- Approval Id
- d801be07bc121f8d
- Drug Approval Emc Name
- Sovaldi 150 mg coated granules in sachet
- Drug Name
- Sovaldi 150 mg coated granules in sachet
- Company Name
- Gilead Sciences Ltd
- Company Address
- 280 High Holborn, London, WC1V 7EE, UK
- Company Telephone
- +44 (0)203 681 4500
- Company Medical Info Direct Line
- 08000 113 700 (UK)
- Company Medical Info Email
- ukmedinfo@gilead.com
- Company Customer Care Direct Line
- +44 (0)203 681 4681
- Atc Code
- J05AP08
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Gilead Sciences Ltd
280 High Holborn
London
WC1V 7EE
United Kingdom
- Authorisation Number
- PLGB 11972/0039
- Authorisation Date
- 01/01/2021
- Instruction Authorisation Holder
- Gilead Sciences Ltd
280 High Holborn
London
WC1V 7EE
United Kingdom
- Instruction Authorisation Number
- PLGB 11972/0039
- Instruction Authorisation Date
- 01/01/2021
- Instruction Composition
- \*\*Sovaldi 150 mg coated granules in sachet\*\*
Each sachet contains 150 mg sofosbuvir.
\*\*Excipients with known effect:\*\*
Each 150 mg sachet contains 173 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Coated granules in sachet.
White to off-white coated granules in sachet.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.4.2 Posology and method of administration
Sovaldi treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
\*\*Posology\*\*
The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (as detailed in Table 2). Sovaldi should be taken with food (see section 5.2).
Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Sovaldi. The recommended co-administered medicinal product(s) and treatment duration for Sovaldi combination therapy are provided in Table 1.
\*\*Table 1: Recommended co-administered medicinal product(s) and treatment duration for adults and paediatric patients treated Sovaldi combination therapy\*\*
| | | |
| --- | --- | --- |
| \*\*Patient population\\*\*\* | \*\*Treatment\*\* | \*\*Duration\*\* |
| Adult patients with genotype 1, 4, 5 or 6 CHC | Sovaldi + ribavirinc + peginterferon alfa | 12 weeksa,b |
| Sovaldi + ribavirinc Only for use in patients ineligible or intolerant to peginterferon alfa (see section 4.4) | 24 weeks |
| Adult and paediatric patients aged 3 years and above with genotype 2 CHC | Sovaldid + ribavirinc,e | 12 weeksb |
| Adult patients with genotype 3 CHC | Sovaldi + ribavirinc + peginterferon alfa | 12 weeksb |
| Sovaldi + ribavirinc | 24 weeks |
| Paediatric patients aged 3 years and above with genotype 3 CHC | Sovaldid + ribavirine | 24 weeks |
| Adult patients with CHC awaiting liver transplantation | Sovaldi + ribavirinc | Until liver transplantationf |
\\* 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 Sovaldi, ribavirin and peginterferon alfa (see section 4.4).
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. Adults: weight-based ribavirin (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg); administered orally in two divided doses with food. Paediatric Patients: for ribavirin dosing recommendations see Table 3 below.
d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above.
e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above.
f. See Special patient populations – Patients awaiting liver transplantation below.
\*\*Table 2: Dosing for paediatric patients aged 3 years and above using Sovaldi oral granules\\*\*\*
| | | |
| --- | --- | --- |
| \*\*Body Weight (kg)\*\* | \*\*Dosing of Sovaldi Oral Granules\*\* | \*\*Sofosbuvir Daily Dose\*\* |
| ≥ 35 | two 200 mg sachets of granules once daily | 400 mg/day |
| 17 to < 35 | one 200 mg sachet of granules once daily | 200 mg/day |
| < 17 | one 150 mg sachet of granules once daily | 150 mg/day |
\\*Sovaldi is also available as film-coated tablet for use in paediatric patients with CHC aged 3 years and above (see section 5.1). Please refer to the Summary of Product Characteristics for Sovaldi 200 mg or 400 mg tablets.
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:
\*\*Table 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-infected paediatric patients aged 3 years and above.\*\*
| | |
| --- | --- |
| \*\*Body weight kg\*\* | \*\*Ribavirin Dose\\*\*\* |
| < 47 | 15 mg/kg/day |
| 47-49 | 600 mg/day |
| 50-65 | 800 mg/day |
| 66-80 | 1000 mg/day |
| > 81 | 1200 mg/day |
\\* The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4.
\*Dose modification in adults\*
Dose reduction of Sovaldi 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. 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 4 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
\*\*Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi in adults\*\*
| | | |
| --- | --- | --- |
| \*\*Laboratory values\*\* | \*\*Reduce ribavirin dose to 600 mg/day if:\*\* | \*\*Discontinue ribavirin if:\*\* |
| Haemoglobin in patients with no cardiac disease | <10 g/dL | <8.5 g/dL |
| Haemoglobin in patients 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).
\*Dose modification in paediatric patients aged 3 years and above\*
Dose reduction of Sovaldi is not recommended.
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. Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation.
\*Discontinuation of dosing\*
If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.4).
\*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.
\*\*Special patient populations\*\*
\*Elderly\*
No dose adjustment is warranted for elderly patients (see section 5.2).
\*Renal impairment\*
No dose adjustment of Sovaldi is required for patients with mild or moderate renal impairment.
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring haemodialysis. Sovaldi can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).
\*Hepatic impairment\*
No dose adjustment of Sovaldi is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of Sovaldi have not been established in patients with decompensated cirrhosis.
\*Patients awaiting liver transplantation\*
The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient (see section 5.1).
\*Adult liver transplant recipients\*
Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. In adults a starting ribavirin dose of 400 mg administered orally in two divided doses with food is recommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to a maximum of 1,000-1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patients weighing ≥75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels (see section 5.1).
\*Paediatric population aged < 3 years\*
The safety and efficacy of Sovaldi in children aged <3 years have not yet been established. No data are available.
\*\*Method of administration\*\*
Oral use.
Sovaldi must be taken shortly before food, shortly after food, or with food.
To help with swallowing of the Sovaldi oral granules you can use food or water as detailed below. Alternatively, Sovaldi can be swallowed without food or water.
\*Taking Sovaldi granules with food to aid swallowing\*
To administer with food to aid swallowability of the granules, patients should be instructed to sprinkle the granules on one or more spoonfuls of non-acidic soft food at or below room temperature. Patients should be instructed to take the Sovaldi granules within 30 minutes of gently mixing with food and to swallow the entire contents without chewing to avoid a bitter taste. Examples of non-acidic foods include chocolate syrup, mashed potato, and ice-cream.
\*Taking Sovaldi granules with water to aid swallowing\*
To administer with water, patients should be instructed that the granules can be taken directly into the mouth and swallowed with water.
\*Taking Sovaldi granules without food or water\*
To administer without food or water, patients should be instructed that the granules can be taken directly into the mouth and swallowed. Patients should be instructed to swallow the entire contents without chewing (see section 5.2).4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 Sovaldi (see section 4.5).4.4 Special warnings and precautions for use
\*\*General\*\*
Sovaldi 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 Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi.
\*\*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 Sovaldi 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 coadministration, 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 Sovaldi.
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.
\*\*Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection\*\*
Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see also sections 4.2 and 5.1).
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 Sovaldi in patients with genotype 5 and 6 HCV infection is very limited (see section 5.1).
\*\*Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection\*\*
Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not been investigated in Phase 3 studies (see section 5.1). 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\*\*
Sovaldi 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 Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended (see also section 4.5).
\*\*Pregnancy and concomitant use with ribavirin\*\*
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
\*\*Use with moderate P-gp inducers\*\*
Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi (see section 4.5).
\*\*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. Sovaldi can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi 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 (see also section 5.2).
\*\*Excipients\*\*
This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not.
Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John's wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see section 5.2).
\*\*Patients treated with vitamin K antagonists\*\*
As liver function may change during treatment with Sovaldi, 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.
\*\*Other interactions\*\*
Drug interaction information for Sovaldi with potential concomitant medicinal products is summarised in Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM) ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The table is not all-inclusive.
