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Technivie(ombitasvir,paritaprevir and ritonavir)tablets

2015-08-01 08:09:44  作者:新特药房  来源:互联网  浏览次数:80  文字大小:【】【】【
简介: 2015年7月27日,艾伯维(AbbVie)丙肝药物获美国FDA已批准Technivie(ombitasvir/paritaprevir/ritonavir)联合利巴韦林(RBV)用于未发生肝硬化的基因型4丙肝(GT-4 HCV)成人患者的治疗。此次批准, ...

2015年7月27日,艾伯维(AbbVie)丙肝药物获美国FDA已批准Technivie(ombitasvir/paritaprevir/ritonavir)联合利巴韦林(RBV)用于未发生肝硬化的基因型4丙肝(GT-4 HCV)成人患者的治疗。此次批准,使Technivie联合RBV疗法成为首个也是唯一一个用于基因型4丙肝的全口服、无干扰素、直接作用的鸡尾酒疗法,同时也标志着该基因型丙肝临床治疗的重大进步。Technivie联合RBV治疗12周,将提供一种治愈率(SVR12)达100%的治疗选择。需要注意的是,Technivie不推荐用于中度肝功能损害的患者(Child-Pugh B级)。
Technivie是一种全口服抗病毒药物,由固定剂量paritaprevir/ritonavir(150mg/100mg)与ombitasvir(25mg)复配而成。Technivie每日口服一次,在进餐时服药,同时配合利巴韦林(1000mg或1200mg,根据体重调整,每日2次)。
之前,FDA已于2014年授予Technivie突破性药物资格,并通过优先审查程序进行了审批。Technivie的获批,是基于IIb期PEARL-I研究的数据。该研究在135例基因型4丙肝成人患者中开展,其中初治组(n=42/42)及既往经聚乙二醇干扰素(pegIFN)联合RBV治疗失败的经治组(n=49/49)接受Technivie联合利巴韦林(RBV)治疗12周,取得了100%的治愈率(SVR12)。此外,接受Technivie单药治疗(无RBV)的初治组SVR12也达到了91%(n=40/44),该治疗组有1例患者(2%)在治疗期间发生病毒学爆发,2例患者(5%)在治疗后病情复发。其他治疗组未发生病毒学失败。
值得一提的是,Technivie(ombitasvir/paritaprevir/ritonavir,25mg/150mg/100mg)中的3种活性药物成分也存在于艾伯维推出的全口服丙肝鸡尾酒疗法Viekira Pak,后者由固定剂量ombitasvir/paritaprevir/ritonavir(25mg/150mg/100mg,每日一次)和dasabuvir(250mg,每日两次)组成,于2014年12月获FDA批准用于基因型1丙肝成人患者。
据美国疾病控制中心(CDC)估计,在美国丙肝患者多达270万,约为艾滋病患者的2倍多。丙肝主要分为6个基因型(基因型1-6,GT 1-6),其中基因型1是美国最主要的丙肝类型,约占74%,而基因型4仅占6%左右,而且在历史上被认为是最难治疗的丙肝类型。不过,在全球范围内,基因型4丙肝患者总数高达3400万,是埃及、中东及非洲地区最主要的丙肝类型,约占这些地区丙肝病例的80%。这也意味着,美国以外的市场,将是艾伯维丙肝新药Technivie一个难得的突破口。


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TECHNIVIE safely and effectively. See full prescribing information for TECHNIVIE.
TECHNIVIE (ombitasvir, paritaprevir and ritonavir) tablets, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
TECHNIVIE is a fixed-dose combination of ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor and is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis. (1)
Limitations of Use: TECHNIVIE is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B). (1)
DOSAGE AND ADMINISTRATION
Recommended dosage: Two tablets taken orally once daily (in the morning) with a meal without regard to fat or calorie content. TECHNIVIE is recommended to be used in combination with ribavirin. (2.1)

