Sofosbuvir: Difference between revisions

Sofosbuvir
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

VisualWikitext

Revision as of 14:27, 1 August 2014

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

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Overview

Sofosbuvir is an antiviral that is FDA approved for the treatment of chronic hepatitis C (CHC) infection. Common adverse reactions include diarrhea, anemia, headache, insomnia, fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

The recommended dose of sofosbuvir is one 400 mg tablet, taken orally, once daily with or without food.

Sofosbuvir should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults. The recommended regimen and treatment duration for sofosbuvir combination therapy is provided in the table below.

This image is provided by the National Library of Medicine.

SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen [See Use in Specific Populations (8.8) and Clinical Studies (14.4)]. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient.

Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation

Sofosbuvir in combination with ribavirin is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection [See Use in Specific Populations (8.9)].

Dose Modification

Dose reduction of sofosbuvir is not recommended.

Genotype 1 and 4

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose.

Genotype 2 and 3

If a patient has a serious adverse reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, if appropriate, until the adverse reaction abates or decreases in severity. Table 2 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.

Discontinuation of Dosing

If the other agents used in combination with sofosbuvir are permanently discontinued, sofosbuvir should also be discontinued.

Severe Renal Impairment and End Stage Renal Disease

No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Sofosbuvir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sofosbuvir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sofosbuvir in pediatric patients.

Contraindications

When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, the contraindications applicable to those agents are applicable to combination therapies. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.
Sofosbuvir combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.

Warnings

Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin

Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

When sofosbuvir is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking sofosbuvir, therefore, two non-hormonal methods of contraception should be used during treatment with sofosbuvir and concomitant ribavirin. Refer also to the prescribing information for ribavirin.

Use with Potent P-gp Inducers

Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John's wort) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. Rifampin and St. John's wort should not be used with sofosbuvir.

Adverse Reactions

Clinical Trials Experience

Sofosbuvir should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety assessment of sofosbuvir is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received sofosbuvir + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received sofosbuvir + ribavirin combination therapy for 16 weeks, 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks, 327 subjects who received sofosbuvir + peginterferon (Peg-IFN) alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks.

The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + ribavirin for 12 weeks, <1% for subjects receiving sofosbuvir + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving sofosbuvir + peginterferon alfa + ribavirin for 12 weeks.

Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

The most common adverse events (≥ 20%) for sofosbuvir + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for sofosbuvir + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

With the exception of anemia and neutropenia, the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir-containing regimens.

Less Common Adverse Reactions Reported in Clinical Trials (<1%)

The following ADRs occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.

Hematologic Effects: Pancytopenia (particularly in subjects receiving concomitant pegylated interferon).
Psychiatric Disorders: Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

Laboratory Abnormalities

Changes in selected hematological parameters are described in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Bilirubin Elevations

Total bilirubin elevation of more than 2.5×ULN was observed in none of the subjects in the sofosbuvir + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + ribavirin 12 weeks and sofosbuvir + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations.

Creatine Kinase Elevations

Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10×ULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, sofosbuvir + peginterferon alfa + ribavirin 12 weeks and sofosbuvir + ribavirin 12 weeks groups, respectively.

Lipase Elevations

Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.

Postmarketing Experience

There is limited information regarding Sofosbuvir Postmarketing Experience in the drug label.

Drug Interactions

Drug 1
Drug 2
Drug 3
Drug 4
Drug 5

Drug 1

(Description)

Drug 2

(Description)

Drug 3

(Description)

Drug 4

(Description)

Drug 5

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Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): (Description)
Pregnancy Category (AUS): (Description)

Labor and Delivery

(Description)

Nursing Mothers

(Description)

Pediatric Use

(Description)

Geriatic Use

(Description)

Gender

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Race

(Description)

Renal Impairment

(Description)

Hepatic Impairment

(Description)

Females of Reproductive Potential and Males

(Description)

Immunocompromised Patients

(Description)

Others

(Description)

Administration and Monitoring

Administration

(Oral/Intravenous/etc)

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

Condition 2

(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

Solution

Compatible

Solution 1
Solution 2
Solution 3

Not Tested

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Solution 3

Variable

Solution 1
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Incompatible

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Y-Site

Compatible

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Not Tested

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Variable

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Incompatible

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Admixture

Compatible

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Not Tested

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Variable

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Incompatible

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Syringe

Compatible

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Not Tested

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Variable

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Incompatible

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TPN/TNA

Compatible

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Not Tested

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Solution 3

Variable

Solution 1
Solution 2
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Incompatible

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Solution 3

Overdosage

Acute Overdose

Signs and Symptoms

(Description)

Management

(Description)

Chronic Overdose

Signs and Symptoms

(Description)

Management

(Description)

Pharmacology

Sofosbuvir
Systematic (IUPAC) name
?
Identifiers
CAS number	?
ATC code	?
PubChem	?
Chemical data
Formula	?
Mol. mass	?
Pharmacokinetic data
Bioavailability	?
Metabolism	?
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Therapeutic considerations
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Legal status
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Mechanism of Action

(Description)

Structure

(Description with picture)

Pharmacodynamics

(Description)

Pharmacokinetics

(Description)

Nonclinical Toxicology

(Description)

Clinical Studies

Condition 1

(Description)

Condition 2

(Description)

Condition 3

(Description)

How Supplied

(Description)

Storage

There is limited information regarding Sofosbuvir Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Sofosbuvir |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Sofosbuvir |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

(Patient Counseling Information)

Precautions with Alcohol

Alcohol-Sofosbuvir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Sofosbuvir Brand Names in the drug label.

