Sofovirotal    Film Coated Tablets 

Sofosbuvir 400mg

                                                                                                

Usage and indications:

Sofovirotal is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.

Dosage and administration:

 Sofovirotal 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 food. Sofosbuvir should be used in combination with other medicinal products. Monotherapy of Sofosbuvir is not recommended. Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Sofosbuvir. The recommended co-administered medicinal product(s) and treatment duration for Sofosbuvir combination therapy are provided in Table 1.

Table 1: Recommended co-administered medicinal product(s) and treatment duration for Sofosbuvir combination therapy

Patient population*

Treatment

Duration

 Patients with genotype 1, 4, 5 or 6 CHC

 Sofosbuvir + ribavirin + peginterferon alfa

12 weeksa,b

Sofosbuvir + ribavirin

Only for use in patients ineligible or intolerant to peginterferon alfa (see section 4.4)

24 weeks

 Patients with genotype 2 CHC

 Sofosbuvir + ribavirin

12 weeksb

 Patients with genotype 3 CHC

 Sofosbuvir + ribavirin + peginterferon alfa

12 weeksb

Sofosbuvir + ribavirin

24 weeks

Patients with CHC awaiting liver transplantation

Sofosbuvir + ribavirin

Until liver transplantationc

* Includes patients co-infected with human immunodeficiency virus (HIV).

a For previously treated patients with HCV genotype 1 infection, no data exists with the combination of Sofosbuvir, ribavirin and peginterferon alfa.

b Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks; especially for those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non CC genotype, prior null response to peginterferon alfa and ribavirin therapy).

c The duration of administration of Sofosbuvir in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient.

The dose of ribavirin, when used in combination with Sofosbuvir is weight-based (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg) and administered orally in two divided doses with food.

Dose modification: 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 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.

Table 2: Ribavirin dose modification guideline for co-administration with Sofosbuvir

Laboratory values

Reduce ribavirin dose to 600 mg/day if:

Discontinue ribavirin if:

Haemoglobin in subjects with no cardiac disease

<10 g/dL

<8.5 g/dL

Haemoglobin in subjects with history of stable cardiac disease

≥2 g/dL decrease in haemoglobin during any 4 week treatment period

<12 g/dL despite 4 weeks at reduced dose

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 are permanently discontinued, Sofosbuvir should also be discontinued.

Special patient populations:

Elderly: No dose adjustment is warranted for elderly patients.

Renal impairment: No dose adjustment of Sofosbuvir is required for patients with mild or moderate renal impairment. The safety and appropriate dose of Sofosbuvir 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 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 have not been established in patients with decompensated cirrhosis.

Patients awaiting liver transplantation: The duration of administration of Sofosbuvir in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient.

Paediatric population: The safety and efficacy of Sofosbuvir in children and adolescents aged <18 years have not yet been established. No data are available.

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 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 (Table 4). The adverse reactions are listed below 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).

Table 4: Adverse drug reactions identified with sofosbuvir in combination with ribavirin or peginterferon alfa and ribavirin

 Frequency

SOFa + RBVb

SOF + PEGc + RBV

Infections and infestations:

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, thoracic and mediastinal disorders:

Very common

 

dyspnoea, cough

Common

dyspnoea, exertional dyspnoea, cough

Exertional dyspnoea

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 and administration site conditions:

Very common

fatigue, irritability

chills, fatigue, influenza-like illness, irritability, pain, pyrexia

Common

pyrexia, asthenia

chest pain, asthenia

a SOF = sofosbuvir; b RBV = ribavirin; c PEG = peginterferon alfa.

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.

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.

Postmarketing Experience

Cardiac Disorders Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with Sofosbuvirin combination with another HCV direct acting antiviral.

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.

Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infections:

Sofosbuvir has not been studied in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infections. Thus, the optimal treatment duration in this population has not been established. Consideration should be given to treating these patients, and potentially extending the duration of therapy with sofosbuvir, peginterferon alfa and ribavirin beyond 12 weeks and up to 24 weeks; especially for those subgroups who have one or more factors historically associated with lower response rates to interferon-based therapies (advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non CC genotype).

Treatment of patients with genotype 5 or 6 HCV infection:

The clinical data to support the use of Sofosbuvir in patients with genotype 5 and 6 HCV infection is very limited.

Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infections:

Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infections with Sofosbuvir have not been investigated in Phase 3 studies. The optimal regimen and treatment duration have not been established. Such regimens should only be used for patients that are intolerant to or ineligible for interferon therapy, and are in urgent need of treatment.

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 in the Summary of Product Characteristics for ribavirin. (Refer to the Summary of Product Characteristics for ribavirin for additional information.)

Use with potent P-gp inducers:

Medicinal products that are potent P-glycoprotein (P-gp) inducers in the intestine (e.g. rifampicin, St. John's wort [Hypericum perforatum], carbamazepine and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sofosbuvir. Such medicinal products should not be used with Sofosbuvir.

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 “CrCl” <50 mL/min.

HCV/HBV (hepatitis B virus) co-infection:

There are no data on the use of Sofosbuvir in patients with HCV/HBV co-infection.

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.

·         Serious Symptomatic Bradycardia When Co-administered with Amiodarone and another HCV Direct Acting Antiviral

Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with Sofosbuvir in combination with an investigational agent (NS5A inhibitor) or simeprevir. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (HARVONI (ledipasvir/sofosbuvir)). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this effect is unknown.

Coadministration of amiodarone with Sofosbuvir in combination with another direct acting antiviral (DAA) is not recommended. For patients taking amiodarone who have no other alternative, viable treatment options and who will be coadministered Sofosbuvir and another DAA:

•           Counsel patients about the risk of serious symptomatic bradycardia

•           Cardiac monitoring in an in-patient setting for the first 48 hours of coadministration is recommended, 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.

Patients who are taking Sofosbuvir in combination with another DAA who need to start amiodarone therapy due to no other alternative, viable treatment options should undergo similar cardiac monitoring as outlined above.

Due to amiodarone’s long half-life, patients discontinuing amiodarone just prior to starting Sofosbuvir in combination with a DAA should also undergo similar cardiac monitoring as outlined above.

Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, and confusion or memory problems.

Pack: Carton box containing a plastic bottle of 28 film coated tablets.

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