Patient Population Treatment Duration
Genotype 4 without cirrhosis TECHNIVIE + ribavirin* 12 weeks
*TECHNIVIE administered without ribavirin for 12 weeks may be considered for treatment-naïve patients who cannot take or tolerate ribavirin [see Microbiology (12.4) and Clinical Studies (14)].
Hepatic impairment: TECHNIVIE is not recommended in patients with moderate hepatic impairment (Child-Pugh B). TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C). (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 12.5 mg ombitasvir, 75 mg paritaprevir, 50 mg ritonavir. (3)
CONTRAINDICATIONS
The contraindications to ribavirin also apply to this combination regimen. (4)
Patients with severe hepatic impairment. (4, 8.6.1, 12.3)
Co-administration with drugs that are: highly dependent on CYP3A for clearance; moderate and strong inducers of CYP3A. (4)
Known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome). (4)
WARNINGS AND PRECAUTIONS
ALT Elevations: Discontinue ethinyl estradiol-containing medications prior to starting TECHNIVIE (alternative contraceptive methods are recommended). Perform hepatic laboratory testing on all patients during the first 4 weeks of treatment. For ALT elevations on TECHNIVIE, monitor closely and follow recommendations in full prescribing information. (5.1)
Risks Associated With Ribavirin Combination Treatment: The warnings and precautions for ribavirin also apply to this combination regimen. (5.2)
Drug Interactions: The concomitant use of TECHNIVIE and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of TECHNIVIE. (5.3)
ADVERSE REACTIONS
The most commonly reported adverse reactions (incidence greater than 10% of subjects, all grades) observed with treatment with ombitasvir, paritaprevir and ritonavir with ribavirin for 12 weeks were asthenia, fatigue, nausea and insomnia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Co-administration of TECHNIVIE can alter the plasma concentrations of some drugs and some drugs may alter the plasma concentrations of TECHNIVIE. The potential for drug-drug interactions must be considered before and during treatment. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.3, 7, 12.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 7/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
TECHNIVIE is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.
Limitations of Use:
TECHNIVIE is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage in Adults
TECHNIVIE is ombitasvir, paritaprevir and ritonavir fixed dose combination tablets.
The recommended dosage of TECHNIVIE is two tablets taken orally once daily (in the morning). Take TECHNIVIE with a meal without regard to fat or calorie content [see Clinical Pharmacology (12.3)].
TECHNIVIE is used in combination with ribavirin (RBV). When administered with TECHNIVIE, the recommended dosage of RBV is based on weight: 1000 mg per day for subjects less than 75 kg and 1200 mg per day for those weighing at least 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information.
Monitor liver chemistry tests before initiating and during therapy [see Warnings and Precautions (5.1)].
Table 1 shows the recommended TECHNIVIE treatment regimen and duration for HCV genotype 4 patients without cirrhosis.
Table 1. Treatment Regimen and Duration for Patients with HCV Genotype 4 without Cirrhosis 

Patient Population Treatment Duration
Genotype 4 without cirrhosis TECHNIVIE + ribavirin* 12 weeks
*TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve patients who cannot take or tolerate ribavirin [see Microbiology (12.4) and Clinical Studies (14)].
2.2 Dosage in Patients with Hepatic Impairment
TECHNIVIE is not recommended in patients with moderate hepatic impairment (Child-Pugh B). TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C) [see Contraindications (4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
TECHNIVIE is a pink-colored, film-coated, oblong, biconvex-shaped tablet debossed “AV1” on one side. Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.
4 CONTRAINDICATIONS(What is this?)
The contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin.
TECHNIVIE is contraindicated:
In patients with severe hepatic impairment due to risk of potential toxicity [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
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 may lead to reduced efficacy of TECHNIVIE.
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 TECHNIVIE [see Drug Interactions (7)].
Table 2. Drugs that are Contraindicated with TECHNIVIE 