\*\*Table 5: Interactions between Sovaldi and other medicinal products\*\*
| | | |
| --- | --- | --- |
| \*\*Medicinal product by therapeutic areas\*\* | \*\*Effects on drug levels.\*\* \*\*Mean ratio (90% confidence interval) for AUC, Cmax, Cmina,b\*\* | \*\*Recommendation concerning co-administration with Sovaldi\*\* |
| \*\*\*ANALEPTICS\*\*\* | | |
| Modafinil | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with modafinil is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended. |
| \*\*\*ANTIARRHYTHMICS\*\*\* | | |
| Amiodarone | Effect on amiodarone and sofosbuvir concentrations unknown. | Coadministration 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 Sovaldi (see sections 4.4 and 4.8). |
| \*\*\*ANTICOAGULANTS\*\*\* | | |
| Vitamin K antagonists | Interaction not studied | Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Sovaldi. |
| \*\*\*ANTICONVULSANTS\*\*\* | | |
| Phenobarbital Phenytoin | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Sovaldi is contraindicated with phenobarbital and phenytoin (see section 4.3). |
| Carbamazepine | \*Sofosbuvir\* ↓ Cmax 0.52 (0.43, 0.62) ↓ AUC 0.52 (0.46, 0.59) Cmin (NA) GS 331007 ↔ Cmax 1.04 (0.97, 1.11) ↔ AUC 0.99 (0.94, 1.04) Cmin (NA) (Induction of P-gp) | Sovaldi is contraindicated with carbamazepine (see section 4.3). |
| Oxcarbazepine | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4). |
| \*\*\*ANTIMYCOBACTERIALS\*\*\* | | |
| Rifampicinf (600 mg single dose) | \*Sofosbuvir\* ↓ Cmax 0.23 (0.19, 0.29) ↓ AUC 0.28 (0.24, 0.32) Cmin (NA) \*GS-331007\* ↔ Cmax 1.23 (1.14, 1.34) ↔ AUC 0.95 (0.88, 1.03) Cmin (NA) (Induction of P-gp) | Sovaldi is contraindicated with rifampicin (see section 4.3). |
| Rifabutin | \*Sofosbuvir\* ↓ Cmax 0.64 (0.53, 0.77) ↓ AUC 0.76 (0.63, 0.91) Cmin (NA) GS 331007 ↔ Cmax 1.15 (1.03, 1.27) ↔ AUC 1.03 (0.95, 1.12) Cmin (NA) (Induction of P-gp) | No dose adjustment of Sovaldi is required when concomitantly used with rifabutin. |
| Rifapentine | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4). |
| \*\*\*HERBAL SUPPLEMENTS\*\*\* | | |
| St. John's wort | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Sovaldi is contraindicated with St. John's wort (see section 4.3). |
| \*\*\*HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS\*\*\* | | |
| Boceprevir (BOC) Telaprevir (TPV) | Interaction not studied. \*Expected:\* ↑ Sofosbuvir (TPV) ↔ Sofosbuvir (BOC) ↔ GS-331007 (TPV or BOC) | No drug-drug interaction data exists regarding the co-administration of Sovaldi with boceprevir or telaprevir. |
| \*\*\*NARCOTIC ANALGESICS\*\*\* | | |
| Methadonef (Methadone maintenance therapy [30 to 130 mg/daily]) | \*R-methadone\* ↔ Cmax 0.99 (0.85, 1.16) ↔ AUC 1.01 (0.85, 1.21) ↔ Cmin 0.94 (0.77, 1.14) \*S-methadone\* ↔ Cmax 0.95 (0.79, 1.13) ↔ AUC 0.95 (0.77, 1.17) ↔ Cmin 0.95 (0.74, 1.22) \*Sofosbuvir\* ↓ Cmax 0.95c (0.68, 1.33) ↑ AUC 1.30c (1.00, 1.69) Cmin (NA) \*GS-331007\* ↓ Cmax 0.73c (0.65, 0.83) ↔ AUC 1.04c (0.89, 1.22) Cmin (NA) | No dose adjustment of sofosbuvir or methadone is required when sofosbuvir and methadone are used concomitantly. |
| \*\*\*IMMUNOSUPPRESSANTS\*\*\* | | |
| Ciclosporine (600 mg single dose) | \*Ciclosporin\* ↔ Cmax 1.06 (0.94, 1.18) ↔ AUC 0.98 (0.85, 1.14) Cmin (NA) \*Sofosbuvir\* ↑ Cmax 2.54 (1.87, 3.45) ↑ AUC 4.53 (3.26, 6.30) Cmin (NA) \*GS-331007\* ↓ Cmax 0.60 (0.53, 0.69) ↔ AUC 1.04 (0.90, 1.20) Cmin (NA) | No dose adjustment of sofosbuvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required. |
| Tacrolimuse (5 mg single dose) | \*Tacrolimus\* ↓ Cmax 0.73 (0.59, 0.90) ↔ AUC 1.09 (0.84, 1.40) Cmin (NA) \*Sofosbuvir\* ↓ Cmax 0.97 (0.65, 1.43) ↑ AUC 1.13 (0.81, 1.57) Cmin (NA) \*GS-331007\* ↔ Cmax 0.97 (0.83, 1.14) ↔ AUC 1.00 (0.87, 1.13) Cmin (NA) | No dose adjustment of sofosbuvir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required. |
| \*\*\*HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS\*\*\* | | |
| Efavirenzf (600 mg once daily)d | \*Efavirenz\* ↔ Cmax 0.95 (0.85, 1.06) ↔ AUC 0.96 (0.91, 1.03) ↔ Cmin 0.96 (0.93, 0.98) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or efavirenz is required when sofosbuvir and efavirenz are used concomitantly. |
| Emtricitabinef (200 mg once daily)d | \*Emtricitabine\* ↔ Cmax 0.97 (0.88, 1.07) ↔ AUC 0.99 (0.94, 1.05) ↔ Cmin 1.04 (0.98, 1.11) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or emtricitabine is required when sofosbuvir and emtricitabine are used concomitantly. |
| Tenofovir disoproxilf (245 mg once daily)d | \*Tenofovir\* ↑ Cmax 1.25 (1.08, 1.45) ↔ AUC 0.98 (0.91, 1.05) ↔ Cmin 0.99 (0.91, 1.07) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or tenofovir disoproxil is required when sofosbuvir and tenofovir disoproxil are used concomitantly. |
| Rilpivirinef (25 mg once daily) | \*Rilpivirine\* ↔ Cmax 1.05 (0.97, 1.15) ↔ AUC 1.06 (1.02, 1.09) ↔ Cmin 0.99 (0.94, 1.04) \*Sofosbuvir\* ↑ Cmax 1.21 (0.90, 1.62) ↔ AUC 1.09 (0.94, 1.27) Cmin (NA) \*GS-331007\* ↔ Cmax 1.06 (0.99, 1.14) ↔ AUC 1.01 (0.97, 1.04) Cmin (NA) | No dose adjustment of sofosbuvir or rilpivirine is required when sofosbuvir and rilpivirine are used concomitantly. |
| \*\*\*HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS\*\*\* | | |
| Darunavir boosted with ritonavirf (800/100 mg once daily) | \*Darunavir\* ↔ Cmax 0.97 (0.94, 1.01) ↔ AUC 0.97 (0.94, 1.00) ↔ Cmin 0.86 (0.78, 0.96) \*Sofosbuvir\* ↑ Cmax 1.45 (1.10, 1.92) ↑ AUC 1.34 (1.12, 1.59) Cmin (NA) \*GS-331007\* ↔ Cmax 0.97 (0.90, 1.05) ↔ AUC 1.24 (1.18, 1.30) Cmin (NA) | No dose adjustment of sofosbuvir or darunavir (ritonavir boosted) is required when sofosbuvir and darunavir are used concomitantly. |
| \*\*\*HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS\*\*\* | | |
| Raltegravirf (400 mg twice daily) | \*Raltegravir\* ↓ Cmax 0.57 (0.44, 0.75) ↓ AUC 0.73 (0.59, 0.91) ↔ Cmin 0.95 (0.81, 1.12) \*Sofosbuvir\* ↔ Cmax 0.87 (0.71, 1.08) ↔ AUC 0.95 (0.82, 1.09) Cmin (NA) \*GS-331007\* ↔ Cmax 1.09 (0.99, 1.20) ↔ AUC 1.03 (0.97, 1.08) Cmin (NA) | No dose adjustment of sofosbuvir or raltegravir is required when sofosbuvir and raltegravir are used concomitantly. |
| \*\*\*ORAL CONTRACEPTIVES\*\*\* | | |
| Norgestimate/ethinyl estradiol | \*Norgestromin\* ↔ Cmax 1.06 (0.93, 1.22) ↔ AUC 1.05 (0.92, 1.20) Cmin (NA) \*Norgestrel\* ↔ Cmax 1.18 (0.99, 1.41) ↔ AUC 1.19 (0.98, 1.44) Cmin (NA) \*Ethinyl estradiol\* ↔ Cmax 1.14 (0.96, 1.36) ↔ AUC 1.08 (0.93, 1.25) Cmin (NA) | No dose adjustment of norgestimate/ethinyl estradiol is required when sofosbuvir and norgestimate/ethinyl estradiol are used concomitantly. |
NA = not available/not applicable
a. Mean ratio (90% CI) of co-administered drug pharmacokinetics with/without sofosbuvir and mean ratio of sofosbuvir and GS-331007 with/without co-administered drug. No effect = 1.00
b. All interaction studies conducted in healthy volunteers
c. Comparison based on historical control
d. Administered as Atripla
e. Bioequivalence boundary 80%-125%
f. Equivalence boundary 70%-143%4.6 Fertility, pregnancy and lactation
\*\*Women of childbearing potential / contraception in males and females\*\*
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see section 4.4). Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
\*\*Pregnancy\*\*
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Sovaldi during pregnancy.
