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丙肝新型组合片包装VIEKIRA PAK(ombitasvir，paritaprevir，ritonavir；dasabuvir)治疗方案，被美国FDA批准为治疗慢性丙型肝炎病毒(HCV)基因型1感染患者，包括患有肝硬化的患者的新药。
2014年12月19日，美国食品药品监督管理局（FDA）批准Viekira Pak（ombitasvir+ paritaprevir+ritonavir片剂联合dasabuvir片剂）用于治疗基因1型慢性丙型肝炎病毒（HCV）感染者，包括合并肝硬化的患者。
丙肝是一种引起肝脏炎症的病毒性疾病，可导致肝功能下降、肝功能衰竭或肝癌。大多感染丙肝病毒的患者在出现明显肝损害前没有任何症状，这一潜伏期可达数十年。据美国疾病控制与预防中心（CDC）的数据显示，美国约有320万人感染HCV，如果得不到适当治疗，其中将有15%～30%的感染者会发展成肝硬化。
Viekira Pak包含三种新药—ombitasvir、paritaprevir和dasabuvir，这三种药物可协同抑制丙肝病毒的生长。Viekira Pak还包含了之前获批用于增加血中paritaprevir浓度的药物—ritonavir。Viekira Pak可以和利巴韦林联合使用，也可以单独使用，但是不推荐失代偿期肝硬化的患者使用。
“新一代的丙肝病毒治疗学正在改变美国丙肝患者的治疗模式，”FDA药物评价和研究中心抗菌产品办公室主任Edward Cox博士说。“我们看到口服新药的持续发展，相比以干扰素为基础的老一代治疗方案，这些新药不仅有非常高的病毒学应答率，而且更加安全。”
Viekira Pak是在过去一年里获得FDA批准、用于治疗慢性HCV感染的第四个药物。FDA于2013年11月批准了Olysio（simeprevir），于2013年12月批准了Sovaldi（索菲布韦），于2014年10月批准了Harvoni（来地帕韦+索菲布韦）。
Viekira Pak的有效性在六个临床实验中得到评估，这些试验总共入组了2308名受试者，他们是患有肝硬化和无肝硬化的慢性HCV感染者。在不同的试验中，受试者随机接受Viekira Pak治疗或安慰剂（糖衣药片）治疗；Viekira Pak联合或不联合利巴韦林治疗；Viekira Pak联合利巴韦林治疗12周或24周。这些试验旨在确定，受试者在治疗结束至少12周后血液中是否还能检测到丙肝病毒（持续病毒学应答，或SVR），SVR用以表明患者的丙肝已经治愈。包括难治性患者在内的多种受试者群体的试验结果显示，在接受Viekira Pak推荐剂量治疗的受试者中，有91%～100%的受试者实现了持续病毒学应答。
Viekira Pak的推荐剂量为：12.5mg ombitasvir+75mg paritaprevir+50mg ritonavir片剂，一天一次，一次2片；和250mg dasabuvir片剂，一天两次，一次1片。
VIEKIRA PAK™ (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) is a prescription medicine used with or without ribavirin to treat adults with genotype 1 chronic (lasting a long time) hepatitis C (hep C) virus infection, including people who have a certain type of cirrhosis (compensated).
VIEKIRA is not for people with advanced cirrhosis (decompensated). If you have cirrhosis, talk to your healthcare provider before taking VIEKIRA.
1. DESCRIPTION
VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
Ombitasvir, paritaprevir, ritonavir fixed dose combination tablet includes a hepatitis C virus NS5A inhibitor (ombitasvir), a hepatitis C virus NS3/4A protease inhibitor (paritaprevir), and a CYP3A inhibitor (ritonavir) that inhibits CYP3A mediated metabolism of paritaprevir, thereby providing increased plasma concentration of paritaprevir. Dasabuvir is a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor, which is supplied as separate tablets in the copackage. Both tablets are for oral administration.
