sofosbuvir plasma concentration and could result in loss of efficacy of Sofosbuvir.
UNDESIRABLE EFFECTS
|
Frequency |
Sofosbuvir + ribavirin |
Sofosbuvir + ribavirin + peg interferon alfa |
|
Infections |
||
|
Common |
nasopharyngitis |
|
|
Blood and lymphatic system disorders: |
||
|
Very common |
haemoglobin decreased |
anaemia, neutropenia, lymphocyte count decreased, platelet count decreased |
|
Common |
anaemia |
|
|
Metabolism and nutrition disorders: |
||
|
Very common |
decreased appetite |
|
|
Common |
weight decreased |
|
|
Psychiatric disorders: |
||
|
Very common |
insomnia |
insomnia |
|
Common |
depression |
depression, anxiety, agitation |
|
Nervous system disorders: |
||
|
Very common |
headache |
dizziness, headache |
|
Common |
disturbance in attention |
migraine, memory impairment, disturbance in attention |
|
Eye disorders: |
||
|
Common |
vision blurred |
|
|
Respiratory disorders: |
||
|
Very common |
dyspnoea, cough |
|
|
Common |
dyspnoea, dyspnoea exertional, cough |
dyspnoea exertional |
|
Gastrointestinal disorders: |
||
|
Very common |
nausea |
diarrhoea, nausea, vomiting |
|
Common |
abdominal discomfort, constipation, dyspepsia |
constipation, dry mouth, gastroesophageal reflux |
|
Hepatobiliary disorders: |
||
|
Very common |
blood bilirubin increased |
blood bilirubin increased |
|
Skin and subcutaneous tissue disorders: |
||
|
Very common |
rash, pruritus |
|
|
Common |
alopecia, dry skin, pruritus |
alopecia, dry skin |
|
Musculoskeletal and connective tissue disorders |
||
|
Very common |
arthralgia, myalgia |
|
|
Common |
arthralgia, back pain, muscle spasms, myalgia |
back pain, muscle spasms |
|
General disorders |
||
|
Very common |
fatigue, irritability |
chills, fatigue, influenza, irritability, pain, pyrexia |
|
Common |
pyrexia, asthenia |
chest pain, asthenia |
WARNINGS AND PRECAUTIONS
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.
Severe bradycardia and heart block:
Life-threatening cases of severe bradycardia and heart block have been observed when sofosbuvir-containing regimens are used in combination with amiodarone. Bradycardia has generally occurred within hours to days, but cases with a longer time to onset have been observed mostly up to 2 weeks after initiating HCV treatment.
Amiodarone should only be used in patients on sofosbuvir 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 undergo cardiac monitoring in an in-patient setting for the first 48 hours of co-administration, after which outpatient or self-monitoring of the heart rate should occur on a daily basis through at least the first 2 weeks of treatment.
Due to the long half-life of amiodarone, cardiac monitoring as outlined above should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated on sofosbuvir.
All patients with concurrent or recent use of amiodarone should be warned of the symptoms of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them.
HCV/HBV (hepatitis B virus) co-infection:
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should therefore be monitored and managed according to current clinical guidelines.
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.
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 for ribavirin.
Use in diabetic patients:
Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct-acting antiviral treatment. Glucose levels of diabetic patients initiating direct-acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medication modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct-acting antiviral therapy is initiated.
Renal impairment:
Safety data are limited in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) and ESRD requiring haemodialysis. Sofosbuvir can be used in these patients with no dose adjustment when no other relevant treatment options are available.
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
Patients treated with vitamin K antagonists:
As liver function may change during treatment with Sofosbuvir, a close monitoring of International Normalised Ratio (INR) values is recommended.
Impact of DAA therapy on drugs metabolized by the liver:
The pharmacokinetics of drugs that are metabolized by the liver (e.g. immunosuppressive agents such as calcineurin inhibitors) may be impacted by changes in liver function during DAA therapy, related to clearance of HCV.
Modafinil:
Co-administration of Sofosbuvir with modafinil is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sofosbuvir. Such co-administration is not recommended.
Amiodarone:
Co-administration of amiodarone with a sofosbuvir-containing regimen may result in serious symptomatic bradycardia.
Use only if no other alternative is available. Close monitoring is recommended if this medicinal product is administered with sofosbuvir.
ANTICONVULSANTS:
Sofosbuvir is contraindicated with phenobarbital, phenytoin, carbamazepine.
Oxcarbazepine: Co-administration of Sofosbuvir with oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sofosbuvir. Such co-administration is not recommended.
ANTIMYCOBACTERIALS:
Rifampicin: Sofosbuvir is contraindicated with rifampicin.
Rifabutin: No dose adjustment of Sofosbuvir is required when concomitantly used with rifabutin.
Rifapentine: Co-administration of Sofosbuvir with rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sofosbuvir. Such co-administration is not recommended.
HERBAL SUPPLEMENTS:
St. John’s wort: sofosbuvir is contraindicated with St. John’s wort.
NARCOTIC ANALGESICS:
Methadone: No dose adjustment of sofosbuvir or methadone is required when sofosbuvir and methadone are used concomitantly.