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin).
\*\*Breast-feeding\*\*
It is unknown whether sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details see section 5.3).
A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during breast-feeding.
\*\*Fertility\*\*
No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicate harmful effects on fertility.4.7 Effects on ability to drive and use machines
Sovaldi has moderate influence on the ability to drive and use machines. Patients should be informed that fatigue and disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8).4.8 Undesirable effects
\*\*Summary of the safety profile in adults\*\*
Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled).
Sovaldi has 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 patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.
\*\*Tabulated summary of adverse reactions\*\*
The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). 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 6: 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 appetited | 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, 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 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; d. Decreased appetite was identified as an adverse drug reaction to Sovaldi in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years
\*\*Description of selected adverse reactions\*\*
\*Cardiac arrhythmias\*
Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimes are used in combination with amiodarone and/or other medicinal products that lower heart rate (see sections 4.4 and 4.5).
\*\*\*Skin disorders\*\*\*
Frequency not known: Stevens-Johnson syndrome
\*\*Other special population(s)\*\*
\*HIV/HCV co-infection\*
The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar to that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1).
\*Patients awaiting liver transplantation\*
The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to liver transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1).
\*Patients with Renal Impairment\*
Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.
\*Adult liver transplant recipients\*
The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronic hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were very common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events.
\*Paediatric population\*
The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on data from 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions specific to Sovaldi have been identified. The adverse reactions observed were generally consistent with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6). Decreased appetite was observed as a very common adverse drug reaction to Sovaldi when given in combination with ribavirin oral solution in paediatric patients 3 to < 12 years.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.
No specific antidote is available for overdose with Sovaldi. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sovaldi 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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antiviral; ATC code: J05AP08
\*\*Mechanism of action\*\*
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 2.6 μM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
\*\*Antiviral activity\*\*
In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67), 0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and 0.085 ± 0.034 μM for genotype 3a (n = 106). In these assays, the \*in vitro\* antiviral activity of sofosbuvir against the 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.
\*\*Resistance\*\*
\*In cell culture\*
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types.
\*In clinical studies - Adults\*
In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA >1,000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients, with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The sofosbuvir-associated resistance substitution S282T was not detected in any of these patients by deep sequencing or population sequencing. The S282T substitution in NS5B was detected in a single subject receiving Sovaldi monotherapy in a Phase 2 study. This subject harboured <1% HCV S282T at baseline and developed S282T (>99%) at 4 weeks post-treatment which resulted in a 13.5-fold change in sofosbuvir EC50 and reduced viral replication capacity. The S282T substitution reverted to wild-type over the next 8 weeks and was no longer detectable by deep sequencing at 12 weeks post-treatment.
Two NS5B substitutions, L159F and V321A, were detected in post-treatment relapse samples from multiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypic susceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected. In addition, S282R and L320F substitutions were detected on treatment by deep sequencing in a pre-transplant subject with a partial treatment response. The clinical significance of these findings is unknown.
\*\*Effect of baseline HCV polymorphisms on treatment outcome\*\*
\*Adult population\*
Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by population sequencing and the S282T substitution was not detected in any subject with available baseline sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any HCV NS5B variant at baseline and treatment outcome.
\*Paediatric population\*
The presence of NS5B RAVs did not impact treatment outcome; all patients with baseline NS5B nucleoside inhibitor RAVs achieved SVR following treatment with sofosbuvir.
\*\*Cross-resistance\*\*
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fully susceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.
\*\*Clinical efficacy and safety\*\*
The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients with genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve patients with genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and the other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C in combination with ribavirin including one in treatment-naïve patients, one in interferon intolerant, ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen, and one in all patients irrespective of prior treatment history or ability to receive treatment with interferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mg daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 180 μg per week. Treatment duration was fixed in each study and was not guided by patients' HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12).
\*\*\*Clinical studies in patients with genotype 1, 4, 5 and 6 chronic hepatitis C\*\*\*
\*Treatment-naïve adult patients - NEUTRINO (study 110)\*
NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4, 5 or 6 HCV infection.
Treated patients (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients were male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 7 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.
\*\*Table 7: Response rates in study NEUTRINO\*\*
| | |
| --- | --- |
| | \*\*SOF+PEG+RBV\*\* \*\*12 weeks\*\* \*\*(n = 327)\*\* |
| Overall SVR12 | 91% (296/327) |
| Outcome for patients without SVR12 | |
| On-treatment virologic failure | 0/327 |
| Relapsea | 9% (28/326) |
| Otherb | 1% (3/327) |
a. The denominator for relapse is the number of patients with HCV RNA 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. 95% of patients received antiretroviral therapy at the time of enrolment. Preliminary SVR12 data are available for 210 patients.
Table 17 presents the response rates by genotype and exposure to prior HCV treatment.
\*\*Table 17: Response rates in study PHOTON-1\*\*
| | | | |
| --- | --- | --- | --- |
| | \*\*Genotype 2/3 treatment-naïve SOF+RBV\*\* \*\*12 weeks\*\* \*\*(n = 68)\*\* | \*\*Genotype 2/3 treatment-experienced SOF+RBV\*\* \*\*24 weeks\*\* \*\*(n = 28)\*\* | \*\*Genotype 1 treatment-naïve SOF+RBV\*\* \*\*24 weeks\*\* \*\*(n = 114)\*\* |
| Overall SVR12 | 75% (51/68) | 93% (26/28) | 76% (87/114) |
| Outcome for patients without SVR12 | | | |
| On-treatment virologic failure | 1% (1/68) | 0/28 | 1% (1/114) |
| Relapsea | 18% (12/67) | 7% (2/28) | 22% (25/113) |
| Otherb | 6% (4/68) | 0/28 | 1% (1/114) |
a. The denominator for relapse is the number of patients with HCV RNA 90%) metabolite, GS-331007, is inactive. It is formed through sequential and parallel pathways to the formation of active metabolite.
\*\*Absorption\*\*
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed ~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. Based on population pharmacokinetic analysis in patients with genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0-24 for sofosbuvir and GS-331007 was 1,010 ng•h/mL and 7,200 ng•h/mL, respectively. Relative to healthy subjects (n = 284), the sofosbuvir and GS-331007 AUC0-24 was 57% higher and 39% lower, respectively in HCV infected patients.
\*Effects of food\*
Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardised high fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was increased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007 was not altered in the presence of a high-fat meal.
\*\*Distribution\*\*
Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide (OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion, GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3, OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Sofosbuvir is approximately 85% bound to human plasma proteins (\*ex vivo\* data) and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
\*\*Biotransformation\*\*
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity \*in vitro\*. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes.
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.
\*\*Elimination\*\*
Following a single 400 mg oral dose of [14C]-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.
\*\*Linearity/non-linearity\*\*
The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.
\*\*Pharmacokinetics in special populations\*\*
\*Gender and race\*
No clinically relevant pharmacokinetic differences due to gender or race have been identified for sofosbuvir and GS-331007.
\*Elderly\*
Population pharmacokinetic analysis in HCV infected patients showed that within the age range (19 to 75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. Clinical studies of sofosbuvir included 65 patients aged 65 and over. The response rates observed for patients over 65 years of age were similar to that of younger patients across treatment groups.
\*Renal impairment\*
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvir and GS-331007 compared to subjects with normal renal function, as described in the text below, are provided in Table 24.
\*\*Table 24: Effect of varying degrees of renal impairment on exposures (AUC) of sofosbuvir and GS-331007 compared to subjects with normal renal function\*\*
| | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | \*\*HCV-Negative Subjects\*\* | | | | | \*\*HCV-Infected Subjects\*\* | |
| Mild RI (eGFR ≥50 and <80 mL/min/1.73m2) | Moderate RI (eGFR ≥30 and <50 mL/min/1.73m2) | Severe RI (eGFR <30 mL/min/1.73m2) | ESRD Requiring Dialysis | | Severe RI (eGFR <30 mL/min/1.73m2) | ESRD Requiring Dialysis |
| Dosed 1 hr Before Dialysis | Dosed 1 hr After Dialysis |
| Sofosbuvir | 1.6-fold↑ | 2.1-fold↑ | 2.7-fold↑ | 1.3-fold↑ | 1.6-fold↑ | ~2-fold↑ | 1.9-fold↑ |
| GS-331007 | 1.6-fold↑ | 1.9-fold↑ | 5.5-fold↑ | ≥10-fold↑ | ≥20-fold↑ | ~7-fold↑ | 21-fold↑ |
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR ≥50 and <80 mL/min/1.73 m2), moderate (eGFR ≥30 and <50 mL/min/1.73 m2), severe renal impairment (eGFR <30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir, relative to adult patients with normal renal function (eGFR >80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.