Ombitasvir
The chemical name of ombitasvir is Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate. The drug substance is white to light yellow to light pink powder, and is practically insoluble in aqueous buffers but is soluble in ethanol. Ombitasvir has the following molecular structure:
Empirical formula: C50H67N7O8•4.5H2O - Molecular weight: 975.20 (hydrate)
Paritaprevir
The chemical name of paritaprevir is (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4] diazacyclopentadecine-14a(5H)-carboxamide dihydrate. The drug substance is white to off-white powder with very low water solubility. Paritaprevir has the following molecular structure:
Empirical formula: C40H43N7O7S•2H2O - Molecular weight: 801.91 (dihydrate)
Ritonavir
The chemical name of ritonavir is [5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester. The drug substance is white to off white to light tan powder practically insoluble in water and freely soluble in methanol and ethanol. Ritonavir has the following molecular structure:
Empirical formula: C37H48N6O5S2 - Molecular weight: 720.95
Ombitasvir, Paritaprevir, Ritonavir Fixed-Dose Combination Tablets
Ombitasvir, paritaprevir, and ritonavir film-coated tablets are co-formulated immediate release tablets. The tablet contains copovidone, K value 28, vitamin E polyethylene glycol succinate, propylene glycol monolaurate Type I, sorbitan monolaurate, colloidal silicon dioxide/colloidal anhydrous silica, sodium stearyl fumarate, polyvinyl alcohol, polyethylene glycol 3350/macrogol 3350, talc, titanium dioxide, and iron oxide red. The strength for the tablet is 12.5 mg ombitasvir, 75 mg paritaprevir, 50 mg ritonavir.
Dasabuvir
The chemical name of dasabuvir is Sodium 3-(3-tert-butyl-4-methoxy-5-{6-[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ide hydrate (1:1:1). The drug substance is white to pale yellow to pink powder, slightly soluble in water and very slightly soluble in methanol and isopropyl alcohol. Dasabuvir has the following molecular structure:
Empirical formula: C26H26N3O5S•Na•H2O - Molecular weight: 533.57 (salt, hydrate)
Dasabuvir is formulated as a 250 mg film-coated, immediate release tablet containing microcrystalline cellulose (D50-100 um), microcrystalline cellulose (D50-50 um), lactose monohydrate, copovidone, croscarmellose sodium, colloidal silicon dioxide/anhydrous colloidal silica, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350/macrogol 3350, talc, and iron oxide yellow, iron oxide red and iron oxide black. Each tablet contains 270.3 mg dasabuvir sodium monohydrate equivalent to 250 mg dasabuvir.
2. INDICATIONS AND USAGE
VIEKIRA PAK with or without ribavirin is indicated for the treatment of patients with genotype 1 chronic hepatitis C virus (HCV) infection including those with compensated cirrhosis.
Limitation of Use:
VIEKIRA PAK is not recommended for use in patients with decompensated liver disease [see Use in Specific Populations (8.7), and Clinical Pharmacology].
3. DOSAGE AND ADMINISTRATION
3.1 Recommended Dosage in Adults
VIEKIRA PAK is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
The recommended oral dosage of VIEKIRA PAK is two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening). Take VIEKIRA PAK with a meal without regard to fat or calorie content [see Clinical Pharmacology].
VIEKIRA PAK is used in combination with ribavirin (RBV) in certain patient populations (see Table 1). When administered with VIEKIRA PAK, the recommended dosage of RBV is based on weight: 1000 mg for subjects ≤75 kg and 1200 mg/day for those >75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
For patients with HCV/HIV-1 co-infection, follow the dosage recommendations in Table 1. Refer to Drug Interactions (7) for dosage recommendations for concomitant HIV-1 antiviral drugs.
Monitor liver chemistry tests before initiating and during therapy [see Warnings and Precautions (5.1)].
Table 1 shows the recommended VIEKIRA PAK treatment regimen and duration based on patient population.
Table 1. Treatment Regimen and Duration by Patient Population (Treatment-Naïve or Interferon-Experienced)
Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
VIEKIRA PAK administered with ribavirin for 12 weeks may be considered for some patients based on prior treatment history [see Clinical Studies].
3.2 Use in Liver Transplant Recipients
In liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score 2 or lower), the recommended duration of VIEKIRA PAK with ribavirin is 24 weeks, irrespective of HCV genotype 1 subtype [see Clinical Studies]. When VIEKIRA PAK is administered with calcineurin inhibitors in liver transplant recipients, dosage adjustment of calcineurin inhibitors is needed [see Drug Interactions (7)].
3.3 Hepatic Impairment
No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in patients with moderate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see Contraindications (4), Use in Specific Populations (8.7), and Clinical Pharmacology].
4. CONTRAINDICATIONS
• 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 in patients with severe hepatic impairment due to risk of potential toxicity [see Use in Specific Populations (8.7) and Clinical Pharmacology].