Look-Alike Drug Names

(Paired Confused Name 1a) — (Paired Confused Name 1b)
(Paired Confused Name 2a) — (Paired Confused Name 2b)
(Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

@@ Line 59: / Line 59: @@
 Drugs that are potent P-gp inducers in the intestine (e.g., [[rifampin]], [[St. John's wort]]) may significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect of sofosbuvir. Rifampin and St. John's wort should not be used with sofosbuvir.
-|clinicalTrials=======Central Nervous System======
+|clinicalTrials=Sofosbuvir should be administered with [[ribavirin]] or [[peginterferon alfa]]/[[ribavirin]]. Refer to the prescribing information of [[peginterferon alfa]] and [[ribavirin]] for a description of adverse reactions associated with their use.
-: (list/description of adverse reactions)
+Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
-======Cardiovascular======
+The safety assessment of sofosbuvir is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received sofosbuvir + [[ribavirin]] (RBV) combination therapy for 12 weeks, 98 subjects who received sofosbuvir + [[ribavirin]] combination therapy for 16 weeks, 250 subjects who received sofosbuvir + ribavirin combination therapy for 24 weeks, 327 subjects who received sofosbuvir + peginterferon (Peg-IFN) alfa + [[ribavirin]] combination therapy for 12 weeks, 243 subjects who received [[peginterferon alfa]] + [[ribavirin]] for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks.
-: (list/description of adverse reactions)
+The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving sofosbuvir + [[ribavirin]] for 12 weeks, <1% for subjects receiving sofosbuvir + [[ribavirin]] for 24 weeks, 11% for subjects receiving [[peginterferon alfa]] + [[ribavirin]] for 24 weeks and 2% for subjects receiving sofosbuvir + [[peginterferon alfa]] + [[ribavirin]] for 12 weeks.
-======Respiratory======
+Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
-: (list/description of adverse reactions)
+The most common adverse events (≥ 20%) for sofosbuvir + [[ribavirin]] combination therapy were [[fatigue]] and [[headache]]. The most common adverse events (≥ 20%) for sofosbuvir + peginterferon alfa + [[ribavirin]] combination therapy were [[fatigue]], [[headache]], [[nausea]], [[insomnia]] and [[anemia]].
-======Gastrointestinal======
+[[File:SofosbuvirTable3.png|800px|thumbnail|left|This image is provided by the National Library of Medicine.]]
+{{clr}}
-: (list/description of adverse reactions)
+With the exception of [[anemia]] and [[neutropenia]], the majority of events presented in Table 3 occurred at severity of grade 1 in sofosbuvir-containing regimens.
-======Hypersensitive Reactions======
+=====Less Common Adverse Reactions Reported in Clinical Trials (<1%)=====
+The following ADRs occurred in <1% of subjects receiving sofosbuvir in a combination regimen in any one trial. These events have been included because of their seriousness or assessment of potential causal relationship.
+* '''Hematologic Effects:''' Pancytopenia (particularly in subjects receiving concomitant pegylated interferon).
+* '''Psychiatric Disorders:''' Severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.
-: (list/description of adverse reactions)
+=====Laboratory Abnormalities=====
+Changes in selected hematological parameters are described in the table below. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.
-======Miscellaneous======
+[[File:SofosbuvirTable4.png|800px|thumbnail|This image is provided by the National Library of Medicine.]]
+{{clr}}
-: (list/description of adverse reactions)
+=====Bilirubin Elevations=====
+Total [[bilirubin]] elevation of more than 2.5×ULN was observed in none of the subjects in the sofosbuvir + [[peginterferon alfa]] + [[ribavirin]] 12 weeks group and in 1%, 3% and 3% of subjects in the [[peginterferon alfa]] + [[ribavirin]] 24 weeks, sofosbuvir + [[ribavirin]] 12 weeks and sofosbuvir + ribavirin 24 weeks groups, respectively. [[Bilirubin]] levels peaked during the first 1 to 2 weeks of treatment and subsequently decreased and returned to baseline levels by post-treatment Week 4. These [[bilirubin]] elevations were not associated with [[transaminase]] elevations.
-=====Condition 2=====
+=====Creatine Kinase Elevations=====
+Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic [[creatine kinase]] elevation of greater than or equal to 10×ULN was observed in <1%, 1% and 2% of subjects in the [[peginterferon alfa]] + [[ribavirin]] 24 weeks, sofosbuvir + [[peginterferon alfa]] + [[ribavirin]] 12 weeks and sofosbuvir + [[ribavirin]] 12 weeks groups, respectively.
-======Central Nervous System======
+=====Lipase Elevations=====
+Isolated, asymptomatic lipase elevation of greater than 3×ULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.
-: (list/description of adverse reactions)
-======Cardiovascular======
-: (list/description of adverse reactions)
-======Respiratory======
-: (list/description of adverse reactions)
-======Gastrointestinal======
-: (list/description of adverse reactions)
-======Hypersensitive Reactions======
-: (list/description of adverse reactions)
-======Miscellaneous======
-: (list/description of adverse reactions)
-|postmarketing=(Description)
 |drugInteractions=* Drug 1
 * Drug 2