In HCV-infected adult patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative adult patients with severe renal impairment.
The pharmacokinetics of sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n = 94) for 8, 12, or 24 weeks or sofosbuvir/velpatasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in the ledipasvir/sofosbuvir and sofosbuvir/velpatasvir Phase 2/3 trials (see section 4.4).
\*Hepatic impairment\*
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in adult HCV-infected patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in adult HCV-infected patients indicated that cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment (see section 4.2).
\*Paediatric population\*
Sofosbuvir and GS-331007 exposures in paediatric patients aged 3 years and above were similar to those in adults from Phase 2/3 studies following administration of sofosbuvir.
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in paediatric patients aged < 3 years (see section 4.2).
\*\*Pharmacokinetic/pharmacodynamic relationship(s)\*\*
Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir as well as GS 331007. However, neither of these entities has been evidenced to be a general surrogate marker for efficacy (SVR12) at the therapeutic 400 mg dose.5.3 Preclinical safety data
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of \*in vitro\* or \*in vivo\* assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and \*in vivo\* mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 30 times (mouse) and 15 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behaviour, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 9 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite ranged from 8 to 28 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*\*Granule Cores\*\*
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hydroxypropyl cellulose
Colloidal anhydrous silica
Sodium stearyl fumarate
\*\*Film-coating\*\*
Hypromellose
Macrogol 400
Amino methacrylate copolymer
Talc
Stearic acid
Sodium lauryl sulfate
Colloidal anhydrous silica6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Sovaldi oral granules,150 mg and 200 mg, are supplied in sachets consisting of polyester/aluminium/polyethylene film in cartons. Each carton contains 28 sachets.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
\*\*Sovaldi 150 mg coated granules in sachet\*\*
Each sachet contains 150 mg sofosbuvir.
\*\*Excipients with known effect:\*\*
Each 150 mg sachet contains 173 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Coated granules in sachet.
White to off-white coated granules in sachet.
## Clinical Particulars
4.1 Therapeutic indications
Sovaldi is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adult and paediatric patients aged 3 years and above (see sections 4.2, 4.4 and 5.1).
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.4.2 Posology and method of administration
Sovaldi treatment should be initiated and monitored by a physician experienced in the management of patients with CHC.
\*\*Posology\*\*
The recommended dose of Sovaldi in paediatric patients aged 3 years and above is based on weight (as detailed in Table 2). Sovaldi should be taken with food (see section 5.2).
Sovaldi should be used in combination with other medicinal products. Monotherapy of Sovaldi is not recommended (see section 5.1). Refer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Sovaldi. The recommended co-administered medicinal product(s) and treatment duration for Sovaldi combination therapy are provided in Table 1.
\*\*Table 1: Recommended co-administered medicinal product(s) and treatment duration for adults and paediatric patients treated Sovaldi combination therapy\*\*
| | | |
| --- | --- | --- |
| \*\*Patient population\\*\*\* | \*\*Treatment\*\* | \*\*Duration\*\* |
| Adult patients with genotype 1, 4, 5 or 6 CHC | Sovaldi + ribavirinc + peginterferon alfa | 12 weeksa,b |
| Sovaldi + ribavirinc Only for use in patients ineligible or intolerant to peginterferon alfa (see section 4.4) | 24 weeks |
| Adult and paediatric patients aged 3 years and above with genotype 2 CHC | Sovaldid + ribavirinc,e | 12 weeksb |
| Adult patients with genotype 3 CHC | Sovaldi + ribavirinc + peginterferon alfa | 12 weeksb |
| Sovaldi + ribavirinc | 24 weeks |
| Paediatric patients aged 3 years and above with genotype 3 CHC | Sovaldid + ribavirine | 24 weeks |
| Adult patients with CHC awaiting liver transplantation | Sovaldi + ribavirinc | Until liver transplantationf |
\\* 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 Sovaldi, ribavirin and peginterferon alfa (see section 4.4).
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. Adults: weight-based ribavirin (<75 kg = 1,000 mg and ≥75 kg = 1,200 mg); administered orally in two divided doses with food. Paediatric Patients: for ribavirin dosing recommendations see Table 3 below.
d. See Table 2 for weight-based Sovaldi dosing recommendations for paediatric patients aged 3 years and above.
e. See Table 3 for weight-based ribavirin dosing recommendations for paediatric patients aged 3 years and above.
f. See Special patient populations – Patients awaiting liver transplantation below.
\*\*Table 2: Dosing for paediatric patients aged 3 years and above using Sovaldi oral granules\\*\*\*
| | | |
| --- | --- | --- |
| \*\*Body Weight (kg)\*\* | \*\*Dosing of Sovaldi Oral Granules\*\* | \*\*Sofosbuvir Daily Dose\*\* |
| ≥ 35 | two 200 mg sachets of granules once daily | 400 mg/day |
| 17 to < 35 | one 200 mg sachet of granules once daily | 200 mg/day |
| < 17 | one 150 mg sachet of granules once daily | 150 mg/day |
\\*Sovaldi is also available as film-coated tablet for use in paediatric patients with CHC aged 3 years and above (see section 5.1). Please refer to the Summary of Product Characteristics for Sovaldi 200 mg or 400 mg tablets.
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:
\*\*Table 3: Guidance for ribavirin dosing when administered in combination with Sovaldi to HCV-infected paediatric patients aged 3 years and above.\*\*
| | |
| --- | --- |
| \*\*Body weight kg\*\* | \*\*Ribavirin Dose\\*\*\* |
| < 47 | 15 mg/kg/day |
| 47-49 | 600 mg/day |
| 50-65 | 800 mg/day |
| 66-80 | 1000 mg/day |
| > 81 | 1200 mg/day |
\\* The daily dosage of ribavirin is weight-based and is administered orally in two divided doses with food.
Concerning co-administration with other direct-acting antivirals against HCV, see section 4.4.
\*Dose modification in adults\*
Dose reduction of Sovaldi 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. 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 4 provides guidelines for dose modifications and discontinuation based on the patient's haemoglobin concentration and cardiac status.
\*\*Table 4: Ribavirin dose modification guideline for co-administration with Sovaldi in adults\*\*
| | | |
| --- | --- | --- |
| \*\*Laboratory values\*\* | \*\*Reduce ribavirin dose to 600 mg/day if:\*\* | \*\*Discontinue ribavirin if:\*\* |
| Haemoglobin in patients with no cardiac disease | <10 g/dL | <8.5 g/dL |
| Haemoglobin in patients 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).
\*Dose modification in paediatric patients aged 3 years and above\*
Dose reduction of Sovaldi is not recommended.
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. Refer to the ribavirin prescribing information for guidance on dose modification or discontinuation.
\*Discontinuation of dosing\*
If the other medicinal products used in combination with Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.4).
\*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.
\*\*Special patient populations\*\*
\*Elderly\*
No dose adjustment is warranted for elderly patients (see section 5.2).
\*Renal impairment\*
No dose adjustment of Sovaldi is required for patients with mild or moderate renal impairment.
Safety data are limited in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and end stage renal disease (ESRD) requiring haemodialysis. Sovaldi can be used in these patients with no dose adjustment when no other relevant treatment options are available (see section 4.4, 4.8, 5.1 and 5.2).
\*Hepatic impairment\*
No dose adjustment of Sovaldi is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh-Turcotte [CPT] class A, B or C) (see section 5.2). The safety and efficacy of Sovaldi have not been established in patients with decompensated cirrhosis.
\*Patients awaiting liver transplantation\*
The duration of administration of Sovaldi in patients awaiting liver transplantation should be guided by an assessment of the potential benefits and risks for the individual patient (see section 5.1).
\*Adult liver transplant recipients\*
Sovaldi in combination with ribavirin is recommended for 24 weeks in liver transplant recipients. In adults a starting ribavirin dose of 400 mg administered orally in two divided doses with food is recommended. If the starting dose of ribavirin is well-tolerated, the dose can be titrated up to a maximum of 1,000-1,200 mg daily (1,000 mg for patients weighing <75 kg and 1,200 mg for patients weighing ≥75 kg). If the starting dose of ribavirin is not well-tolerated, the dose should be reduced as clinically indicated based on haemoglobin levels (see section 5.1).
\*Paediatric population aged < 3 years\*
The safety and efficacy of Sovaldi in children aged <3 years have not yet been established. No data are available.
\*\*Method of administration\*\*
Oral use.
Sovaldi must be taken shortly before food, shortly after food, or with food.
To help with swallowing of the Sovaldi oral granules you can use food or water as detailed below. Alternatively, Sovaldi can be swallowed without food or water.
\*Taking Sovaldi granules with food to aid swallowing\*
To administer with food to aid swallowability of the granules, patients should be instructed to sprinkle the granules on one or more spoonfuls of non-acidic soft food at or below room temperature. Patients should be instructed to take the Sovaldi granules within 30 minutes of gently mixing with food and to swallow the entire contents without chewing to avoid a bitter taste. Examples of non-acidic foods include chocolate syrup, mashed potato, and ice-cream.
