Sovaldi (sofosbuvir)

No dosing information is available for this tab.

Sofosbuvir is administered orally once daily with or without food.

Sofosbuvir is commercially available for oral administration as film-coated tablets and as pellets that should be swallowed whole or mixed with soft food and swallowed whole. The pellets can be used in pediatric patients who cannot swallow tablets.

Sofosbuvir pellets taken with food:One or more spoonfuls of nonacidic soft food at or below room temperature (e.g., pudding, chocolate syrup, mashed potato, ice cream) should be added to a bowl. The entire contents of the appropriate number of single-dose packets of pellets (see Table 1) should be sprinkled onto the food and gently mixed with a spoon. No pellets should remain in the packet(s). The entire mixture containing the pellets should be ingested within 30 minutes after preparation; the pellets in the mixture should be swallowed whole without chewing to avoid a bitter aftertaste. Any unused portion of the mixture should be discarded and should not be stored or used later.

Sofosbuvir pellets taken without food:The entire contents of a single-dose packet of pellets should be poured directly into the mouth and the pellets swallowed whole without chewing to avoid a bitter aftertaste. Water may be swallowed after the pellets, if needed. If 2 packets of pellets are indicated (see Table 1), the process should be repeated. No pellets should remain in the packet(s).

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Hepatitis C Agents/P-Gp Inducers; Phenobarbital

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inducers of P-glycoprotein (P-gp) may decrease the absorption of ledipasvir,(1) sofosbuvir,(1-4) velpatasvir,(3,4) and voxilaprevir.(4)

CLINICAL EFFECTS: Concurrent or recent use of a P-gp inducer may result in decreased levels and effectiveness of ledipasvir,(1) sofosbuvir,(1-4) velpatasvir,(3,4) and voxilaprevir.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of ledipasvir-sofosbuvir,(1) sofosbuvir,(2) sofosbuvir/velpatasvir,(3) and sofosbuvir-velpatasvir-voxilaprevir,(4) do not recommend coadministration with inducers of P-gp.

DISCUSSION: A study of 24 healthy subjects found that carbamazepine (300 mg twice daily) decreased the maximum concentration (Cmax) and exposure (AUC, area-under-curve) of sofosbuvir both by 48%.(3) In a study in 31 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of ledipasvir by 35% and 59%, respectively.(1) In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of sofosbuvir by 77% and 72%, respectively.(2-4) In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of velpatasvir by 71% and 82%, respectively.(3-4) In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of voxilaprevir by 9% and 73%, respectively.(4) Agents linked to this monograph include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, rifapentine, St. John's wort, and tipranavir.(1-6)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Oatp1b1-3 Inhibitors/Brincidofovir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of brincidofovir.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from brincidofovir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of brincidofovir states that alternative medications that are not OATP1B1 or 1B3 inhibitors should be considered. If concurrent use is necessary, instruct the patient to take the OATP1B1 or 1B3 inhibitor at least 3 hours after brincidofovir and increase monitoring for side effects, including transaminase and bilirubin elevations and GI side effects like diarrhea.(1)

DISCUSSION: In a clinical trial, single-dose oral cyclosporine (600 mg, an OATP1B1 and 1B3 inhibitor) increased the mean brincidofovir area-under-curve (AUC) and maximum concentration (Cmax) by 374% and 269%, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cyclosporine, darunavir, eltrombopag, encorafenib, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, lopinavir, ombitasvir-paritaprevir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, sofosbuvir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)

Sofosbuvir + Selected Direct Acting Antivirals/Amiodarone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.(1-7)

CLINICAL EFFECTS: Concurrent or recent use of amiodarone with sofosbuvir plus another direct acting antiviral may result in symptomatic bradycardia, which can be life-threatening, and cardiac arrest.(1-7)

PREDISPOSING FACTORS: Patients who are also receiving a beta-blocker or who have underlying cardiac comorbidities and/or advanced liver disease may be at a higher risk of developing symptomatic bradycardia.(1-7)

