Side Effects of Viekira Pak (dasabuvir, ombitasvir, paritaprevir, and ritonavir)

Viekira Pak (dasabuvir, ombitasvir, paritaprevir, and ritonavir) is a combination of antiviral drugs used to treat patients with hepatitis C virus (HCV) genotype 1. 

The drugs work in three different ways to help stop HCV from multiplying: 

• They block the effect of proteases, which are enzymes HCV uses for making new virus, leading to reduced numbers of HCV copies in the body. 
• Ombitasvir blocks HCV NS5A protease, while paritaprevir blocks HCV NS3/4A protease. 
• Dasabuvir blocks a viral structure called NS5B palm polymerase which is also needed for replication of HCV. 

Ritonavir is not active against the HCV virus. It is used to increase blood levels of paritaprevir by inhibiting the breakdown of paritaprevir.

Common side effects of Viekira Pak when used with ribavirin include:

• tiredness,
• nausea,
• itching,
• skin reactions such as redness or rash,
• sleep problems (insomnia), and
• feeling weak.

Common side effects of Viekira Pak when used without ribavirin include:

• nausea,
• itching, and
• problems sleeping.

Serious side effects of Viekira Pak include:

• allergic reactions,
• anemia, and
• increases in liver enzymes and bilirubin.

Drug interactions of Viekira Pak include afluzosin hydrochloride, due to the risk of low blood pressure. Certain anti-seizure medications, rifampin, and St. John's wort may reduce the effectiveness of treatment with Viekira Pak. 

Ergot derivatives when used with Viekira Pak can result in ergot toxicity. 

Combination birth control pills that contain ethinyl estradiol should be avoided due to the potential for liver damage. 

Combining certain “statin” drugs with Viekira Pak can increase the risk for serious muscle pain and injury, including rhabdomyolysis. Combining Viekira Pak and pimozide may increase the risk for abnormal heart beats. 

Combining efavirenz and Viekira Pak may increase the risk of liver damage. 

Combining Viekira Pak with drugs used to treat erectile dysfunction may increase the risk of vision problems, low blood pressure, fainting, and priapism (painful, long-lasting erection). 

Viekira Pak increases blood levels of triazolam and midazolam, leading to increased sedation and respiratory depression. 

Viekira Pak has not been evaluated in pregnant women and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When Viekira Pak is administered with ribavirin, the combination regimen should not be used in pregnant women and in men who can father children. Ribavirin is known to cause birth defects and should be avoided during pregnancy. 

There is an antiretroviral pregnancy registry that monitors the use of products such as Viekira Pak in HCV/HIV-1 co-infected women. Patients are advised to enroll in this program to help study and understand the safety of antiretroviral therapy during pregnancy. 

It is unknown if any of the drugs contained in Viekira Pak are excreted into human milk. Due to the lack of conclusive safety data, Viekira Pak should be used cautiously while breastfeeding. 

The most common side effects of Viekira Pak when used with ribavirin include:

• tiredness,
• nausea,
• itching,
• skin reactions such as redness or rash,
• sleep problems (insomnia), and
• feeling weak.

The most common side effects of Viekira Pak when used without ribavirin include:

• nausea,
• itching, and
• problems sleeping.

Other side effects include:

• allergic reactions,
• anemia, and
• increases in liver enzymes and bilirubin.

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

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 Pak 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 was based on data from seven clinical trials in more than 2,000 subjects who received Viekira Pak with or without ribavirin for 12 or 24 weeks.

Viekira Pak With Ribavirin In Placebo-Controlled Trials

The safety of Viekira Pak in combination with ribavirin was assessed in 770 subjects with chronic HCV genotype 1 (GT1) infection in two placebo-controlled trials (SAPPHIRE-I and -II). Adverse reactions that occurred more often in subjects treated with Viekira Pak in combination 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 3: Adverse Reactions with ≥ 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with Viekira Pak in Combination with Ribavirin Compared to Placebo for 12 Weeks

Viekira Pak With And Without Ribavirin In Regimen-Controlled Trials

Viekira Pak with and without ribavirin was assessed in 401 and 509 subjects with chronic HCV infection, 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 Viekira Pak in combination 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 both Viekira Pak in combination with ribavirin and Viekira Pak alone.