\*Taking Sovaldi granules with water to aid swallowing\*
To administer with water, patients should be instructed that the granules can be taken directly into the mouth and swallowed with water.
\*Taking Sovaldi granules without food or water\*
To administer without food or water, patients should be instructed that the granules can be taken directly into the mouth and swallowed. Patients should be instructed to swallow the entire contents without chewing (see section 5.2).4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 Sovaldi (see section 4.5).4.4 Special warnings and precautions for use
\*\*General\*\*
Sovaldi 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 Sovaldi are permanently discontinued, Sovaldi should also be discontinued (see section 4.2). Consult the Summary of Product Characteristics for co-prescribed medicinal products before starting therapy with Sovaldi.
\*\*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 Sovaldi 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 coadministration, 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 Sovaldi.
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.
\*\*Treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection\*\*
Sovaldi has not been studied in a Phase 3 study in treatment-experienced patients with genotype 1, 4, 5 and 6 HCV infection. Thus, the optimal treatment duration in this population has not been established (see also sections 4.2 and 5.1).
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 Sovaldi in patients with genotype 5 and 6 HCV infection is very limited (see section 5.1).
\*\*Interferon-free therapy for genotype 1, 4, 5 and 6 HCV infection\*\*
Interferon-free regimens for patients with genotype 1, 4, 5 and 6 HCV infection with Sovaldi have not been investigated in Phase 3 studies (see section 5.1). 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\*\*
Sovaldi 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 Sovaldi and telaprevir or boceprevir. Such co-administration is not recommended (see also section 4.5).
\*\*Pregnancy and concomitant use with ribavirin\*\*
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for a period of time after the treatment as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
\*\*Use with moderate P-gp inducers\*\*
Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration of such medicinal products is not recommended with Sovaldi (see section 4.5).
\*\*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. Sovaldi can be used in these patients with no dose adjustment when no other relevant treatment options are available (see sections 4.8, 5.1 and 5.2). When Sovaldi 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 (see also section 5.2).
\*\*Excipients\*\*
This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
Sofosbuvir is a nucleotide prodrug. After oral administration of Sovaldi, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic and intestinal metabolism. Intracellular hydrolytic prodrug cleavage catalysed by enzymes including carboxylesterase 1 and sequential phosphorylation steps catalysed by nucleotide kinases result in formation of the pharmacologically active uridine nucleoside analogue triphosphate. The predominant inactive circulating metabolite GS-331007 that accounts for greater than 90% of drug-related material systemic exposure is formed through pathways sequential and parallel to formation of active metabolite. The parent sofosbuvir accounts for approximately 4% of drug-related material systemic exposure (see section 5.2). In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not.
Medicinal products that are strong P-gp inducers in the intestine (carbamazepine, phenobarbital, phenytoin, rifampicin and St. John's wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi and thus are contraindicated with Sovaldi (see section 4.3). Medicinal products that are moderate P-gp inducers in the intestine (e.g. modafinil, oxcarbazepine and rifapentine) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of Sovaldi. Co-administration with such medicinal products is not recommended with Sovaldi (see section 4.4). Co-administration of Sovaldi with medicinal products that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration, thus Sovaldi may be co-administered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of medicinal products that are substrates of these transporters.
The intracellular metabolic activation pathway of sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant medicinal products (see section 5.2).
\*\*Patients treated with vitamin K antagonists\*\*
As liver function may change during treatment with Sovaldi, 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.
\*\*Other interactions\*\*
Drug interaction information for Sovaldi with potential concomitant medicinal products is summarised in Table 5 below (where 90% confidence interval (CI) of the geometric least-squares mean (GLSM) ratio were within “↔”, extended above “↑”, or extended below “↓” the predetermined equivalence boundaries). The table is not all-inclusive.
\*\*Table 5: Interactions between Sovaldi and other medicinal products\*\*
| | | |
| --- | --- | --- |
| \*\*Medicinal product by therapeutic areas\*\* | \*\*Effects on drug levels.\*\* \*\*Mean ratio (90% confidence interval) for AUC, Cmax, Cmina,b\*\* | \*\*Recommendation concerning co-administration with Sovaldi\*\* |
| \*\*\*ANALEPTICS\*\*\* | | |
| Modafinil | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with modafinil is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended. |
| \*\*\*ANTIARRHYTHMICS\*\*\* | | |
| Amiodarone | Effect on amiodarone and sofosbuvir concentrations unknown. | Coadministration 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 Sovaldi (see sections 4.4 and 4.8). |
| \*\*\*ANTICOAGULANTS\*\*\* | | |
| Vitamin K antagonists | Interaction not studied | Close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with Sovaldi. |
| \*\*\*ANTICONVULSANTS\*\*\* | | |
| Phenobarbital Phenytoin | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Sovaldi is contraindicated with phenobarbital and phenytoin (see section 4.3). |
| Carbamazepine | \*Sofosbuvir\* ↓ Cmax 0.52 (0.43, 0.62) ↓ AUC 0.52 (0.46, 0.59) Cmin (NA) GS 331007 ↔ Cmax 1.04 (0.97, 1.11) ↔ AUC 0.99 (0.94, 1.04) Cmin (NA) (Induction of P-gp) | Sovaldi is contraindicated with carbamazepine (see section 4.3). |
| Oxcarbazepine | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4). |
| \*\*\*ANTIMYCOBACTERIALS\*\*\* | | |
| Rifampicinf (600 mg single dose) | \*Sofosbuvir\* ↓ Cmax 0.23 (0.19, 0.29) ↓ AUC 0.28 (0.24, 0.32) Cmin (NA) \*GS-331007\* ↔ Cmax 1.23 (1.14, 1.34) ↔ AUC 0.95 (0.88, 1.03) Cmin (NA) (Induction of P-gp) | Sovaldi is contraindicated with rifampicin (see section 4.3). |
| Rifabutin | \*Sofosbuvir\* ↓ Cmax 0.64 (0.53, 0.77) ↓ AUC 0.76 (0.63, 0.91) Cmin (NA) GS 331007 ↔ Cmax 1.15 (1.03, 1.27) ↔ AUC 1.03 (0.95, 1.12) Cmin (NA) (Induction of P-gp) | No dose adjustment of Sovaldi is required when concomitantly used with rifabutin. |
| Rifapentine | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Co-administration of Sovaldi with rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of Sovaldi. Such co-administration is not recommended (see section 4.4). |
| \*\*\*HERBAL SUPPLEMENTS\*\*\* | | |
| St. John's wort | Interaction not studied. \*Expected:\* ↓ Sofosbuvir ↔ GS-331007 (Induction of P-gp) | Sovaldi is contraindicated with St. John's wort (see section 4.3). |
| \*\*\*HCV ANITIVIRAL AGENTS: HCV PROTEASE INHIBITORS\*\*\* | | |
| Boceprevir (BOC) Telaprevir (TPV) | Interaction not studied. \*Expected:\* ↑ Sofosbuvir (TPV) ↔ Sofosbuvir (BOC) ↔ GS-331007 (TPV or BOC) | No drug-drug interaction data exists regarding the co-administration of Sovaldi with boceprevir or telaprevir. |
| \*\*\*NARCOTIC ANALGESICS\*\*\* | | |