PATIENT MANAGEMENT: Concurrent use is potentially life-threatening. The FDA advises that sofosbuvir/ledipasvir or sofosbuvir combined with another direct acting antiviral should not be combined with amiodarone(1) and the manufacturer states concurrent therapy should only be used when other alternative antiarrhythmic treatments are not tolerated or contraindicated.(2-7) The AASLD/IDSA hepatitis C guidelines state patients being treated with amiodarone should not receive sofosbuvir-based regimens due to risk of life-threatening arrhythmias. Due to the long half-life of amiodarone, the guidelines advise that persons should be off amiodarone for at least 6 months before initiating sofosbuvir. If alternatives are deemed not to be clinically appropriate and the decision is made to start sofosbuvir in this setting, continued vigilance for bradycardia should be exercised.(8) If alternative treatment options are unavailable, or if sofosbuvir is initiated in a patient in whom amiodarone was discontinued in the previous three months, counsel patients about the risk of serious symptomatic bradycardia. Patients should undergo cardiac monitoring in an in-patient setting for the first 48 hours of coadministration and should then self-monitor their heart rate (or be monitored in a doctor's office) on a daily basis for at least the first two-weeks of treatment.(1-7) Instruct patients receiving concurrent therapy (and patients in whom amiodarone was recently discontinued) to seek medical attention immediately if they develop signs of symptomatic bradycardia, which may include: near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pains, and/or confusion or memory problems.(1-7)

DISCUSSION: Nine cases of symptomatic bradycardia have been reported with sofosbuvir in combination with ledipasvir (n=3), simeprevir (n=1), or daclatasvir (n=5; marketed internationally, investigational agent in US). Seven patients were also receiving a beta-blocker. Six cases occurred within the first 24 hours of concurrent therapy, while the other cases occurred within 2-12 days of initiation of concurrent therapy. One case involved a fatal cardiac arrest and 3 required pacemaker insertion. In 3 cases, symptomatic bradycardia recurred following rechallenge with sofosbuvir. In one case, amiodarone was discontinued and sofosbuvir was re-initiated 8 weeks later with no reoccurrence of bradycardia.(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Oatp1b1-3 Inhibitors/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Atogepant is a substrate of OATP1B1 and 1B3. Inhibitors of these transporters may increase the GI absorption and/or decrease the hepatic uptake of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atogepant, including nausea, constipation and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant states that, when used concurrently with an OATP inhibitor for prevention of episodic migraine, the atogepant dose should be limited to 10 mg or 30 mg once daily. When used concurrently with an OATP inhibitor for prevention of chronic migraines, the atogepant dose should be limited to 30 mg once daily.(1)

DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin, an OATP inhibitor, increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir, teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)

Slt Direct-Acting Antiviral/Slt Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Warfarin sensitivity may be decreased during concurrent therapy with direct-acting antivirals. Improved hepatic function as a result of successful treatment of Hepatitis C may also play a role.

CLINICAL EFFECTS: Use of direct-acting antivirals in the treatment of Hepatitis C may result in decreased warfarin effects, which may increase the risk of thrombosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin during treatment with direct-acting antivirals. Consider more frequent monitoring of INR during concurrent therapy and after the completion of therapy with direct-acting antivirals until a stable warfarin dose is established.

DISCUSSION: In a clinical study of 43 patients treated with elbasvir-grazoprevir, the warfarin sensitivity index (WSI) (steady state INR/mean daily warfarin dose) decreased from 0.53 +/- 0.25 to 0.4 +/- 0.22 at treatment completion with elbasvir-grazoprevir which represents a 25.2% decrease. Twelve weeks after treatment completion the WSI returned to 0.51 +/- 0.28. Mean weekly warfarin dose requirement increased over the course of therapy, from 40.3 +/- 22.0 mg to 44.6 +/- 23.4 mg, and returned to near original warfarin dose requirement after therapy at 46 mg. Time in therapeutic range for INR dropped from 74.1% to 39.8% during treatment and returned to 64.9% after treatment.(1) In a retrospective review of patients treated with either ombitasvir-paritaprevir-ritonavir-dasabuvir or sofosbuvir, the warfarin sensitivity index (steady state INR/mean daily warfarin dose) decreased 23% during therapy. The percentage of subtherapeutic INRs increased from 28% prior to treatment to 58% during treatment.(2) Pharmacokinetic studies found no significant effects on warfarin from either ombitasvir-paritaprevir-ritonavir(3) or ombitasvir-paritaprevir-ritonavir-dasabuvir.(4) There have been case reports of decreased warfarin effects and increased warfarin dosage requirements during the treatment of Hepatitis C with: ombitasvir-paritaprevir-ritonavir-dasabuvir,(5) sofosbuvir,(6) sofosbuvir-ledipasvir,(7) and sofosbuvir-velpatasvir.(8) There is a case report of decreased INR following the addition of ombitasvir-paritaprevir-ritonavir-dasabuvir to acenocoumarol.(9)

Because sofosbuvir must be used in conjunction with other antivirals, the contraindications for all antivirals included in the multiple-drug regimen should be considered. (See Precautions Related to Multiple-drug Treatment Regimens under Cautions: Warnings/Precautions.)