• 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.
Drugs that are strong inducers of CYP3A and CYP2C8 and may lead to reduced efficacy of VIEKIRA PAK.
Drugs that are strong inhibitors of CYP2C8 and may increase dasabuvir plasma concentrations and the risk of QT prolongation. Table 2 lists drugs that are contraindicated with VIEKIRA PAK [see Drug Interactions (7)].
Table 2. Drugs that are Contraindicated with VIEKIRA PAK
• VIEKIRA PAK is contraindicated in patients with known hypersensitivity (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir.
5. WARNINGS AND PRECAUTIONS
During clinical trials with VIEKIRA PAK with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all subjects [see Adverse Reactions (6.1)]. ALT elevations were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within two to eight weeks of onset with continued dosing of VIEKIRA PAK with or without ribavirin.
These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with VIEKIRA PAK [see Contraindications (4)]. Alternative methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during VIEKIRA PAK therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with VIEKIRA PAK.
Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of subjects taking these other estrogens, caution is warranted for co-administration with VIEKIRA PAK [see Adverse Reactions (6.1)].
Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should be repeated and monitored closely:
• Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
• Consider discontinuing VIEKIRA PAK if ALT levels remain persistently greater than 10 times the ULN.
• Discontinue VIEKIRA PAK if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
5.2 Risks Associated With Ribavirin Combination Treatment
If VIEKIRA PAK is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply to this combination regimen. Refer to the ribavirin prescribing information for a full list of the warnings and precautions for ribavirin.
5.3 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
The concomitant use of VIEKIRA PAK and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
• Loss of therapeutic effect of VIEKIRA PAK and possible development of resistance
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of VIEKIRA PAK.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during VIEKIRA PAK therapy; review concomitant medications during VIEKIRA PAK therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].
5.4 Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
The ritonavir component of VIEKIRA PAK is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with VIEKIRA PAK should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
6. ADVERSE REACTIONS
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:
• Increased Risk of ALT Elevations [see Warnings and Precautions (5.1)]
6.1 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 six Phase 3 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 infection in two placebo-controlled trials (SAPPHIRE-I and -II) [see Clinical Studies]. 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
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, dermatitis, 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]. 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
Grouped term ‘pruritus’ included the preferred terms pruritus and pruritus generalized.
VIEKIRA PAK with Ribavirin in Subjects with Compensated Cirrhosis
VIEKIRA PAK with ribavirin was assessed in 380 subjects with compensated cirrhosis who were treated for 12 (n=208) or 24 (n=172) weeks duration (TURQUOISE-II) [see Clinical Studies]. 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.
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 [see Contraindications (4) and Warnings and Precautions (5.1)]. 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 (5.1)].
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 [see Warnings and Precautions (5.4), Adverse Reactions (6.1) and Clinical Studies]. 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].
7. DRUG INTERACTIONS
See also Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology.
7.1 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.
7.2 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 inteactions with ritonavir.
Table 5. Established Drug Interactions Based on Drug Interaction Trials
See Clinical Pharmacology.
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%).
7.4 Drugs without Clinically Significant Interactions with VIEKIRA PAK
No dose adjustments are recommended when VIEKIRA PAK is co-administered with the following medications: digoxin, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, methadone, progestin only contraceptives, raltegravir, warfarin and zolpidem.
8. USE IN SPECIFIC POPULATIONS
8.1 Usage in Pregnancy
Pregnancy Category B
Pregnancy Exposure Registry
There is an Antiretroviral Pregnancy Registry that monitors pregnancy outcomes in women who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals. Physicians are encouraged to register patients by calling 1-800-258-4263.
Risk Summary
Adequate and well controlled studies with VIEKIRA PAK have not been conducted in pregnant women. In animal reproduction studies, no evidence of teratogenicity was observed with the administration of ombitasvir (mice and rabbits), paritaprevir, ritonavir (mice and rats), or dasabuvir (rats and rabbits) at exposures higher than the recommended clinical dose [see Data]. Because animal reproduction studies are not always predictive of human response, VIEKIRA PAK should be used during pregnancy only if clearly needed.
If VIEKIRA PAK is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.