Drug Class Drug(s) within Class
that are
Contraindicated
Clinical Comments
Alpha1-adrenoreceptor
antagonist
Alfuzosin HCl Potential for hypotension.
Anticonvulsants Carbamazepine,
phenytoin,
phenobarbital
Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
Antimycobacterial Rifampin Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
Ergot derivatives Ergotamine, dihydroergotamine, ergonovine, methylergonovine Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, 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 (5.1)].
Herbal Product St. John’s Wort (Hypericum perforatum) Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
HMG-CoA Reductase Inhibitors Lovastatin,
simvastatin
Potential for myopathy including rhabdomyolysis.
Neuroleptics Pimozide Potential for cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor Efavirenz Co-administration of efavirenz based regimens with paritaprevir, ritonavir was poorly tolerated and resulted in liver enzyme elevations.
Phosphodiesterase-5 (PDE5) inhibitor 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.
Sedatives/hypnotics Triazolam
Orally administered midazolam
Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with TECHNIVIE 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.
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of ALT Elevations
During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of 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.
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 TECHNIVIE [see Contraindications (4)]. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended during TECHNIVIE therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with TECHNIVIE.
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. Due to the limited number of subjects taking these other estrogens in clinical studies, caution is warranted for co-administration with TECHNIVIE [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 TECHNIVIE if ALT levels remain persistently greater than 10 times the ULN.
Discontinue TECHNIVIE 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
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 TECHNIVIE and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
Loss of therapeutic effect of TECHNIVIE and possible development of resistance
Possible clinically significant adverse reactions from greater exposures of concomitant drugs or components of TECHNIVIE.
See Table 4 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 TECHNIVIE therapy; review concomitant medications during TECHNIVIE 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 TECHNIVIE 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 TECHNIVIE should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.
6 ADVERSE REACTIONS
TECHNIVIE should be 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 ombitasvir, paritaprevir and ritonavir 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 of TECHNIVIE is based on data from a clinical study that included 135 HCV genotype 4-infected subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects without cirrhosis who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks (PEARL-I).
Adverse reactions that occurred in subjects treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 3. The majority of adverse reactions in PEARL-I were mild in severity. None of the subjects who received ombitasvir, paritaprevir and ritonavir with ribavirin experienced a serious adverse reaction. None of the subjects receiving ombitasvir, paritaprevir and ritonavir with or without ribavirin discontinued treatment due to an adverse reaction.
Table 3. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in Subjects Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks 

PEARL-I
Adverse Reaction Ombitasvir, paritaprevir,
ritonavir + RBV
12 Weeks
N = 91
%
Ombitasvir, paritaprevir,
ritonavir
12 Weeks
N = 44
%
Asthenia 29 25
Fatigue 15 7
Nausea 14 9
Insomnia 13 5
Pruritus* 7 5
Skin reactions$,# 7 5
*Grouped term ‘pruritus’ includes the preferred terms pruritus and pruritus generalized.
$Grouped term ‘skin reactions’ includes the preferred 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 and urticaria.
#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
None of the 135 HCV GT4 infected subjects treated with TECHNIVIE experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment [see Warnings and Precautions (5.1)].
Serum Bilirubin Elevations
Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects receiving TECHNIVIE; all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations.
Anemia/Decreased Hemoglobin
The mean change from baseline in hemoglobin levels in subjects treated with TECHNIVIE in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with TECHNIVIE alone was -0.4 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. One subject treated with TECHNIVIE with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. Four percent (4/91) of subjects treated with TECHNIVIE with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels; none received a blood transfusion or erythropoietin. No subjects treated with TECHNIVIE alone had a hemoglobin level less than 8 g/dL.
6.2 Post-Marketing Experience
Hypersensitivity reactions (including angioedema) have been observed.
7 DRUG INTERACTIONS
7.1 Potential for TECHNIVIE to Affect Other Drugs
Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir and ritonavir are inhibitors of BCRP and P-gp. Ritonavir is an inhibitor of CYP3A4. Co-administration of TECHNIVIE with drugs that are substrates of CYP3A, P-gp, 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 TECHNIVIE
Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of TECHNIVIE with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Paritaprevir is a substrate of BCRP, OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of TECHNIVIE.
7.3 Established and Other Potential Drug Interactions
If dosage adjustments of concomitant medications are made due to treatment with TECHNIVIE, dosages should be re-adjusted after administration of TECHNIVIE is completed. Dosage adjustment is not required for TECHNIVIE.
Table 4 provides the effect of co-administration of TECHNIVIE on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of TECHNIVIE. See Contraindications (4) for drugs that are contraindicated with TECHNIVIE. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.
Table 4. Established Drug Interactions Based on Drug Interaction Trials 

Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments
ANTIARRHYTHMICS
digoxin ↑ digoxin Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended.
amiodarone*,
bepridil*,
disopyramide*,
flecainide*,
lidocaine (systemic)*,
mexiletine*,
propafenone*,
quinidine*
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with TECHNIVIE.
ANTIFUNGALS
ketoconazole ↑ ketoconazole When TECHNIVIE is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole* ↓ voriconazole Co-administration of TECHNIVIE with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTICS  
quetiapine ↑ quetiapine
  • Initiation of TECHNIVIE in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
  • Initiation of quetiapine in patients taking TECHNIVIE: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine ↑ amlodipine Consider dose reduction for amlodipine. Clinical monitoring is recommended.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone* ↑ fluticasone Concomitant use of TECHNIVIE with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide ↑ furosemide (Cmax) Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir or atazanavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with atazanavir or atazanavir/ritonavir is not recommended.
darunavir/ritonavir ↓ darunavir (Ctrough) When co-administered with TECHNIVIE, darunavir 800 mg (without ritonavir) should be taken at the same time as TECHNIVIE.
lopinavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with lopinavir/ritonavir is not recommended.
rilpivirine ↑ rilpivirine Co-administration of TECHNIVIE with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
pravastatin ↑ pravastatin When TECHNIVIE is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine ↑ cyclosporine When initiating therapy with TECHNIVIE, 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 TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
tacrolimus ↑ tacrolimus When initiating therapy with TECHNIVIE, the dose of tacrolimus needs to be reduced. Do not administer tacrolimus on the day TECHNIVIE is initiated. Beginning the day after TECHNIVIE is initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. Typical tacrolimus dosing is 0.5 mg every 7 days.
Measure tacrolimus blood concentrations and adjust dose or dosing frequency to determine subsequent dose modifications. Upon completion of TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of tacrolimus should be guided by assessment of tacrolimus blood concentrations. Frequent assessment of renal function and tacrolimus related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol* ↑ salmeterol Concurrent administration of TECHNIVIE 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.
NARCOTIC ANALGESICS
buprenorphine/naloxone ↑ buprenorphine
↑ norbuprenorphine
No dose adjustment of buprenorphine/naloxone is required upon co-administration with TECHNIVIE. Patients should be closely monitored for sedation and cognitive effects.
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.
SEDATIVES/HYPNOTICS
alprazolam ↑ alprazolam Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
*Not studied.
See Clinical Pharmacology, Tables 5 and 6.
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%).
7.4 Drugs without Clinically Significant Interactions with TECHNIVIE
No dosage adjustments are recommended when TECHNIVIE is co-administered with the following medications: duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, gemfibrozil, methadone, progestin only contraceptives, raltegravir, rosuvastatin, warfarin and zolpidem.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
Risk Summary
Adequate and well controlled studies with TECHNIVIE 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 or ritonavir (mice and rats) at exposures higher than the recommended clinical dose [see Data]. Because animal reproduction studies are not always predictive of human response, TECHNIVIE should be used during pregnancy only if clearly needed.
When TECHNIVIE 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 of ribavirin in males and females of child-bearing potential.
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 or ritonavir. For ombitasvir, the highest dose tested produced exposures approximately 29-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 143-fold (mouse) or 12-fold (rat) the exposures of paritaprevir in humans at the recommended clinical dose.
8.3 Nursing Mothers
It is not known whether any of the components of TECHNIVIE or their metabolites are present in human milk. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13 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 TECHNIVIE and any potential adverse effects on the breastfed child from TECHNIVIE or from the underlying maternal condition.
When TECHNIVIE is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen (see prescribing information for ribavirin).
8.4 Pediatric Use
Safety and effectiveness of TECHNIVIE in pediatric patients less than 18 years of age have not been established.
8.5 Geriatric Use
No dosage adjustment of TECHNIVIE is warranted in geriatric patients. Clinical study PEARL-I did not include sufficient numbers of patients older than 65 years of age to assess safety or efficacy, or to determine if they responded differently than younger patients.
8.6 Hepatic Impairment
No dosage adjustment of TECHNIVIE is required in patients with mild hepatic impairment (Child-Pugh A). TECHNIVIE is not recommended in HCV-infected patients with moderate hepatic impairment (Child-Pugh B) because the safety has not been established. TECHNIVIE is contraindicated in patients with severe (Child-Pugh C) hepatic impairment [see Dosage and Administration (2.2), Contraindications (4) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dosage adjustment of TECHNIVIE is required in patients with mild, moderate or severe renal impairment. TECHNIVIE 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 (12.3)].
10 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 be instituted immediately.
11 DESCRIPTION
TECHNIVIE is a fixed-dose combination tablet containing ombitasvir, paritaprevir, and ritonavir for oral administration.
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.
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 molecular formula is C50H67N7O8•4.5H2O (hydrate) and the molecular weight for the drug substance is 975.20 (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:


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 molecular formula is C40H43N7O7S•2H2O (dihydrate) and the molecular weight for the drug substance is 801.91 (dihydrate). The drug substance is white to off-white powder with very low water solubility. Paritaprevir has the following molecular structure:


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 molecular formula is C37H48N6O5S2 and the molecular weight for the drug substance is 720.95. 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:


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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
TECHNIVIE combines two direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology (12.4)].
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).
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of a combination of ombitasvir, paritaprevir and ritonavir plus 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 and 1.8 times the therapeutic concentrations of paritaprevir and ombitasvir, the combination did not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
Absorption
Ombitasvir, paritaprevir and ritonavir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir 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 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 ombitasvir and paritaprevir when administered with ritonavir as TECHNIVIE was approximately 48.1% and 52.6%, respectively.
Based on the population pharmacokinetic analysis, the median steady-state AUC0-24 for ombitasvir, paritaprevir and ritonavir were 1239, 2276 and 6072 ng·hr/mL, respectively, when administered to HCV genotype 4-infected subjects. Median steady-state Cmax for ombitasvir, paritaprevir, and ritonavir were 82, 194 and 543 ng/mL, respectively, when administered to HCV genotype 4-infected subjects.
Effects of Food on Oral Absorption
Relative to fasting conditions, administration of ombitasvir, paritaprevir and ritonavir with a moderate fat meal (approximately 600 Kcal, 20-30% calories from fat) increased the mean AUC by 82%, 211% and 49%, respectively.
Relative to fasting conditions, administration of ombitasvir, paritaprevir and ritonavir with a high fat meal (approximately 900 Kcal, 60% calories from fat) increased the mean AUC by 76%, 180%, and 44%, respectively.
Ombitasvir, paritaprevir, and ritonavir should always be administered with a meal.
Distribution
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 volume of distribution (V) was 173 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 volume of distribution (V) was 103 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.
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.
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.
Ombitasvir, paritaprevir and ritonavir 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.
Ombitasvir, paritaprevir and ritonavir are neither inhibitors nor substrates of organic cation transporter 1 (OCT1).
Specific Populations
Hepatic Impairment
The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and another antiviral drug were evaluated in non-HCV infected subjects with mild hepatic impairment (Child-Pugh A; score of 5-6), moderate hepatic impairment (Child-Pugh B, score of 7-9) and severe hepatic impairment (Child-Pugh C, score of 10-15).
Relative to subjects with normal hepatic function, ombitasvir, paritaprevir and ritonavir mean AUC values decreased by 8%, 29% and 34%, respectively, in subjects with mild hepatic impairment.
Relative to subjects with normal hepatic function, ombitasvir and ritonavir mean AUC values decreased by 30% and 30%, respectively and paritaprevir mean AUC values increased by 62% in subjects with moderate hepatic impairment.
Relative to subjects with normal hepatic function, paritaprevir and ritonavir mean AUC values increased by 945% and 13% respectively and ombitasvir mean AUC values decreased by 54% in subjects with severe hepatic impairment.
Renal Impairment
The single dose pharmacokinetics of ombitasvir, paritaprevir and ritonavir 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, and ritonavir 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 TECHNIVIE in non-HCV infected subjects with End Stage Renal Disease (ESRD).
Relative to subjects with normal renal function, ritonavir AUC values increased by 40%, while ombitasvir and paritaprevir AUC values were unchanged in subjects with mild renal impairment.
Relative to subjects with normal renal function, ritonavir AUC values increased by 76%, while ombitasvir and paritaprevir AUC values were unchanged in subjects with moderate renal impairment.
Relative to subjects with normal renal function, paritaprevir and ritonavir AUC values increased by 25% and 108%, respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment.
Pediatric Population
The pharmacokinetics of TECHNIVIE in pediatric patients less than 18 years of age has not been established [see Use in Specific Populations (8.4)].
Sex
No dosage adjustment is recommended based on sex or body weight.
Race/Ethnicity
No dosage adjustment is recommended based on race or ethnicity.
Age
No dosage adjustment is recommended in geriatric patients [see Use in Specific Populations (8.5)].
Drug Interactions
See also Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)
The effects of drugs discussed in Table 4 on the exposures of the individual components of TECHNIVIE are shown in Table 5. For information regarding clinical recommendations, see Drug Interactions (7).
Table 5. Drug Interactions: Change in Pharmacokinetic Parameters of the Individual Components of TECHNIVIE in the Presence of Co-administered Drug 

