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What Is Viekira Pak?
Viekira Pak is an antiviral treatment for hepatitis C.
It's a combination therapy that includes the medicines ombitasvir, paritaprevir, dasabuvir, and ritonavir.
The drugs work together to attack the virus at three separate stages of the disease to stop the virus from reproducing.
Viekira Pak is used in people with genotype 1 chronic hepatitis C, including those with a certain type of liver disease called cirrhosis (compensated).
The medicine is only available with a doctor's prescription, and it may be used with or without the drug ribavirin.
Viekira Pak was approved by the Food and Drug Administration (FDA) in 2014. It's marketed by AbbVie, Inc.
Viekira Pak Warnings
Viekira Pak isn't suitable for use in people with advanced cirrhosis (decompensated). Talk to your doctor if you have cirrhosis before taking this medicine.
It's not known if this drug is safe or effective in children under 18 years of age.
Tell your doctor about all medical conditions you have or have previously had, including liver problems (other than those associated with hepatitis C) and human immunodeficiency virus (HIV).
You shouldn't take Viekira Pak if you use any of the following medications:
- Alfuzosin hydrochloride (Uroxatral)
- Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol)
- Efavirenz (Atripla, Sustiva)
- Ergot containing medicines such as ergotamine tartrate (Cafergot, Ergomar, Ergostat, Medihaler, Migergot, Wigraine, Wigrettes), dihydroergotamine mesylate (D.H.E. 45, Migranal), and methylergonovine (Ergotrate, Methergine)
- Birth control pills or patches such as Lo Loestrin FE, Norinyl, Ortho Tri-Cyclen Lo, Ortho Evra, and others
- Hormone replacement therapy such as FEM HRT
- A vaginal ring such as NuvaRing
- Gemfibrozil (Lopid)
- Lovastatin (Advicor, Altoprev, Mevacor)
- Midazolam, when taken by mouth
- Phenytoin, (Dilantin, Phenytek)
- Phenobarbital (Luminal)
- Pimozide (Orap)
- Rifampin (Rifadin, Rifamate, Rifater, Rimactane)
- Sildenafil citrate (Revatio), when taken for pulmonary artery hypertension (PAH)
- Simvastatin (Simcor, Vytorin, Zocor)
- St. John's wort or any product that contains St. John's wort
- Triazolam (Halcion)
Also, tell your physician if you've had a liver transplant. If you take tacrolimus (Prograf) or cyclosporine (Gengraf, Neoral, Sandimmune) to prevent organ rejection, the amount of these drugs in your blood can increase if you're also taking Viekira Pak.
Tell your healthcare provider if you've ever had a severe skin rash after taking the drug ritonavir (Norvir).
It's not known whether Viekira Pak will prevent you from infecting others with hepatitis C during treatment. Talk to your doctor about ways to prevent the spread of the virus.
Pregnancy and Viekira Pak
It's not known whether Viekira Pak will harm an unborn baby. Tell your doctor if you're pregnant or might become pregnant while undergoing treatment with this medicine.
When taking Viekira Pak with ribavirin, be sure to research the pregnancy warnings for that drug as well.
It's not known whether the drugs pass into breast milk. Tell your doctor if you are breastfeeding while taking Viekira Pak.
Viekira Pak Dosage
Viekira Pak includes two different tablets. The pink tablet contains ombitasvir, paritaprevir, and ritonavir, and the beige tablet contains dasabuvir.
Take both types of tablets exactly as prescribed. Don't take more or less of the medicine than is recommended.
Your prescription will include a monthly carton that contains enough medicine for 28 days. Each daily dose pack contains four tablets, which is all of your medicine for one day.
Take the two pink tablets with one of the beige tablets at about the same time each morning. Take the second beige tablet at about the same time each evening.
Don't stop taking this medicine without first talking to your doctor.
Viekira Pak Overdose
If you suspect an overdose, contact a poison control center or emergency room immediately.
You can get in touch with a poison control center at (800) 222-1222.
Missed Dose of Viekira Pak
If you miss a dose of the pink tablets, and it's less than 12 hours from the time you usually take the dose, take it with a meal as soon as you remember. Then, take your next dose at your usual time with a meal.
If you miss a dose of the pink tablets, and it's more than 12 hours from the time you usually take the dose, skip the missed dose. Take your next dose at your usual time with a meal.
If you miss a dose of the beige tablet, and it's less than six hours from the time you usually take the dose, take it with a meal as soon as you remember. Then, take your next dose at your usual time with a meal.
If you miss a dose of the beige tablet, and it's more than six hours from the time you usually take the dose, skip the missed dose. Then, take your next dose at your usual time with a meal.