Data
Animal data
In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals treated throughout pregnancy with ombitasvir and its major inactive human metabolites (M29, M36), paritaprevir, ritonavir, or dasabuvir. For ombitasvir, the highest dose tested produced exposures approximately 28-fold (mouse) or 4-fold (rabbit) the exposures in humans at the recommended clinical dose. The highest doses of the major, inactive human metabolites similarly tested produced exposures approximately 26-fold the exposures in humans at the recommended clinical dose. For paritaprevir, ritonavir, the highest doses tested produced exposures approximately 98-fold (mouse) or 8-fold (rat) the exposures in humans at the recommended clinical dose. For dasabuvir, the highest dose tested produced exposures approximately 48-fold (rat) or 12-fold (rabbit) the exposures in humans at the recommended clinical dose.
8.3 Nursing Mothers
It is not known whether any of the components of VIEKIRA PAK or their metabolites are present in human milk. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13, and dasabuvir were the predominant components observed in the milk of lactating rats, without effect on nursing pups.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VIEKIRA PAK and any potential adverse effects on the breastfed child from VIEKIRA PAK or from the underlying maternal condition.
If VIEKIRA PAK is administered with ribavirin, the nursing mothers information for ribavirin also applies to this combination regimen (see prescribing information for ribavirin).
8.4 Pediatric Use
Safety and effectiveness of VIEKIRA PAK in pediatric patients less than 18 years of age have not been established.
8.5 Geriatric Use
No dosage adjustment of VIEKIRA PAK is warranted in geriatric patients. Of the total number of subjects in clinical studies of VIEKIRA PAK, 8.5% (174/2053) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Hepatic Impairment
No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe (Child-Pugh C) hepatic impairment [see Contraindications (4) and Clinical Pharmacology].
8.7 Renal Impairment
No dosage adjustment of VIEKIRA PAK is required in patients with mild, moderate or severe renal impairment. VIEKIRA PAK has not been studied in patients on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use in patients with renal impairment [see Clinical Pharmacology].
8.8 Other HCV Genotypes
The safety and efficacy of VIEKIRA PAK has not been established in patients with HCV genotypes other than genotype 1.
9. OVERDOSAGE
In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately.
10. MECHANISM OF ACTION
Ritonavir is not active against HCV. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).
VIEKIRA PAK combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.
Ombitasvir
Ombitasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of ombitasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.
Paritaprevir
Paritaprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with IC50 values of 0.18 nM and 0.43 nM, respectively. Paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 2a, 2b, 3a, and 4a with IC50 values of 2.4 nM, 6.3 nM, 14.5 nM, and 0.16 nM, respectively.
Dasabuvir
Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited a panel of genotype 1a and 1b NS5B polymerases with median IC50 values of 2.8 nM (range 2.4 nM to 4.2 nM; n = 3) and 3.7 nM (range 2.2 nM to 10.7 nM; n = 4), respectively. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. Dasabuvir had reduced activity in biochemical assays against NS5B polymerases from HCV genotypes 2a, 2b, 3a and 4a (IC50 values ranging from 900 nM to >20 μM).
11. PHARMACODYNAMICS
Cardiac Electrophysiology
The effect of a combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir on QTc interval was evaluated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects. At concentrations approximately 6, 1.8 and 2 times the therapeutic concentrations of paritaprevir, ombitasvir, and dasabuvir, the combination did not prolong QTc to any clinically relevant extent.
12. PHARMACOKINETICS
Absorption
Ombitasvir, paritaprevir, ritonavir and dasabuvir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir and dasabuvir exposures increased in a dose proportional manner, paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is minimal for ombitasvir and dasabuvir and approximately 1.5-to 2-fold for ritonavir and paritaprevir. Steady state exposures are achieved after approximately 12 days of dosing.
The absolute bioavailability of dasabuvir estimated to be approximately 70%. The absolute bioavailability of ombitasvir, paritaprevir, and ritonavir was not evaluated.
Based on the population pharmacokinetic analysis, the median steady-state AUC0-24 for ombitasvir, paritaprevir and ritonavir were 1000, 2220 and 6180 ng•hr/mL, respectively, and the median steady-state AUC0-12 for dasabuvir was 3240 ng•hr/mL when VIEKIRA PAK was administered to HCV-infected subjects. Median steady-state Cmax for ombitasvir, paritaprevir, ritonavir and dasabuvir were 68, 262, 682 and 667 ng/mL, respectively, when VIEKIRA PAK was administered to HCV-infected subjects.