Co-administered
Drug
Dose of Co-
administered
Drug (mg)
n DAA Ratio (with/without co-administered drug) of
DAA Pharmacokinetic Parameters (90% CI);
No Effect = 1.00
        Cmax AUC Cmin
Alprazolama 0.5 single
dose
12 ombitasvir 0.98
(0.93, 1.04)
1.00
(0.96, 1.04)
0.98
(0.93, 1.04)
paritaprevir 0.91
(0.64, 1.31)
0.96
(0.73, 1.27)
1.12
(1.02, 1.23)
ritonavir 0.92
(0.84, 1.02)
0.96
(0.89, 1.03)
1.01
(0.94, 1.09)
Amlodipinea 5 single dose 14 ombitasvir 1.00
(0.95, 1.06)
1.00
(0.97, 1.04)
1.00
(0.97, 1.04)
paritaprevir 0.77
(0.64, 0.94)
0.78
(0.68, 0.88)
0.88
(0.80, 0.95)
ritonavir 0.96
(0.87, 1.06)
0.93
(0.89, 0.98)
0.95
(0.89, 1.01)
Atazanavirb 300 once daily 10 ombitasvir 0.83
(0.74, 0.94)
0.91
(0.81, 1.02)
0.98
(0.87, 1.11)
paritaprevir 2.74
(1.76, 4.27)
2.87
(2.08, 3.97)
3.71
(2.87, 4.79)
ritonavir 0.85
(0.72, 0.99)
0.97
(0.84, 1.13)
1.45
(1.29, 1.64)
Carbamazepinea 200 once daily
followed by
200 twice daily
12 ombitasvir 0.69
(0.61, 0.78)
0.69
(0.64, 0.74)
NA
paritaprevir 0.34
(0.25, 0.48)
0.30
(0.23, 0.38)
NA
ritonavir 0.17
(0.12, 0.24)
0.13
(0.09, 0.17)
NA
Cyclosporine 10 single dosec 12 ombitasvir 1.06
(1.02, 1.11)
1.10
(1.07, 1.12)
1.10
(1.06, 1.14)
paritaprevir 1.39
(1.10, 1.75)
1.46
(1.29, 1.64)
1.18
(1.08, 1.30)
ritonavir 1.13
(0.94, 1.35)
1.20
(1.10, 1.30)
1.11
(0.89, 1.37)
Darunavirb 800 once daily 9 ombitasvir 1.01
(0.87, 1.17)
1.01
(0.91, 1.11)
1.06
(0.99, 1.13)
paritaprevir 2.09
(1.35, 3.24)
1.94
(1.36, 2.75)
1.85
(1.41, 2.42)
ritonavir 0.83
(0.68, 1.01)
0.80
(0.73, 0.87)
0.91
(0.78, 1.06)
Digoxin 0.5 single dose 11 ombitasvir 0.99
(0.95-1.04)
1.02
(0.98-1.06)
1.01
(0.98-1.05)
paritaprevir 1.15
(0.97-1.36)
1.12
(1.00-1.25)
0.97
(0.84-1.13)
ritonavir 1.06
(0.99-1.13)
1.01
(0.98-1.05)
0.95
(0.86-1.04)
Ethinyl estradiol/
Norgestimate
Ethinyl
estradiol
0.035 and
Norgestimate
0.25 once daily
7d ombitasvir 1.05
(0.81, 1.35)
0.97
(0.81, 1.15)
0.96
(0.88, 1.12)
paritaprevir 0.70
(0.40, 1.21)
0.66
(0.42, 1.04)
0.87
(0.67, 1.14)
ritonavir 0.80
(0.53, 1.21)
0.71
(0.54, 0.94)
0.79
(0.68, 0.93)
Furosemidea 20 single dose 12 ombitasvir 1.14
(1.03, 1.26)
1.07
(1.01, 1.12)
1.12
(1.08, 1.16)
paritaprevir 0.93
(0.63, 1.36)
0.92
(0.70, 1.21)
1.26
(1.16, 1.38)
ritonavir 1.10
(0.96, 1.27)
1.04
(0.92, 1.18)
1.07
(0.99, 1.17)
Ketoconazole 400 once daily 12 ombitasvir 0.98
(0.92, 1.04)
1.26
(1.20, 1.32)
NA
paritaprevir 1.72
(1.32, 2.26)
2.16
(1.76, 2.66)