| Methadonef (Methadone maintenance therapy [30 to 130 mg/daily]) | \*R-methadone\* ↔ Cmax 0.99 (0.85, 1.16) ↔ AUC 1.01 (0.85, 1.21) ↔ Cmin 0.94 (0.77, 1.14) \*S-methadone\* ↔ Cmax 0.95 (0.79, 1.13) ↔ AUC 0.95 (0.77, 1.17) ↔ Cmin 0.95 (0.74, 1.22) \*Sofosbuvir\* ↓ Cmax 0.95c (0.68, 1.33) ↑ AUC 1.30c (1.00, 1.69) Cmin (NA) \*GS-331007\* ↓ Cmax 0.73c (0.65, 0.83) ↔ AUC 1.04c (0.89, 1.22) Cmin (NA) | No dose adjustment of sofosbuvir or methadone is required when sofosbuvir and methadone are used concomitantly. |
| \*\*\*IMMUNOSUPPRESSANTS\*\*\* | | |
| Ciclosporine (600 mg single dose) | \*Ciclosporin\* ↔ Cmax 1.06 (0.94, 1.18) ↔ AUC 0.98 (0.85, 1.14) Cmin (NA) \*Sofosbuvir\* ↑ Cmax 2.54 (1.87, 3.45) ↑ AUC 4.53 (3.26, 6.30) Cmin (NA) \*GS-331007\* ↓ Cmax 0.60 (0.53, 0.69) ↔ AUC 1.04 (0.90, 1.20) Cmin (NA) | No dose adjustment of sofosbuvir or ciclosporin is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of ciclosporin may be required. |
| Tacrolimuse (5 mg single dose) | \*Tacrolimus\* ↓ Cmax 0.73 (0.59, 0.90) ↔ AUC 1.09 (0.84, 1.40) Cmin (NA) \*Sofosbuvir\* ↓ Cmax 0.97 (0.65, 1.43) ↑ AUC 1.13 (0.81, 1.57) Cmin (NA) \*GS-331007\* ↔ Cmax 0.97 (0.83, 1.14) ↔ AUC 1.00 (0.87, 1.13) Cmin (NA) | No dose adjustment of sofosbuvir or tacrolimus is required at initiation of co-administration. Afterwards, close monitoring and potential dose adjustment of tacrolimus may be required. |
| \*\*\*HIV ANTIVIRAL AGENTS: REVERSE TRANSCRIPTASE INHIBITORS\*\*\* | | |
| Efavirenzf (600 mg once daily)d | \*Efavirenz\* ↔ Cmax 0.95 (0.85, 1.06) ↔ AUC 0.96 (0.91, 1.03) ↔ Cmin 0.96 (0.93, 0.98) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or efavirenz is required when sofosbuvir and efavirenz are used concomitantly. |
| Emtricitabinef (200 mg once daily)d | \*Emtricitabine\* ↔ Cmax 0.97 (0.88, 1.07) ↔ AUC 0.99 (0.94, 1.05) ↔ Cmin 1.04 (0.98, 1.11) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or emtricitabine is required when sofosbuvir and emtricitabine are used concomitantly. |
| Tenofovir disoproxilf (245 mg once daily)d | \*Tenofovir\* ↑ Cmax 1.25 (1.08, 1.45) ↔ AUC 0.98 (0.91, 1.05) ↔ Cmin 0.99 (0.91, 1.07) \*Sofosbuvir\* ↓ Cmax 0.81 (0.60, 1.10) ↔ AUC 0.94 (0.76, 1.16) Cmin (NA) \*GS-331007\* ↓ Cmax 0.77 (0.70, 0.84) ↔ AUC 0.84 (0.76, 0.92) Cmin (NA) | No dose adjustment of sofosbuvir or tenofovir disoproxil is required when sofosbuvir and tenofovir disoproxil are used concomitantly. |
| Rilpivirinef (25 mg once daily) | \*Rilpivirine\* ↔ Cmax 1.05 (0.97, 1.15) ↔ AUC 1.06 (1.02, 1.09) ↔ Cmin 0.99 (0.94, 1.04) \*Sofosbuvir\* ↑ Cmax 1.21 (0.90, 1.62) ↔ AUC 1.09 (0.94, 1.27) Cmin (NA) \*GS-331007\* ↔ Cmax 1.06 (0.99, 1.14) ↔ AUC 1.01 (0.97, 1.04) Cmin (NA) | No dose adjustment of sofosbuvir or rilpivirine is required when sofosbuvir and rilpivirine are used concomitantly. |
| \*\*\*HIV ANTIVIRAL AGENTS: HIV PROTEASE INHIBITORS\*\*\* | | |
| Darunavir boosted with ritonavirf (800/100 mg once daily) | \*Darunavir\* ↔ Cmax 0.97 (0.94, 1.01) ↔ AUC 0.97 (0.94, 1.00) ↔ Cmin 0.86 (0.78, 0.96) \*Sofosbuvir\* ↑ Cmax 1.45 (1.10, 1.92) ↑ AUC 1.34 (1.12, 1.59) Cmin (NA) \*GS-331007\* ↔ Cmax 0.97 (0.90, 1.05) ↔ AUC 1.24 (1.18, 1.30) Cmin (NA) | No dose adjustment of sofosbuvir or darunavir (ritonavir boosted) is required when sofosbuvir and darunavir are used concomitantly. |
| \*\*\*HIV ANTIVIRAL AGENTS: INTEGRASE INHIBITORS\*\*\* | | |
| Raltegravirf (400 mg twice daily) | \*Raltegravir\* ↓ Cmax 0.57 (0.44, 0.75) ↓ AUC 0.73 (0.59, 0.91) ↔ Cmin 0.95 (0.81, 1.12) \*Sofosbuvir\* ↔ Cmax 0.87 (0.71, 1.08) ↔ AUC 0.95 (0.82, 1.09) Cmin (NA) \*GS-331007\* ↔ Cmax 1.09 (0.99, 1.20) ↔ AUC 1.03 (0.97, 1.08) Cmin (NA) | No dose adjustment of sofosbuvir or raltegravir is required when sofosbuvir and raltegravir are used concomitantly. |
| \*\*\*ORAL CONTRACEPTIVES\*\*\* | | |
| Norgestimate/ethinyl estradiol | \*Norgestromin\* ↔ Cmax 1.06 (0.93, 1.22) ↔ AUC 1.05 (0.92, 1.20) Cmin (NA) \*Norgestrel\* ↔ Cmax 1.18 (0.99, 1.41) ↔ AUC 1.19 (0.98, 1.44) Cmin (NA) \*Ethinyl estradiol\* ↔ Cmax 1.14 (0.96, 1.36) ↔ AUC 1.08 (0.93, 1.25) Cmin (NA) | No dose adjustment of norgestimate/ethinyl estradiol is required when sofosbuvir and norgestimate/ethinyl estradiol are used concomitantly. |
NA = not available/not applicable
a. Mean ratio (90% CI) of co-administered drug pharmacokinetics with/without sofosbuvir and mean ratio of sofosbuvir and GS-331007 with/without co-administered drug. No effect = 1.00
b. All interaction studies conducted in healthy volunteers
c. Comparison based on historical control
d. Administered as Atripla
e. Bioequivalence boundary 80%-125%
f. Equivalence boundary 70%-143%4.6 Fertility, pregnancy and lactation
\*\*Women of childbearing potential / contraception in males and females\*\*
When Sovaldi is used in combination with ribavirin or peginterferon alfa/ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin (see section 4.4). Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
\*\*Pregnancy\*\*
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sofosbuvir in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. No effects on foetal development have been observed in rats and rabbits at the highest doses tested. However, it has not been possible to fully estimate exposure margins achieved for sofosbuvir in the rat relative to the exposure in humans at the recommended clinical dose (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Sovaldi during pregnancy.
However, if ribavirin is co-administered with sofosbuvir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics for ribavirin).
\*\*Breast-feeding\*\*
It is unknown whether sofosbuvir and its metabolites are excreted in human milk.
Available pharmacokinetic data in animals have shown excretion of metabolites in milk (for details see section 5.3).
A risk to newborns/infants cannot be excluded. Therefore, Sovaldi should not be used during breast-feeding.
\*\*Fertility\*\*
No human data on the effect of Sovaldi on fertility are available. Animal studies do not indicate harmful effects on fertility.4.7 Effects on ability to drive and use machines
Sovaldi has moderate influence on the ability to drive and use machines. Patients should be informed that fatigue and disturbance in attention, dizziness and blurred vision have been reported during treatment with sofosbuvir in combination with peginterferon alfa and ribavirin (see section 4.8).4.8 Undesirable effects
\*\*Summary of the safety profile in adults\*\*
Assessment of adverse reactions is based on pooled data from five Phase 3 clinical studies (both controlled and uncontrolled).
Sovaldi has 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 patients receiving sofosbuvir and ribavirin or sofosbuvir, ribavirin and peginterferon alfa were fatigue, headache, nausea and insomnia.
\*\*Tabulated summary of adverse reactions\*\*
The following adverse drug reactions have been identified with sofosbuvir in combination with ribavirin or in combination with peginterferon alfa and ribavirin (Table 6). 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 6: 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 appetited | 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, 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 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; d. Decreased appetite was identified as an adverse drug reaction to Sovaldi in combination with ribavirin oral solution in paediatric patients aged 3 to < 12 years
\*\*Description of selected adverse reactions\*\*
\*Cardiac arrhythmias\*
Cases of severe bradycardia and heart block have been observed when sofosbuvir containing-regimes are used in combination with amiodarone and/or other medicinal products that lower heart rate (see sections 4.4 and 4.5).
\*\*\*Skin disorders\*\*\*
Frequency not known: Stevens-Johnson syndrome
\*\*Other special population(s)\*\*
\*HIV/HCV co-infection\*
The safety profile of sofosbuvir and ribavirin in HCV/HIV co-infected adult patients was similar to that observed in mono-infected HCV patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1).
\*Patients awaiting liver transplantation\*
The safety profile of sofosbuvir and ribavirin in HCV infected adult patients prior to liver transplantation was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1).