Effects of Food on Oral Absorption
Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate fat meal (approximately 600 Kcal, 20-30% calories from fat) increased the mean AUC by 82%, 211%, 49%, and 30%, respectively.
Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high fat meal (approximately 900 Kcal, 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.
Ombitasvir, paritaprevir, ritonavir, and dasabuvir should always be administered with a meal.
Ombitasvir: Ombitasvir was approximately 99.9% bound to human plasma proteins over a concentration range of 0.09 to 9 μg per mL. The mean blood-to-plasma concentration ratio was 0.49. The apparent volume of distribution (V/F) was 50.1 L.
Paritaprevir: Paritaprevir was approximately 97 to 98.6% bound to human plasma proteins over a concentration range of 0.08 to 8 μg per mL. The mean blood-to-plasma concentration ratio was 0.7. The apparent volume of distribution (V/F) was 16.7 L.
Ritonavir: Ritonavir was greater than 99% bound to human plasma proteins over a concentration range of 0.007 to 22 μg per mL. The mean blood-to-plasma concentration ratio was 0.6. The apparent volume of distribution (V/F) was 21.5 L.
Dasabuvir: Dasabuvir was greater than 99.5% bound to human plasma proteins over a concentration range of 0.05 to 5 μg per mL. The mean blood-to-plasma concentration ratio was 0.7. The apparent volume of distribution (V/F) was 396 L.
Metabolism
Ombitasvir: Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism.
Paritaprevir: Paritaprevir is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5.
Ritonavir: Ritonavir is predominantly metabolized by CYP3A, and to a lesser extent, by CYP2D6.
Dasabuvir: Dasabuvir is predominantly metabolized by CYP2C8, and to a lesser extent by CYP3A.
Elimination
Ombitasvir: Following a single dose administration of 14C-ombitasvir, approximately 90.2% of the radioactivity was recovered in feces with limited radioactivity (1.91%) in urine; unchanged ombitasvir accounted for 87.8% of the radioactivity in the feces and 0.03% in the urine. The mean elimination half-life of ombitasvir was approximately 21 to 25 hours.
Paritaprevir: Following a single dose administration of 14C-paritaprevir co-dosed with 100 mg of ritonavir, approximately 88% of the radioactivity was recovered in feces with limited radioactivity (8.8%) in urine; unchanged paritaprevir accounted for 1.1% of the radioactivity in the feces and 0.05% in the urine. The mean plasma half-life of paritaprevir was approximately 5.5 hours.
Ritonavir: Following dosing of ritonavir with ombitasvir and paritaprevir, mean plasma half-life of ritonavir was approximately 4 hours. Following a single 600 mg dose of 14C-ritonavir oral solution, 86.4% of the radioactivity was recovered in the feces and 11.3% of the dose was excreted in the urine.
Dasabuvir: Following a single dose administration of 14C-dasabuvir, approximately 94.4% of the radioactivity was recovered in feces with limited radioactivity (approximately 2%) in urine; unchanged dasabuvir accounted for 26% of the radioactivity in the feces and 0.03% in the urine. The mean plasma half-life of dasabuvir was approximately 5.5 to 6 hours.
Ombitasvir, paritaprevir, ritonavir, and dasabuvir do not inhibit organic anion transporter (OAT1) in vivo and based on in vitro data, are not expected to inhibit organic cation transporter (OCT2), organic anion transporter (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.
Specific Populations
Hepatic Impairment
The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and dasabuvir were evaluated in non-HCV infected subjects with mild hepatic impairment (Child-Pugh Category A; score of 5-6), moderate hepatic impairment (Child-Pugh Category B, score of 7-9) and severe hepatic impairment (Child-Pugh Category C, score of 10-15).
Relative to subjects with normal hepatic function, ombitasvir, paritaprevir and ritonavir AUC values decreased by 8%, 29% and 34%, respectively, and dasabuvir AUC values increased by 17% in subjects with mild hepatic impairment.
Relative to subjects with normal hepatic function, ombitasvir, ritonavir and dasabuvir AUC values decreased by 30%, 30% and 16%, respectively, and paritaprevir AUC values increased by 62% in subjects with moderate hepatic impairment.
Relative to subjects with normal hepatic function, paritaprevir, ritonavir and dasabuvir AUC values increased by 945%, 13%, and 325% respectively, and ombitasvir AUC values decreased by 54% in subjects with severe hepatic impairment.