Sofosbuvir used in conjunction with ribavirin or in conjunction with peginterferon alfa and ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant. (See Precautions Related to Multiple-drug Treatment Regimens under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• Hypoglycemic disorder
• Reactivation of hepatitis B

Sofosbuvir in conjunction with ribavirin: Common adverse effects include fatigue, headache, and decreased appetite.

Sofosbuvir in conjunction with peginterferon alfa and ribavirin: Common adverse effects include fatigue, headache, nausea, insomnia, and anemia.

Less Frequent

• Anemia

Rare or Very Rare

• Angioedema
• Dysglycemia
• Neutropenic disorder
• Pancytopenia
• Reactivation of hepatitis B
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation

More Frequent

• Fatigue
• General weakness
• Headache disorder
• Insomnia
• Nausea
• Pruritus of skin

Less Frequent

• Anorexia
• Chills
• Diarrhea
• Elevated serum lipase
• Fever
• Flu-like symptoms
• Irritability
• Myalgia
• Skin rash

Rare or Very Rare

• Depression

No enhanced messaging available.

Safety and efficacy of sofosbuvir for the treatment of HCV genotype 2 or 3 infection have not been established in children younger than 3 years of age.

Safety and efficacy of sofosbuvir for the treatment of HCV genotype 1 or 4 infection have not been established in pediatric patients of any age.

Safety, efficacy, and pharmacokinetics of sofosbuvir in pediatric patients 3 years of age or older with HCV genotype 2 or 3 infection have been established in an open-label clinical study. Safety, efficacy, and pharmacokinetics of the drug in pediatric patients 3 years of age or older are comparable to those in adults.

Safety and efficacy of sofosbuvir for the treatment of HCV genotype 2 or 3 infection in pediatric patients 3 years of age or older with compensated cirrhosis are supported by data indicating that sofosbuvir and GS-331007 exposures in pediatric patients are comparable to those in adults and that such exposures in adults without cirrhosis are comparable to those in adults with compensated cirrhosis. Therefore, efficacy in pediatric patients with compensated cirrhosis is expected to be similar to that in adults with compensated cirrhosis.

Adverse effects of sofosbuvir reported in pediatric patients 3 years of age and older with HCV genotype 2 or 3 infection are similar to those observed in adults.

There are no adequate and well-controlled studies using sofosbuvir in pregnant women. In animal studies, no adverse developmental outcomes were observed at sofosbuvir exposures greater than those attained in humans using the recommended dosage.

When sofosbuvir is used in conjunction with ribavirin, clinicians should consider that ribavirin may cause fetal toxicity and/or death and extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients receiving the ribavirin-containing regimen. (See Cautions: Pregnancy, Fertility, and Lactation, in Ribavirin 8:18.32.)

It is not known whether sofosbuvir or its metabolites are distributed into human milk.

The predominant metabolite of sofosbuvir (GS-331007) is distributed into milk in rats (milk concentrations approximately 10% of the maternal plasma concentrations 1 hour after a single 20-mg/kg dose). GS-331007 had no apparent effects on the nursing pups.

The benefits of breast-feeding and the importance of sofosbuvir to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

When sofosbuvir is used in conjunction with ribavirin, the potential for adverse reactions to ribavirin in nursing infants should be considered and a decision should be made whether to discontinue nursing or the ribavirin-containing regimen, taking into account the importance of the treatment regimen to the woman. (See Precautions Related to Multiple-drug Treatment Regimens under Warnings/Precautions: Other Warnings/Precautions, in Cautions .)

Sofosbuvir dosage adjustments are not needed in geriatric patients.

There are no clinically important differences in response rates to sofosbuvir in patients 65 years of age or older compared with younger adults.

Population pharmacokinetic analysis in HCV-infected adults 19-75 years of age indicates there are no clinically important age-related differences in sofosbuvir or GS-331007 exposure in this age group.