Side Effects of Viekira Pak
Serious side effects have been reported with Viekira Pak. See the “Viekira Pak Precautions” section.
Common side effects of Viekira Pak include:
- feeling tired
- feeling weak or lacking energy
- trouble sleeping
This is not a complete list of Viekira Pak side effects. Ask your doctor or pharmacist for more information.
Tell your doctor if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Viekira Pak and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
Viekira Pak falls into category B. There are no well-done studies that have been done in humans with Viekira Pak. In animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.
Viekira Pak Dosage and Administration
Prior to and during treatment, perform appropriate laboratory tests and clinical evaluation to assess for evidence of hepatic decompensation.1 (See Hepatic Effects under Cautions.)
Ombitasvir/paritaprevir/ritonavir commercially available copackaged with dasabuvir (Viekira Pak) for use when multiple-drug regimen of ombitasvir/paritaprevir/ritonavir with dasabuvir indicated.1
Administer ombitasvir/paritaprevir/ritonavir orally once daily (in the morning) with a meal;1 administer dasabuvir orally twice daily (morning and evening) with a meal.1
If a dose of ombitasvir/paritaprevir/ritonavir is missed and remembered within 12 hours of scheduled time, take dose as soon as possible.1 If a missed dose of ombitasvir/paritaprevir/ritonavir is remembered >12 hours after originally scheduled time, skip missed dose and resume regular dosing schedule.1
If a dose of dasabuvir is missed and remembered within 6 hours of scheduled time, take dose as soon as possible.1 If a missed dose of dasabuvir is remembered >6 hours after originally scheduled time, skip missed dose and resume regular dosing schedule.1
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Each fixed-combination tablet of ombitasvir/paritaprevir/ritonavir contains ombitasvir 12.5 mg, paritaprevir 75 mg, and ritonavir 50 mg.1
Each tablet of dasabuvir sodium contains 250 mg of dasabuvir.1
AdultsTreatment of Chronic HCV Infection HCV Genotype 1 Infection Oral
2 tablets of ombitasvir/paritaprevir/ritonavir once daily in the morning (total of 25 mg of ombitasvir, 150 mg of paritaprevir, and 100 mg of ritonavir) and 1 tablet of dasabuvir (250 mg) twice daily (morning and evening).1
Duration of treatment is 12 or 24 weeks depending patient type.1 For certain patients, ribavirin also included in treatment regimen.1 (See Table 1.)
Manufacturer states a treatment duration of 12 weeks can be considered for some patients based on prior treatment history.1
Duration of Treatment
HCV genotype 1a infection without cirrhosis
Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin
HCV genotype 1a infection with compensated cirrhosis
Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin
HCV genotype 1b infection without cirrhosis
Ombitasvir/paritaprevir/ritonavir with dasabuvir
HCV genotype 1b infection with compensated cirrhosis
Ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin
Adults with unknown genotype 1 subtype or mixed genotype 1 subtypes: Follow treatment recommendations for HCV genotype 1a infection.1 (See Table 1.)HCV Genotype 1 Infection in Individuals Coinfected with HIV Oral
Use same ombitasvir/paritaprevir/ritonavir with dasabuvir dosage and same HCV genotype-specific multiple-drug regimen and treatment duration recommended for patients without HIV infection.1 (See Table 1.)HCV Genotype 1 Infection in Liver Transplant Recipients Oral
HCV genotype 1a or 1b infection in liver transplant recipients with normal hepatic function and Metavir score ≤2: Use ombitasvir/paritaprevir/ritonavir with dasabuvir in conjunction with ribavirin for 24 weeks.1
Mild hepatic impairment (Child-Pugh class A): Dosage adjustments not needed.1
Moderate or severe hepatic impairment (Child-Pugh class B or C): Contraindicated.1 (See Hepatic Impairment under Cautions.)
Mild, moderate, or severe renal impairment: Dosage adjustments not needed.1
Dosage adjustments not needed based solely on age.1 (See Geriatric Use under Cautions.)
Precautions While Using Viekira Pak
It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.
Using this medicine together with ribavirin while you are pregnant can harm your unborn baby. These medicines may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Avoid pregnancy during combination treatment with this medicine and ribavirin for 6 months of stopping treatment. If a pregnancy occurs while you are using these medicines, tell your doctor right away.