\*Patients with Renal Impairment\*
Sofosbuvir in a fixed dose combination with ledipasvir was administered for 12 weeks to 18 patients with genotype 1 CHC and severe renal impairment in an open-label study (Study 0154). The safety of sofosbuvir in a fixed dose combination with either ledipasvir or velpatasvir has been studied in 154 patients with ESRD requiring dialysis (Study 4062 and Study 4063). In this setting, exposure of sofosbuvir metabolite GS-331007 is 20-fold increased, exceeding levels where adverse reactions have been observed in preclinical trials. In this limited clinical safety data set, the rate of adverse events and deaths was not clearly elevated from what is expected in ESRD patients.
\*Adult liver transplant recipients\*
The safety profile of sofosbuvir and ribavirin in liver transplant adult recipients with chronic hepatitis C was similar to that observed in patients treated with sofosbuvir and ribavirin in Phase 3 clinical studies (see section 5.1). In study 0126, decreases in haemoglobin during treatment were very common with 32.5% (13/40 patients) experiencing a decline in haemoglobin to <10 g/dL, 1 of whom also had a decline to <8.5 g/dL. Eight patients (20%) received epoetin and/or a blood product. In 5 patients (12.5%), study drugs were discontinued, modified or interrupted due to adverse events.
\*Paediatric population\*
The safety and efficacy of Sovaldi in paediatric patients aged 3 years and above are based on data from 106 patients who were treated with Sovaldi and ribavirin for 12 weeks (genotype 2 patients) and for 24 weeks (genotype 3 patients) in a Phase 2, open-label clinical trial. No adverse drug reactions specific to Sovaldi have been identified. The adverse reactions observed were generally consistent with those observed in clinical studies of Sovaldi plus ribavirin in adults (see Table 6). Decreased appetite was observed as a very common adverse drug reaction to Sovaldi when given in combination with ribavirin oral solution in paediatric patients 3 to < 12 years.
\*\*Reporting of suspected adverse reactions\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
The highest documented dose of sofosbuvir was a single supratherapeutic dose of sofosbuvir 1,200 mg administered to 59 healthy subjects. In that study, there were no untoward effects observed at this dose level, and adverse reactions were similar in frequency and severity to those reported in the placebo and sofosbuvir 400 mg treatment groups. The effects of higher doses are unknown.
No specific antidote is available for overdose with Sovaldi. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with Sovaldi 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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use, direct-acting antiviral; ATC code: J05AP08
\*\*Mechanism of action\*\*
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a with a 50% inhibitory concentration (IC50) value ranging from 0.7 to 2.6 μM. GS-461203 (the active metabolite of sofosbuvir) is not an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
\*\*Antiviral activity\*\*
In HCV replicon assays, the effective concentration (EC50) values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a were 0.04, 0.11, 0.05, 0.05 and 0.04 μM, respectively, and EC50 values of sofosbuvir against chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a were 0.014 to 0.015 μM. The mean ± SD EC50 of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.068 ± 0.024 μM for genotype 1a (n = 67), 0.11 ± 0.029 μM for genotype 1b (n = 29), 0.035 ± 0.018 μM for genotype 2 (n = 15) and 0.085 ± 0.034 μM for genotype 3a (n = 106). In these assays, the \*in vitro\* antiviral activity of sofosbuvir against the 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.
\*\*Resistance\*\*
\*In cell culture\*
HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. In biochemical assays, recombinant NS5B polymerase from genotypes 1b, 2a, 3a and 4a expressing the S282T substitution showed reduced susceptibility to GS-461203 compared to respective wild-types.
\*In clinical studies - Adults\*
In a pooled analysis of 991 patients who received sofosbuvir in Phase 3 studies, 226 patients qualified for resistance analysis due to virologic failure or early study drug discontinuation and having HCV RNA >1,000 IU/mL. Post-baseline NS5B sequences were available for 225 of the 226 patients, with deep sequencing data (assay cutoff of 1%) from 221 of these patients. The sofosbuvir-associated resistance substitution S282T was not detected in any of these patients by deep sequencing or population sequencing. The S282T substitution in NS5B was detected in a single subject receiving Sovaldi monotherapy in a Phase 2 study. This subject harboured <1% HCV S282T at baseline and developed S282T (>99%) at 4 weeks post-treatment which resulted in a 13.5-fold change in sofosbuvir EC50 and reduced viral replication capacity. The S282T substitution reverted to wild-type over the next 8 weeks and was no longer detectable by deep sequencing at 12 weeks post-treatment.
Two NS5B substitutions, L159F and V321A, were detected in post-treatment relapse samples from multiple genotype 3 HCV infected patients in the Phase 3 clinical studies. No shift in the phenotypic susceptibility to sofosbuvir or ribavirin of subject isolates with these substitutions was detected. In addition, S282R and L320F substitutions were detected on treatment by deep sequencing in a pre-transplant subject with a partial treatment response. The clinical significance of these findings is unknown.
\*\*Effect of baseline HCV polymorphisms on treatment outcome\*\*
\*Adult population\*
Baseline NS5B sequences were obtained for 1,292 patients from Phase 3 studies by population sequencing and the S282T substitution was not detected in any subject with available baseline sequence. In an analysis evaluating the effect of baseline polymorphisms on treatment outcome, no statistically significant association was observed between the presence of any HCV NS5B variant at baseline and treatment outcome.
\*Paediatric population\*
The presence of NS5B RAVs did not impact treatment outcome; all patients with baseline NS5B nucleoside inhibitor RAVs achieved SVR following treatment with sofosbuvir.
\*\*Cross-resistance\*\*
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were fully susceptible to other classes of anti-HCV agents. Sofosbuvir retained activity against the NS5B substitutions L159F and L320F associated with resistance to other nucleoside inhibitors. Sofosbuvir was fully active against substitutions associated with resistance to other direct-acting antivirals with different mechanisms of actions, such as NS5B non-nucleoside inhibitors, NS3 protease inhibitors and NS5A inhibitors.
\*\*Clinical efficacy and safety\*\*
The efficacy of sofosbuvir was evaluated in five Phase 3 studies in a total of 1,568 adult patients with genotypes 1 to 6 chronic hepatitis C. One study was conducted in treatment-naïve patients with genotype 1, 4, 5 or 6 chronic hepatitis C in combination with peginterferon alfa 2a and ribavirin and the other four studies were conducted in patients with genotype 2 or 3 chronic hepatitis C in combination with ribavirin including one in treatment-naïve patients, one in interferon intolerant, ineligible or unwilling patients, one in patients previously treated with an interferon-based regimen, and one in all patients irrespective of prior treatment history or ability to receive treatment with interferon. Patients in these studies had compensated liver disease including cirrhosis. Sofosbuvir was administered at a dose of 400 mg once daily. The ribavirin dose was weight-based at 1,000-1,200 mg daily administered in two divided doses, and the peginterferon alfa 2a dose, where applicable, was 180 μg per week. Treatment duration was fixed in each study and was not guided by patients' HCV RNA levels (no response guided algorithm).
Plasma HCV RNA values were measured during the clinical studies using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU/mL. Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate for all studies which was defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment (SVR12).
\*\*\*Clinical studies in patients with genotype 1, 4, 5 and 6 chronic hepatitis C\*\*\*
\*Treatment-naïve adult patients - NEUTRINO (study 110)\*
NEUTRINO was an open-label, single-arm study that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve patients with genotype 1, 4, 5 or 6 HCV infection.
Treated patients (n = 327) had a median age of 54 years (range: 19 to 70); 64% of the patients were male; 79% were White; 17% were Black; 14% were Hispanic or Latino; mean body mass index was 29 kg/m2 (range: 18 to 56 kg/m2); 78% had baseline HCV RNA greater than 6 log10 IU/mL; 17% had cirrhosis; 89% had HCV genotype 1 and 11% had HCV genotype 4, 5 or 6. Table 7 presents the response rates for the treatment group of sofosbuvir + peginterferon alfa + ribavirin.
\*\*Table 7: Response rates in study NEUTRINO\*\*
| | |
| --- | --- |
| | \*\*SOF+PEG+RBV\*\* \*\*12 weeks\*\* \*\*(n = 327)\*\* |
| Overall SVR12 | 91% (296/327) |
| Outcome for patients without SVR12 | |
| On-treatment virologic failure | 0/327 |
| Relapsea | 9% (28/326) |
| Otherb | 1% (3/327) |
a. The denominator for relapse is the number of patients with HCV RNA 500 cells/mm3 or had virologically suppressed HIV-1 with a CD4+ cell count >200 cells/mm3. 95% of patients received antiretroviral therapy at the time of enrolment. Preliminary SVR12 data are available for 210 patients.
Table 17 presents the response rates by genotype and exposure to prior HCV treatment.