IMMUNOSUPPRESSANTS:
Ciclosporine, Tacrolimuse: No dose adjustment of sofosbuvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin or tacrolimus may be required.
HIV ANTIVIRAL AGENTS:
REVERSE TRANSCRIPTASE INHIBITORS:
Efavirenz, Tenofovir disoproxil, Rilpivirine: No dose adjustment of sofosbuvir or efavirenz or Tenofovir disoproxil or Rilpivirine is required when sofosbuvir are used concomitantly.
HIV PROTEASE INHIBITORS:
No dose adjustment of sofosbuvir or darunavir (ritonavir boosted) is required when sofosbuvir and darunavir are used concomitantly.
INTEGRASE INHIBITORS:
Raltegravir: No dose adjustment of sofosbuvir or raltegravir is required when sofosbuvir and raltegravir are used concomitantly.
ORAL CONTRACEPTIVES:
Norgestimate/ethinyl estradiol: No dose adjustment of norgestimate/ethinyl estradiol is required when sofosbuvir and norgestimate/ethinyl estradiol are used concomitantly.
Pregnancy:
There are no or limited amount of data from the use of sofosbuvir in pregnant women.
When Sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must be taken to avoid pregnancy.
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.
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 for ribavirin.
Breast-feeding:
It is unknown whether sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals have shown excretion of metabolites in milk.
A risk to newborns/infants cannot be excluded. Therefore, sofosbuvir should not be used during breast-feeding.
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.
POSOLOGY AND METHOD OF ADMINISTRATION
The recommended dose of Sofosbuvir in adults is one 400 mg tablet, taken orally, once daily with food.
Sofosbuvir should be used in combination with other medicinal products. Monotherapy of Sofosbuvir is not recommended.
Recommended co-administered medicinal product(s) and treatment duration for adults and paediatric patients treated with Sofosbuvir combination therapy:
|
Duration |
Treatment |
Patient population |
|
12 weeks |
Sofosbuvir + ribavirinc + peginterferon alfa |
Adult patients with genotype 1, 4, 5 or 6 CHC |
|
24 weeks |
Sofosbuvir + ribavirinc Only for use in patients ineligible or intolerant to peginterferon alfa |
|
|
12 weeks |
Sofosbuvir + ribavirin |
patients CHC with genotype 2 |
|
12 weeks |
Sofosbuvir + ribavirinc + peginterferon alfa |
patients CHC with genotype 3 |
|
24 weeks |
Sofosbuvir + ribavirinc |
|
|
Until liver transplantation |
Sofosbuvir + ribavirinc |
Adult patients with CHC awaiting liver transplantation |
The recommended dose of Sofosbuvir in pediatric patients aged 3 years and above is based on weight (as detailed in Table 2).
Sofosbuvir oral granules are available for the treatment of chronic HCV-infection in paediatric patients aged 3 years and above having difficulty in swallowing film-coated tablets.
|
Sofosbuvir Daily Dose |
Dosing of Sofosbuvir Tablets |
Body Weight (kg) |
|
400 mg/day |
one 400 mg tablet once daily or two 200 mg tablets once daily |
35 ≤ |
|
200 mg/day |
one 200 mg tablet once daily |
17 to < 35 |
In paediatric patients aged 3 years and above the following ribavirin dosing is recommended where ribavirin is divided into two daily doses and given with food.
Guidance for ribavirin dosing when administered in combination with Sofosbuvir to HCV-infected paediatric patients aged 3 years and above:
|
RBV daily dose |
Body weight (kg) |
|
15 mg/kg/day |
47 > |
|
600 mg/day |
49 – 47 |
|
800 mg/day |
65 -50 |
|
1000 mg/day |
80-66 |
|
1200 mg/day |
81 < |
Dose modification in adults:
Dose reduction of Sofosbuvir is not recommended.
If sofosbuvir is used in combination with peginterferon alfa, and a patient has a serious adverse reaction potentially related to this medicinal product, the peginterferon alfa dose should be reduced or discontinued.
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 provides guidelines for dose modifications and discontinuation based on the patient’s haemoglobin concentration and cardiac status.
Ribavirin dose modification guideline for co-administration with Sofosbuvir in adults:
|
Discontinue ribavirin if: |
Reduce ribavirin dose to 600 mg/day if: |
Laboratory values |
|
8.5 g/dL > |
10 g/dL > |
Haemoglobin in patients with no cardiac disease |
|
< 12 g/dL despite 4 weeks at reduced dose |
≥ 2 g/dL decrease in haemoglobin during any 4 week treatment period |
Haemoglobin in patients with history of stable cardiac disease |
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).
Vomiting and missed doses:
Patients should be instructed that if vomiting occurs within 2 hours of dosing an additional dose 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 dose 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.
Paediatric population aged < 3 years:
The safety and efficacy of sofosbuvir in children aged <3 years have not yet been established. No data are available.
OVERDOSE
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.
STORAGE CONDITIONS
Store at temperature below 30 °C, in the outer carton.
PACKAGING
Sovir is supplied in a carton pack includes plastic container contains 28 film coated tablets and enclosed leaflet.