Table 4: Adverse Events with ≥ 5% Greater Frequency Reported in Subjects with Chronic HCV GT1 Infection Treated with Viekira Pak in Combination with Ribavirin Compared to Viekira Pak for 12 Weeks

Viekira Pak With Ribavirin In GT1-infected Subjects With Compensated Cirrhosis

Viekira Pak with ribavirin was assessed in 380 subjects with genotype 1 infection and compensated cirrhosis who were treated with Viekira Pak 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 Viekira Pak for 12 and 24 weeks with SAEs was 6% and 5%, respectively and 2% of subjects permanently discontinued treatment due to adverse events in each treatment arm.

Viekira Pak Without Ribavirin In GT1b-infected Subjects With Compensated Cirrhosis

Viekira Pak 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 Viekira Pak alone and 10% of subjects receiving Viekira Pak with ribavirin reported rash-related events. In SAPPHIRE-I and -II 16% of subjects receiving Viekira Pak with ribavirin and 9% of subjects receiving placebo reported skin reactions. In TURQUOISE-II, 18% and 24% of subjects receiving Viekira Pak with ribavirin for 12 or 24 weeks reported skin reactions.

The majority of events were graded as mild in severity. There were no serious events or severe cutaneous reactions, such as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM) or drug rash with eosinophilia and systemic symptoms (DRESS).

Laboratory Abnormalities

Serum ALT Elevations

Approximately 1% of subjects treated with Viekira Pak 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. 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.

Serum Bilirubin Elevations

Post-baseline elevations in bilirubin at least 2 x ULN were observed in 15% of subjects receiving Viekira Pak with ribavirin compared to 2% in those receiving Viekira Pak alone. 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 Viekira Pak in combination with ribavirin was -2.4 g/dL and the mean change in subjects treated with Viekira Pak alone 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 Viekira Pak with ribavirin had hemoglobin levels decrease to less than 8.0 g/dL during treatment. Seven percent of subjects treated with Viekira Pak in combination 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 Viekira Pak alone had a hemoglobin level less than 10 g/dL.

Viekira Pak In HCV/HIV-1 Co-infected Subjects

Viekira Pak with ribavirin was 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.

Viekira Pak In Selected Liver Transplant Recipients

Viekira Pak with ribavirin was 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.

Post-Marketing Adverse Reactions

The following adverse reactions have been identified during post approval use of Viekira Pak. 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.

Potential For Viekira Pak To Affect Other Drugs

Ombitasvir, paritaprevir, and dasabuvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of CYP3A4. Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP. Co-administration of Viekira Pak with drugs that are substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.

Potential For Other Drugs To Affect One Or More Components Of Viekira Pak

Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of Viekira Pak with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Dasabuvir is primarily metabolized by CYP2C8 enzymes. Co-administration of Viekira Pak with drugs that inhibit CYP2C8 may increase dasabuvir plasma concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir, dasabuvir and ritonavir are substrates of P-gp. Ombitasvir, paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of Viekira Pak.

Established And Other Potential Drug Interactions

If dose adjustments of concomitant medications are made due to treatment with Viekira Pak, doses should be re-adjusted after administration of Viekira Pak is completed. Dose adjustment is not required for Viekira Pak.

Table 5 provides the effect of co-administration of Viekira Pak on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of Viekira Pak. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.

Table 5: Established Drug Interactions Based on Drug Interaction Trials

Drugs Without Clinically Significant Interactions With Viekira Pak

No dose adjustments are recommended when Viekira Pak is co-administered with the following medications:

• abacavir,
• dolutegravir,
• digoxin,
• duloxetine,
• emtricitabine/tenofovir disoproxil fumarate,
• escitalopram,
• lamivudine,
• methadone,
• progestin only contraceptives,
• raltegravir,
• sofosbuvir,
• sulfamethoxazole,
• trimethoprim,
• warfarin and
• zolpidem.