Do not use the following medicines while you are using this medicine: alfuzosin (Uroxatral®), cisapride (Propulsid®), colchicine (Colcrys®), dronedarone (Multaq®), efavirenz (Sustiva®), ethinyl estradiol (Norinyl®, Ortho Evra®), everolimus (Afinitor®), gemfibrozil (Lopid®), lurasidone (Latuda®), oral midazolam (Versed®), pimozide (Orap®), ranolazine (Ranexa®), rifampin (Rifadin®, Rimactane®), sildenafil (Revatio®), sirolimus (Rapamune®), St. John's wort, tacrolimus (Prograf®), triazolam (Halcion®), certain medicines to lower cholesterol (such as atorvastatin, lovastatin, simvastatin, Mevacor®, Zocor®), medicine to treat seizures (such as carbamazepine, phenobarbital, phenytoin, Tegretol®), or ergot medicines (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine, Cafergot®, Ergomar®, Wigraine®). Using Viekira Pak® with any of these medicines can cause very serious medical problems.
Check with your doctor right away if you are weak or tired, have onset of confusion, have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.
Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.
Viekira Pak Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:Less common
- Abdominal or stomach pain
- bloating of the abdomen or stomach
- dark urine
- light-colored stools
- nausea and vomiting
- yellow eyes or skin
- Blistering, peeling, or loosening of the skin
- joint or muscle pain
- red skin lesions, often with a purple center
- red, irritated eyes
- sore throat
- sores, ulcers, or white spots in the mouth or on the lips
- unusual tiredness or weakness
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:More common
- Itching skin or rash
- lack or loss of strength
- trouble sleeping
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
Consumer Information Use and Disclaimer
- If your symptoms or health problems do not get better or if they become worse, call your doctor.
- Do not share your drugs with others and do not take anyone else's drugs.
- Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
- Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
- This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Viekira Pak is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
- If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
This information should not be used to decide whether or not to take Viekira Pak or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Viekira Pak (ombitasvir, paritaprevir, ritonavir, and dasabuvir tablets). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
Review Date: October 4, 2017
- Viekira Pak is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity [see Warnings and Precautions (5.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
- If Viekira Pak is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.
- Viekira Pak is contraindicated:
- With drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
- With drugs that are moderate or strong inducers of CYP3A and strong inducers of CYP2C8 and may lead to reduced efficacy of Viekira Pak.
- With drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation.
- In patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome).
Table 2 lists drugs that are contraindicated with Viekira Pak [see Drug Interactions (7)].
|Drug Class||Drug(s) within Class |
|Alfuzosin HCL||Potential for hypotension.|
|Anti-anginal||Ranolazine||Potential for serious and/or life-threatening reactions.|
|Antiarrhythmic||Dronedarone||Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.|
|Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of Viekira Pak.|
|Anti-gout||Colchicine||Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.|
|Antihyperlipidemic agent||Gemfibrozil||Increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation.|
|Antimycobacterial||Rifampin||Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of Viekira Pak.|
|Potential for serious and/or life-threatening reactions. |
Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
|Ergot derivatives||Ergotamine, |
|Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergotamine, dihydroergotamine, or methylergonovine.|
|Ethinyl estradiol-containing products||Ethinyl estradiol-containing medications such as combined oral contraceptives||Potential for ALT elevations [see Warnings and Precautions (5.3)].|
|GI Motility Agent||Cisapride||Potential for serious and/or life threatening reactions such as cardiac arrhythmias|
|Herbal Product||St. John’s Wort (Hypericum perforatum)||Ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of Viekira Pak.|
|HMG-CoA Reductase |
|Potential for myopathy including rhabdomyolysis.|
|Increased potential for serious and/or life threatening immunosuppressant associated adverse events.|
|Non-nucleoside reverse transcriptase inhibitor||Efavirenz||Co-administration of efavirenz based regimens with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations.|
|Sildenafil when dosed |
as Revatio for the
treatment of pulmonary
arterial hypertension (PAH)
|There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.|
Orally administered midazolam
|Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with Viekira Pak may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.|
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 [see Warnings and Precautions (5.2)]
- Increased Risk of ALT Elevations [see Warnings and Precautions (5.3)]
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) [see Clinical Studies (14.1, 14.2)]. 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%.
|SAPPHIRE-I and -II|
|Viekira Pak + RBV |
N = 770
N = 255
|*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized. |
$Grouped terms: rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer, urticaria.
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) [see Clinical Studies (14.1, 14.2)]. 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.
|PEARL-II, -III and -IV|
|Viekira Pak + RBV |
N = 401
|Viekira Pak |
N = 509
|*Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized.|
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) [see Clinical Studies (14.1, 14.3)]. 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) [see Clinical Studies (14.1, 14.3)]. 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.
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).
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 [see Contraindications (4) and Warnings and Precautions (5.3)]. 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 (5.3)].
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.
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 [see Warnings and Precautions (5.6), Adverse Reactions (6.1) and Clinical Studies (14.6)]. 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 [see Clinical Studies (14.5)].
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 [see Warnings and Precautions (5.2)].
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 [see Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].
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.