\*\*Table 17: Response rates in study PHOTON-1\*\*
| | | | |
| --- | --- | --- | --- |
| | \*\*Genotype 2/3 treatment-naïve SOF+RBV\*\* \*\*12 weeks\*\* \*\*(n = 68)\*\* | \*\*Genotype 2/3 treatment-experienced SOF+RBV\*\* \*\*24 weeks\*\* \*\*(n = 28)\*\* | \*\*Genotype 1 treatment-naïve SOF+RBV\*\* \*\*24 weeks\*\* \*\*(n = 114)\*\* |
| Overall SVR12 | 75% (51/68) | 93% (26/28) | 76% (87/114) |
| Outcome for patients without SVR12 | | | |
| On-treatment virologic failure | 1% (1/68) | 0/28 | 1% (1/114) |
| Relapsea | 18% (12/67) | 7% (2/28) | 22% (25/113) |
| Otherb | 6% (4/68) | 0/28 | 1% (1/114) |
a. The denominator for relapse is the number of patients with HCV RNA 90%) metabolite, GS-331007, is inactive. It is formed through sequential and parallel pathways to the formation of active metabolite.
\*\*Absorption\*\*
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in patients with chronic hepatitis C. Following oral administration, sofosbuvir was absorbed quickly and the peak plasma concentration was observed ~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. Based on population pharmacokinetic analysis in patients with genotypes 1 to 6 HCV infection (n = 986), steady-state AUC0-24 for sofosbuvir and GS-331007 was 1,010 ng•h/mL and 7,200 ng•h/mL, respectively. Relative to healthy subjects (n = 284), the sofosbuvir and GS-331007 AUC0-24 was 57% higher and 39% lower, respectively in HCV infected patients.
\*Effects of food\*
Relative to fasting conditions, the administration of a single dose of sofosbuvir with a standardised high fat meal slowed the rate of absorption of sofosbuvir. The extent of absorption of sofosbuvir was increased approximately 1.8-fold, with little effect on peak concentration. The exposure to GS-331007 was not altered in the presence of a high-fat meal.
\*\*Distribution\*\*
Sofosbuvir is not a substrate for hepatic uptake transporters, organic anion-transporting polypeptide (OATP) 1B1 or 1B3, and organic cation transporter (OCT) 1. While subject to active tubular secretion, GS-331007 is not a substrate for renal transporters including organic anion transporter (OAT) 1 or 3, OCT2, MRP2, P-gp, BCRP or MATE1. Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, MRP2, BSEP, OATP1B1, OATP1B3 and OCT1. GS-331007 is not an inhibitor of OAT1, OCT2, and MATE1.
Sofosbuvir is approximately 85% bound to human plasma proteins (\*ex vivo\* data) and the binding is independent of drug concentration over the range of 1 μg/mL to 20 μg/mL. Protein binding of GS-331007 was minimal in human plasma. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7.
\*\*Biotransformation\*\*
Sofosbuvir is extensively metabolised in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalysed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity \*in vitro\*. Sofosbuvir and GS-331007 are not substrates or inhibitors of UGT1A1 or CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 enzymes.
After a single 400 mg oral dose of [14C]-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug-related material (sum of molecular weight-adjusted AUC of sofosbuvir and its metabolites) systemic exposure, respectively.
\*\*Elimination\*\*
Following a single 400 mg oral dose of [14C]-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.
\*\*Linearity/non-linearity\*\*
The dose linearity of sofosbuvir and its primary metabolite, GS-331007, was evaluated in fasted healthy subjects. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 400 mg.
\*\*Pharmacokinetics in special populations\*\*
\*Gender and race\*
No clinically relevant pharmacokinetic differences due to gender or race have been identified for sofosbuvir and GS-331007.
\*Elderly\*
Population pharmacokinetic analysis in HCV infected patients showed that within the age range (19 to 75 years) analysed, age did not have a clinically relevant effect on the exposure to sofosbuvir and GS-331007. Clinical studies of sofosbuvir included 65 patients aged 65 and over. The response rates observed for patients over 65 years of age were similar to that of younger patients across treatment groups.
\*Renal impairment\*
A summary of the effect of varying degrees of renal impairment (RI) on the exposures of sofosbuvir and GS-331007 compared to subjects with normal renal function, as described in the text below, are provided in Table 24.
\*\*Table 24: Effect of varying degrees of renal impairment on exposures (AUC) of sofosbuvir and GS-331007 compared to subjects with normal renal function\*\*
| | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | \*\*HCV-Negative Subjects\*\* | | | | | \*\*HCV-Infected Subjects\*\* | |
| Mild RI (eGFR ≥50 and <80 mL/min/1.73m2) | Moderate RI (eGFR ≥30 and <50 mL/min/1.73m2) | Severe RI (eGFR <30 mL/min/1.73m2) | ESRD Requiring Dialysis | | Severe RI (eGFR <30 mL/min/1.73m2) | ESRD Requiring Dialysis |
| Dosed 1 hr Before Dialysis | Dosed 1 hr After Dialysis |
| Sofosbuvir | 1.6-fold↑ | 2.1-fold↑ | 2.7-fold↑ | 1.3-fold↑ | 1.6-fold↑ | ~2-fold↑ | 1.9-fold↑ |
| GS-331007 | 1.6-fold↑ | 1.9-fold↑ | 5.5-fold↑ | ≥10-fold↑ | ≥20-fold↑ | ~7-fold↑ | 21-fold↑ |
The pharmacokinetics of sofosbuvir were studied in HCV negative adult patients with mild (eGFR ≥50 and <80 mL/min/1.73 m2), moderate (eGFR ≥30 and <50 mL/min/1.73 m2), severe renal impairment (eGFR <30 mL/min/1.73 m2) and patients with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir, relative to adult patients with normal renal function (eGFR >80 mL/min/1.73 m2). GS-331007 is efficiently removed by haemodialysis with an extraction coefficient of approximately 53%. Following a single 400 mg dose of sofosbuvir, a 4 hour haemodialysis removed 18% of administered sofosbuvir dose.
In HCV-infected adult patients with severe renal impairment treated with sofosbuvir 200 mg with ribavirin (n=10) or sofosbuvir 400 mg with ribavirin (n=10) for 24 weeks or ledipasvir/sofosbuvir 90/400 mg (n=18) for 12 weeks, the pharmacokinetics of sofosbuvir and GS-331007 were consistent with that observed in HCV negative adult patients with severe renal impairment.
The pharmacokinetics of sofosbuvir, and GS-331007 were studied in HCV-infected adult patients with ESRD requiring dialysis treated with ledipasvir/sofosbuvir (n = 94) for 8, 12, or 24 weeks or sofosbuvir/velpatasvir (n = 59) for 12 weeks, and compared to patients without renal impairment in the ledipasvir/sofosbuvir and sofosbuvir/velpatasvir Phase 2/3 trials (see section 4.4).
\*Hepatic impairment\*
The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in adult HCV-infected patients with moderate and severe hepatic impairment (CPT class B and C). Relative to patients with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in adult HCV-infected patients indicated that cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment (see section 4.2).
\*Paediatric population\*
Sofosbuvir and GS-331007 exposures in paediatric patients aged 3 years and above were similar to those in adults from Phase 2/3 studies following administration of sofosbuvir.
The pharmacokinetics of sofosbuvir and GS-331007 have not been established in paediatric patients aged < 3 years (see section 4.2).
\*\*Pharmacokinetic/pharmacodynamic relationship(s)\*\*
Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir as well as GS 331007. However, neither of these entities has been evidenced to be a general surrogate marker for efficacy (SVR12) at the therapeutic 400 mg dose.5.3 Preclinical safety data
In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic toxicity studies at exposures 9 times (rat) and 27 times (dog) higher than the clinical exposure.
Sofosbuvir was not genotoxic in a battery of \*in vitro\* or \*in vivo\* assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and \*in vivo\* mouse micronucleus assays.
Carcinogenicity studies in mice and rats do not indicate any carcinogenicity potential of sofosbuvir administered at doses up to 600 mg/kg/day in mouse and 750 mg/kg/day in rat. Exposure to GS-331007 in these studies was up to 30 times (mouse) and 15 times (rat) higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir had no effects on embryo-foetal viability or on fertility in rat and was not teratogenic in rat and rabbit development studies. No adverse effects on behaviour, reproduction or development of offspring in rat were reported. In rabbit studies exposure to sofosbuvir was 9 times the expected clinical exposure. In the rat studies, exposure to sofosbuvir could not be determined but exposure margins based on the major human metabolite ranged from 8 to 28 times higher than the clinical exposure at 400 mg sofosbuvir.
Sofosbuvir-derived material was transferred through the placenta in pregnant rats and into the milk of lactating rats.
## Pharmaceutical Particulars
6.1 List of excipients
\*\*Granule Cores\*\*
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Hydroxypropyl cellulose
Colloidal anhydrous silica
Sodium stearyl fumarate
\*\*Film-coating\*\*
Hypromellose
Macrogol 400
Amino methacrylate copolymer
Talc
Stearic acid
Sodium lauryl sulfate
Colloidal anhydrous silica6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Sovaldi oral granules,150 mg and 200 mg, are supplied in sachets consisting of polyester/aluminium/polyethylene film in cartons. Each carton contains 28 sachets.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
