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Sovaldi

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Sovaldi

Side Effects
Interactions

SIDE EFFECTS

Adverse Reactions From Clinical Trials Experience

SOVALDI 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 SOVALDI is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received SOVALDI + ribavirin (RBV) combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + 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 SOVALDI + ribavirin for 12 weeks, < 1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.

Treatment-emergent adverse events observed in ≥ 15% of subjects in clinical trials are provided in Table 3. 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 SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events ( ≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Table 3 Treatment-Emergent Adverse Events (All Grades) Reported in ≥ 15% of Subjects in Any Treatment Arm

  Interferon-free Regimens Interferon-containing Regimens
PBO 12 weeks SOVALDI + RBVa 12 weeks SOVALDI + RBVa 24 weeks Peg-IFN alfa + RBVb 24 weeks SOVALDI + Peg-IFN alfa + RBVa 12 weeks
N=71 N=650 N=250 N=243 N=327
Fatigue 24% 38% 30% 55% 59%
Headache 20% 24% 30% 44% 36%
Nausea 18% 22% 13% 29% 34%
Insomnia 4% 15% 16% 29% 25%
Pruritus 8% 11% 27% 17% 17%
Anemia 0% 10% 6% 12% 21%
Asthenia 3% 6% 21% 3% 5%
Rash 8% 8% 9% 18% 18%
Decreased Appetite 10% 6% 6% 18% 18%
Chills 1% 2% 2% 18% 17%
Influenza Like Illness 3% 3% 6% 18% 16%
Pyrexia 0% 4% 4% 14% 18%
Diarrhea 6% 9% 12% 17% 12%
Neutropenia 0% < 1% < 1% 12% 17%
Myalgia 0% 6% 9% 16% 14%
Irritability 1% 10% 10% 16% 13%
a Subjects received weight-based ribavirin (1000 mg per day if weighing < 75 kg or 1200 mg per day if weighing ≥ 75 kg).
b Subjects received 800 mg ribavirin per day regardless of weight.

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

Less Common Adverse Reactions Reported in Clinical Trials ( < 1%): The following ADRs occurred in < 1% of subjects receiving SOVALDI 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 Table 4. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Table 4 : Percentage of Subjects Reporting Selected Hematological Parameters

Hematological Parameters Interferon-free Regimens Interferon-containing Regimens
PBO 12 weeks SOVALDI + RBVa 12 weeks SOVALDI + RBVa 24 weeks Peg-IFN + RBVb 24 weeks SOVALDI + Peg-IFN + RBVa 12 weeks
N=71 N=647 N=250 N=242 N=327
Hemoglobin (g/dL)
   < 10 0 8% 6% 14% 23%
   < 8.5 0 1% < 1% 2% 2%
Neutrophils (x109/L)
   ≥ 0.5 - < 0.75 1% < 1% 0 12% 15%
   < 0.5 0 < 1% 0 2% 5%
Platelets (x109/L)
   ≥ 25 - < 50 3% < 1% 1% 7% < 1%
   < 25 0 0 0 0 0
a Subjects received weight-based ribavirin (1000 mg per day if weighing < 75 kg or 1200 mg per day if weighing ≥ 75 kg).
b Subjects received 800 mg ribavirin per day regardless of weight.

Bilirubin Elevations

Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + 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 10xULN was observed in < 1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively.

Lipase Elevations

Isolated, asymptomatic lipase elevation of greater than 3xULN 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.

Read the Sovaldi (sofosbuvir tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Potential For Drug Interactions

After oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material [See CLINICAL PHARMACOLOGY]. 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. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI [See WARNINGS AND PRECAUTIONS]. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered 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 drugs 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 drugs [See CLINICAL PHARMACOLOGY].

Potentially Significant Drug Interactions

Drug interaction information for SOVALDI with potential concomitant drugs is summarized in Table 5. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. The table is not all-inclusive [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Table 5 : Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactiona

Concomitant Drug Class: Drug Name Effect on Concentrationb Clinical Comment
Anticonvulsants: carbamazepine
phenytoin
phenobarbital
oxcarbazepine
↓ sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital or oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.
Antimycobacterials:
rifabutin rifampin
rifapentine
↓sofosbuvir
↓ GS-331007
Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.
SOVALDI should not be used with rifampin, a potent intestinal P-gp inducer [See WARNINGS AND PRECAUTIONS].
Herbal Supplements: St. John's wort (Hypericum perforatum) ↓ sofosbuvir
↓ GS-331007
SOVALDI should not be used with St. John's wort, a potent intestinal P-gp inducer [See WARNINGS AND PRECAUTIONS].
HIV Protease Inhibitors: tipranavir/ritonavir ↓ sofosbuvir
↓GS-331007
Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.
a This table is not all inclusive.
b ↓ = decrease.

Drugs Without Clinically Significant Interactions With SOVALDI

In addition to the drugs included in Table 5, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug [See CLINICAL PHARMACOLOGY]: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

Last reviewed on RxList: 12/18/2013
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
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