SOVALDI SIDE EFFECTS

Last updated on MDtodate: 10/12/2022

SIDE EFFECTS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Serious Symptomatic Bradycardia When Coadministered with Amiodarone

Clinical Trials Experience

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.

When SOVALDI is administered with ribavirin or peginterferon alfa/ribavirin, refer to the respective prescribing information for a description of adverse reactions associated with their use.

Adverse Reactions In Adult Subjects

The safety assessment of SOVALDI was 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, less than 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.

Adverse events observed in at least 15% of subjects in the Phase 3 clinical trials outlined above are provided in Table 1. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

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

Table 1: Adverse Events (All Grades and without Regard to Causality)Reported in ≥15% of Subjects with HCV 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 5 occurred at severity of grade 1 in SOVALDI-containing regimens.

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

The following adverse reactions occurred in less than 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 2. A side-by-side tabulation is displayed to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Table 2: Percentage of Subjects Reporting Selected HematologicalParameters

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 less than 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 less than 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.

Patients with HCV/HIV-1 Coinfection

SOVALDI used in combination with ribavirin was assessed in 223 HCV/HIV-1 coinfected subjects. The safety profile in HCV/HIV-1 coinfected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases. Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Adverse Reactions in Pediatric Subjects 3 Years of Age and Older

The safety assessment of SOVALDI in pediatric subjects 3 years of age and older is based on data from 106 subjects who were treated with SOVALDI plus ribavirin for 12 weeks (genotype 2 subjects) or 24 weeks (genotype 3 subjects) in a Phase 2, open-label clinical trial. The adverse reactions observed were consistent with those observed in clinical studies of SOVALDI plus ribavirin in adults. Among pediatric subjects 3 years to < 12 years of age taking SOVALDI in combination with ribavirin oral solution, decreased appetite was observed in 13% (7/54) subjects.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of SOVALDI. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with a sofosbuvir-containing regimen.

Skin And Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling Angioedema