7.3 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. See Contraindications (4) for drugs that are contraindicated with Viekira Pak. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.
|Concomitant Drug Class: Drug Name||Effect on Concentration||Clinical Comments|
|ANGIOTENSIN RECEPTOR BLOCKERS e.g.|
|↑ angiotensin receptor blockers||Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.|
|↑ antiarrhythmics||For contraindicated antiarrhythmics [see Contraindications (4)]. |
Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with Viekira Pak.
|metformin||↔ metformin||Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.|
|ketoconazole||↑ ketoconazole||When Viekira Pak is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.|
|voriconazole*||↓ voriconazole||Co-administration of Viekira Pak with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.|
|quetiapine*||↑ quetiapine||For contraindicated antipsychotics [see Contraindications (4)]. |
|CALCIUM CHANNEL BLOCKERS|
|↑ calcium channel blockers||Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.|
|fluticasone*||↑ fluticasone||Concomitant use of Viekira Pak with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.|
|furosemide||↑ furosemide (Cmax)||Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.|
|↑ paritaprevir||When coadministered with Viekira Pak, atazanavir 300 mg (without ritonavir) should only be given in the morning.|
|darunavir/ritonavir||↓ darunavir (Ctrough)||Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions: |
Darunavir 800 mg once daily (without ritonavir) can be co-administered with Viekira Pak.
Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information:
Co-administration of darunavir/ritonavir 600/100 mg twice daily with Viekira Pak is not recommended.
|lopinavir/ritonavir||↑ paritaprevir||Co-administration of Viekira Pak with lopinavir/ritonavir is not recommended.|
|rilpivirine||↑ rilpivirine||For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)]. |
Co-administration of Viekira Pak with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
|HMG CoA REDUCTASE INHIBITORS|
|rosuvastatin||↑ rosuvastatin||For contraindicated HMG-CoA Reductase Inhibitors [see Contraindications (4)]. |
When Viekira Pak is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.
|pravastatin||↑ pravastatin||When Viekira Pak is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.|
|cyclosporine||↑ cyclosporine||For contraindicated immunosuppressants [see Contraindications (4)]. |
When initiating therapy with Viekira Pak, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of Viekira Pak therapy, the appropriate time to resume pre-Viekira Pak dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
|LONG ACTING BETA-ADRENOCEPTOR AGONIST|
|salmeterol*||↑ salmeterol||Concurrent administration of Viekira Pak and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.|
|carisoprodol||↓ carisoprodol |
(metabolite of carisoprodol)
|Increase dose if clinically indicated.|
(metabolite of cyclobenzaprine)
|Increase dose if clinically indicated.|
|↑ buprenorphine |
(metabolite of buprenorphine)
|Patients should be closely monitored for sedation and cognitive effects.|
|↑ hydrocodone |
|Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of Viekira Pak therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.|
|PROTON PUMP INHIBITORS|
|omeprazole||↓ omeprazole||Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.|
|alprazolam||↑ alprazolam||For contraindicated Sedatives/Hypnotics [see Contraindications (4)]. |
Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
|diazepam||↓ diazepam |
(metabolite of diazepam)
|Increase dose if clinically indicated.|
|See Clinical Pharmacology, Tables 8 and 9. |
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%).
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (150 mg per kg per day). Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg per kg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25 mg.
Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Paritaprevir, ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (300/30 mg per kg per day). Similarly, paritaprevir, ritonavir was not carcinogenic in a 2-year rat study up to the highest dose tested (300/30 mg per kg per day), resulting in paritaprevir exposures approximately 9-fold higher than those in humans at 150 mg.
Paritaprevir was positive in an in vitro chromosome aberration test using human lymphocytes. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).
Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (2000 mg per kg per day). Similarly, dasabuvir was not carcinogenic in a 2-year rat study up to the highest dose tested (800 mg per kg per day), resulting in dasabuvir exposures approximately 19-fold higher than those in humans at 500 mg.
Dasabuvir was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.
If Viekira Pak is administered with ribavirin, refer to the prescribing information for ribavirin for information on carcinogenesis, and mutagenesis.
Impairment of Fertility
Ombitasvir had no effects on embryo-fetal viability or on fertility when evaluated in mice up to the highest dose of 200 mg per kg per day. Ombitasvir exposures at this dose were approximately 25-fold the exposure in humans at the recommended clinical dose.
Paritaprevir, ritonavir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 300/30 mg per kg per day. Paritaprevir exposures at this dose were approximately 2- to 5-fold the exposure in humans at the recommended clinical dose.
Dasabuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 800 mg per kg per day. Dasabuvir exposures at this dose were approximately 16-fold the exposure in humans at the recommended clinical dose.
If Viekira Pak is administered with ribavirin, refer to the prescribing information for ribavirin for information on Impairment of Fertility.