VIEKIRA XR SIDE EFFECTS

SIDE EFFECTS

The following adverse reaction is described below and elsewhere in the labeling:

• Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
• Increased Risk of ALT Elevations

Clinical Trials Experience

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

If VIEKIRA XR is administered with ribavirin (RBV), refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.

The safety assessment was based on data from seven clinical trials in more than 2,000 subjects who received the components of VIEKIRA XR with or without ribavirin for 12 or 24 weeks.

Components Of VIEKIRA XR With Ribavirin In GT 1-Infected Subjects Without Cirrhosis

The safety of the components of VIEKIRA XR with ribavirin were assessed in 770 subjects with chronic HCV genotype 1 (GT1) infection without cirrhosis in two placebo-controlled trials (SAPPHIRE-I and -II) . Adverse reactions that occurred more often in subjects treated with the components of VIEKIRA XR with ribavirin compared to placebo were fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia (see Table 3). The majority of the adverse reactions were mild in severity. Two percent of subjects experienced a serious adverse event (SAE). The proportion of subjects who permanently discontinued treatment due to adverse reactions was less than 1%.

Table 1: Adverse Reactions with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection without Cirrhosis Treated with the Components of VIEKIRA XR with Ribavirin Compared to Placebo for 12 Weeks

Components Of VIEKIRA XR With And Without Ribavirin In GT1-Infected Subjects Without Cirrhosis

The components of VIEKIRA XR with and without ribavirin were assessed in 401 and 509 subjects with chronic HCV infection GT1 infection without cirrhosis, respectively, in three clinical trials (PEARL-II, PEARL-III and PEARL-IV). Pruritus, nausea, insomnia, and asthenia were identified as adverse events occurring more often in subjects treated with the components of VIEKIRA XR with ribavirin (see Table 4). The majority of adverse events were mild to moderate in severity. The proportion of subjects who permanently discontinued treatment due to adverse events was less than 1% for the components of VIEKIRA XR with or without ribavirin.

Table 2: Adverse Events with ≥5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection without Cirrhosis Treated with the Components of VIEKIRA XR with or without Ribavirin for 12 Weeks

Components Of VIEKIRA XR With Ribavirin In GT1-Infected Subjects With Compensated Cirrhosis

The components of VIEKIRA XR with ribavirin were assessed in 380 subjects with genotype 1 infection and compensated cirrhosis who were treated with the components of VIEKIRA XR plus ribavirin for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II). The type and severity of adverse events in subjects with compensated cirrhosis was comparable to non-cirrhotic subjects in other phase 3 trials. Fatigue, skin reactions and dyspnea occurred at least 5% more often in subjects treated for 24 weeks. The majority of adverse events occurred during the first 12 weeks of dosing in both treatment arms. Most of the adverse events were mild to moderate in severity. The proportion of subjects treated with the components of VIEKIRA XR for 12 and 24 weeks who experienced SAEs were 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm.

Components Of VIEKIRA XR Without Ribavirin In GT1b-Infected Subjects With Compensated Cirrhosis

The components of VIEKIRA XR without ribavirin for 12 weeks was assessed in 60 subjects with genotype 1b infection and compensated cirrhosis (TURQUOISE-III). The type and severity of adverse events and laboratory abnormalities in genotype 1b-infected subjects with compensated cirrhosis were comparable to subjects in other trials without ribavirin.

Skin Reactions

In PEARL-II, -III and -IV, 7% of subjects receiving the components of VIEKIRA XR alone and 10% of subjects receiving the components of VIEKIRA XR with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving the components of VIEKIRA XR with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving the components of VIEKIRA XR with ribavirin for 12 or 24 weeks reported skin reactions. The majority of events were graded as mild in severity.

Laboratory Abnormalities

Serum ALT Elevations

Approximately 1% of subjects treated with the components of VIEKIRA XR experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. The incidence increased to 25% (4/16) among women taking a concomitant ethinyl estradiol containing medication [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. The incidence of clinically relevant ALT elevations among women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy was 3% (2/59).

ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. The majority of these ALT elevations were assessed as drug-related liver injury. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT [see WARNINGS AND PRECAUTIONS].

Serum Bilirubin Elevations

Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving the components of VIEKIRA XR with ribavirin compared to 2% in those receiving the components of VIEKIRA XR without ribavirin. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with serum ALT elevations.

Anemia/Decreased Hemoglobin

Across all Phase 3 studies, the mean change from baseline in hemoglobin levels in subjects treated with the components of VIEKIRA XR with ribavirin was -2.4 g/dL and the mean change in subjects treated with the components of VIEKIRA XR without ribavirin was -0.5 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. Less than 1% of subjects treated with the components of VIEKIRA XR with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with the components of VIEKIRA XR with ribavirin underwent a ribavirin dose reduction due to a decrease in hemoglobin levels; three subjects received a blood transfusion and five required erythropoietin. One patient discontinued therapy due to anemia. No subjects treated with the components of VIEKIRA XR without ribavirin had a hemoglobin level less than 10 g/dL.

Components Of VIEKIRA XR With Ribavirin In HCV/HIV-1 Co-infected Subjects

The components of VIEKIRA XR with ribavirin were assessed in 63 subjects with HCV/HIV-1 co-infection who were on stable antiretroviral therapy. The most common adverse events occurring in at least 10% of subjects were fatigue (48%), insomnia (19%), nausea (17%), headache (16%), pruritus (13%), cough (11%), irritability (10%), and ocular icterus (10%).

Elevations in total bilirubin greater than 2 x ULN (mostly indirect) occurred in 34 (54%) subjects. Fifteen of these subjects were also receiving atazanavir at the time of bilirubin elevation and nine also had adverse events of ocular icterus, jaundice or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases. No subject experienced a grade 3 ALT elevation.

Seven subjects (11%) had at least one post-baseline hemoglobin value of less than 10 g/dL, and six of these subjects had a ribavirin dose modification; no subject in this small cohort required a blood transfusion or erythropoietin.

Median declines in CD4+ T-cell counts of 47 cells/mm³ and 62 cells/mm³ were observed at the end of 12 and 24 weeks of treatment, respectively, and most returned to baseline levels post-treatment. Two subjects had CD4+ T-cell counts decrease to less than 200 cells/mm³ during treatment without a decrease in CD4%. No subject experienced an AIDS-related opportunistic infection.

Components Of VIEKIRA XR With Ribavirin In Selected Liver Transplant Recipients

The components of VIEKIRA XR with ribavirin were assessed in 34 post-liver transplant subjects with recurrent HCV infection. Adverse events occurring in more than 20% of subjects included fatigue 50%, headache 44%, cough 32%, diarrhea 26%, insomnia 26%, asthenia 24%, nausea 24%, muscle spasms 21% and rash 21%. Ten subjects (29%) had at least one post-baseline hemoglobin value of less than 10 g/dL. Ten subjects underwent a ribavirin dose modification due to decrease in hemoglobin and 3% (1/34) had an interruption of ribavirin. Five subjects received erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of the components of VIEKIRA XR. Because these 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.

Immune System Disorders: Hypersensitivity reactions (including angioedema).

Hepatobiliary Disorders: Hepatic decompensation, hepatic failure

Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM).

SRC: NLM .