No dosage adjustment of VIEKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). VIEKIRA PAK is not recommended in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). VIEKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (3.3), Contraindications (4) and Use in Specific Populations (8.6)].
Renal Impairment
The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and dasabuvir were evaluated in non-HCV infected subjects with mild (CLcr: 60 to 89 mL/min), moderate (CLcr: 30 to 59 mL/min), and severe (CLcr: 15 to 29 mL/min) renal impairment.
Overall, changes in exposure of ombitasvir, paritaprevir, ritonavir and dasabuvir in non-HCV infected subjects with mild-, moderate-and severe renal impairment are not expected to be clinically relevant. Pharmacokinetic data are not available on the use of VIEKIRA PAK in non-HCV infected subjects with End Stage Renal Disease (ESRD).
Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 19%, 42% and 21%, respectively, while ombitasvir AUC values were unchanged in subjects with mild renal impairment.
Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 33%, 80% and 37%, respectively, while ombitasvir AUC values were unchanged in subjects with moderate renal impairment.
Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 45%, 114% and 50%, respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment [see Use in Specific Populations (8.7)].
Pediatric Population
The pharmacokinetics of VIEKIRA PAK in pediatric patients less than 18 years of age has not been established [see Use in Specific Populations (8.4)].
Sex
No dose adjustment is recommended based on sex or body weight.
Race/Ethnicity
No dose adjustment is recommended based on race or ethnicity.
Age
No dose adjustment is recommended in geriatric patients [see Use in Specific Populations (8.5)].
Drug Interaction Studies
See also Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)
The effects of drugs discussed in Table 5 on the exposures of the individual components of VIEKIRA PAK are shown in Table 6. For information regarding clinical recommendations, see Drug Interactions (7).
Table 6. Drug Interactions: Change in Pharmacokinetic Parameters of the Individual Components of VIEKIRA PAK in the Presence of Co-administered Drug
a. Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of VIEKIRA PAK.
b. 30 mg cyclosporine was administered with VIEKIRA PAK and 100 mg in the reference arm without VIEKIRA PAK.
c. Darunavir administered with VIEKIRA PAK in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.
d. Darunavir administered with VIEKIRA PAK in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening.
e. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after the morning dose of VIEKIRA PAK compared to darunavir administered with 100 mg ritonavir in the evening.
f. N=3 for dasabuvir.
g. Study was conducted with paritaprevir, ritonavir and dasabuvir.
h. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of VIEKIRA PAK.
i. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval
Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).
Ombitasvir, paritaprevir and ritonavir were dosed once daily and dasabuvir was dosed twice daily in all the above studies except studies with gemfibrozil, ketoconazole and carbamazepine that used single doses.
Table 7 summarizes the effects of VIEKIRA PAK on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Drug Interactions (7).
Table 7. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIEKIRA PAK
a. Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of VIEKIRA PAK.
b. Atazanavir or darunavir or lopinavir parameters are reported.
c. Dose normalized parameters reported.
d. 30 mg cyclosporine was administered with VIEKIRA PAK and 100 mg in the reference arm without VIEKIRA PAK.
e. Darunavir administered with VIEKIRA PAK in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.
f. Darunavir administered with VIEKIRA PAK in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening.
g. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of VIEKIRA PAK compared to darunavir administered with 100 mg ritonavir in the evening.
h. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of VIEKIRA PAK.
i. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
NA: not available/not applicable; CI: Confidence interval
Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).
Ombitasvir, paritaprevir and ritonavir were dosed once daily and dasabuvir was dosed twice daily in all the above studies except studies with ketoconazole and carbamazepine that used single doses.
13. HOW SUPPLIED/STORAGE AND HANDLING
1) How Available:
a) Brand name: VIEKIRA PAK, by AbbVie Inc.
b) Generic drugs: None.
2) How Supplied:
VIEKIRA PAK is dispensed in a monthly carton for a total of 28 days of therapy. Each monthly carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.
Each child resistant daily dose pack contains four tablets: two 12.5/75/50 mg ombitasvir, paritaprevir, ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need to be taken in the morning and evening. The NDC number is NDC 0074-3093-28.
Ombitasvir, paritaprevir, ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong biconvex shaped, debossed with “AV1” on one side. Dasabuvir 250 mg tablets are beige-colored, film-coated, oval-shaped, debossed with “AV2” on one side.
3) Storage and Handling:
Store at or below 30°C (86°F).
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