NA
ritonavir 1.27
(1.11, 1.45)
1.51
(1.36, 1.68)
NA
Lopinavir/
ritonavir
400/100 twice daily 18 ombitasvir 1.07
(1.01, 1.13)
1.25
(1.19, 1.32)
1.48
(1.39, 1.57)
paritaprevir 4.76
(3.54, 6.39)
6.10
(4.30, 8.67)
12.33
(7.30, 20.84)
ritonavir 1.74
(1.39, 2.17)
2.78
(2.42, 3.20)
10.02
(7.66, 13.11)
Lopinavir/
ritonavire
800/200 once daily 11 ombitasvir 0.97
(0.87, 1.08)
1.09
(1.00, 1.19)
1.24
(1.13, 1.35)
paritaprevir 1.78
(1.26, 2.52)
3.55
(2.37, 5.32)
14.78
(9.41, 23.23)
ritonavir 1.80
(1.30, 2.48)
3.09
(2.36, 4.06)
23.16
(15.55, 34.51)
Omeprazole 40 once daily 12 ombitasvir 0.96
(0.81, 1.14)
1.00
(0.88, 1.12)
0.97
(0.89, 1.107)
paritaprevir 1.02
(0.64, 1.62)
0.93
(0.64, 1.34)
0.83
(0.67, 1.04)
ritonavir 1.06
(0.95, 1.18)
1.07
(0.96, 1.21)
1.07
(0.97, 1.18)
Pravastatin 10 once daily 10 ombitasvir 0.98
(0.90, 1.06)
0.94
(0.88, 1.02)
0.97
(0.90, 1.03)
paritaprevir 1.44
(1.15, 1.81)
1.33
(1.09, 1.62)
1.28
(0.83, 1.96)
ritonavir 1.37
(1.05, 1.79)
1.37
(0.84, 2.24)
0.85
(0.76, 0.96)
Rilpivirinea 25 once daily
(morning)f
10 ombitasvir 1.11
(1.02, 1.20)
1.09
(1.04, 1.14)
1.05
(1.01, 1.08)
paritaprevir 1.30
(0.94, 1.81)
1.23
(0.93, 1.64)
0.95
(0.84, 1.07)
ritonavir 1.10
(0.98, 1.24)
1.08
(0.93, 1.27)
0.97
(0.91, 1.04)
Tacrolimus 0.5 single doseg 11 ombitasvir 0.94
(0.89, 1.00)
0.95
(0.91, 1.00)
0.95
(0.92, 0.99)
paritaprevir 0.71
(0.55, 0.91)
0.79
(0.69, 0.92)
0.84
(0.74, 0.97)
ritonavir 0.884
(0.76, 0.93)
0.89
(0.85, 0.93)
1.04
(0.96, 1.13)
  1. Study evaluated interaction with ombitasvir/paritaprevir/ritonavir plus dasabuvir; results extrapolated to ombitasvir/paritaprevir/ritonavir.
  2. Atazanavir or darunavir administered with ombitasvir/paritaprevir/ritonavir in the morning was compared to atazanavir or darunavir administered with 100 mg ritonavir in the morning.
  3. 10 mg cyclosporine was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 100 mg cyclosporine was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.
  4. Data shown is combined data for ombitasvir/paritaprevir/ritonavir with (N=3) and without (N=4) dasabuvir.
  5. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of ombitasvir/paritaprevir/ritonavir.
  6. Similar changes were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
  7. 0.5 mg tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 2 mg tacrolimus was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.


NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval

Doses of ombitasvir, paritaprevir, ritonavir were 25 mg, 150 mg and 100 mg, respectively.

For studies conducted with ombitasvir/paritaprevir/ritonavir plus dasabuvir, doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).

Ombitasvir, paritaprevir and ritonavir were dosed once daily (and where applicable, dasabuvir was dosed twice daily) in all the above studies except studies with ketoconazole and carbamazepine that used single doses.

Table 6 summarizes the effects of TECHNIVIE on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Drug Interactions (7).
Table 6. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of TECHNIVIE 

Co-administered
Drug
Dose of Co-administered
Drug (mg)
 n  Ratio (with/without TECHNIVIE) of Co-administered Drug Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
      Cmax AUC Cmin
Alprazolama 0.5 single dose 12 1.09
(1.03, 1.15)
1.34
(1.15, 1.55)
NA
Amlodipinea 5 single dose 14 1.26
(1.11, 1.44)
2.57
(2.31, 2.86)
NA
Atazanavirb 300 once daily 11 0.90
(0.83, 0.97)
0.93
(0.85, 1.02)
0.81
(0.72, 0.91)
Buprenorphine Buprenorphine:
4 to 24 once
daily and
Naloxone:
1 to 6 once
daily
11 1.19
(1.01, 1.40)c
1.51
(1.27, 1.78)c
1.65
(1.30, 2.08)c
Norbuprenorphine 1.82
(1.41, 2.36)c
2.11
(1.65, 2.70)c
1.87
(1.48, 2.36)c
Naloxone 0.99
(0.84, 1.16)c
1.11
(0.91, 1.37)c
NA
Carbamazepinea 200 once daily followed by 200 twice daily 12 1.10
(1.07, 1.14)
1.17
(1.13, 1.22)
1.35
(1.27, 1.45)
Carbamazepine’s metabolite, carbamazepine-10,11-epoxide (CBZE) 0.84
(0.82, 0.87)
0.75
(0.73, 0.77)
0.57
(0.54, 0.61)
Cyclosporine 10 single dosed 12 0.83
(0.72, 0.94)c
4.28
(3.66, 5.01)c
12.85
(10.61, 15.55)c
Darunavirb 800 once daily 9 0.99
(0.92, 1.08)
0.92
(0.84, 1.00)
0.74
(0.63, 0.88)
Digoxin 0.5 single dose 11 1.58
(1.43-1.73)
1.36
(1.21-1.53)
1.24
(1.07-1.43)
Ethinyl Estradiole Ethinyl estradiol 0.035 and Norgestimate 0.25 once daily 8 1.16
(0.90, 1.50)
1.06
(0.96, 1.17)
1.12
(0.94, 1.33)
Norelgestromine 9 2.01
(1.77, 2.29)
2.60
(2.30, 2.95)
3.11
(2.51, 3.85)
Norgestrele 9 2.26
(1.91, 2.67)
2.54
(2.09, 3.09)
2.93
(2.39, 3.57)
Furosemidea 20 single dose 12 1.42
(1.17, 1.72)
1.08
(1.00, 1.17)
NA
Ketoconazole 400 once daily 12 1.10
(1.05, 1.16)
2.05
(1.93, 2.18)
NA
Lopinavir/ritonavirf 400/100 twice daily 18 1.06
(0.99, 1.14)
1.13
(1.09, 1.17)
1.34
(1.26, 1.42)
Lopinavir/ritonavirf,g 800/200 once daily 12 1.05
(0.95, 1.17)
1.17
(1.09, 1.26)
3.50
(2.69, 4.56)
Omeprazole 40 once daily 12 0.48
(0.29, 0.78)
0.46
(0.27, 0.77)
NA
Pravastatin 10 once daily 10 1.43
(1.09, 1.88)
1.76
(1.46, 2.13)
NA
Rilpivirinea 25 once daily
(morning)h
8 2.55
(2.08, 3.12)
3.25
(2.80, 3.77)
3.62
(3.12, 4.21)
Tacrolimus 0.5 single dosei 11 4.27
(3.49, 5.22)c
85.81
(67.88, 108.49)c
24.61
(19.69, 30.77)c
  1. Study evaluated interaction with ombitasvir/paritaprevir/ritonavir plus dasabuvir; results extrapolated to ombitasvir/paritaprevir/ritonavir.
  2. Atazanavir or darunavir administered with ombitasvir/paritaprevir/ritonavir in the morning was compared to atazanavir or darunavir administered with 100 mg ritonavir in the morning.
  3. Dose normalized parameters reported.
  4. 10 mg cyclosporine was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 100 mg cyclosporine was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.
  5. Data shown is combined data for ombitasvir/paritaprevir/ritonavir with (N=3) and without (N=6) dasabuvir.
  6. Lopinavir parameters are reported.
  7. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of ombitasvir/paritaprevir/ritonavir.
  8. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
  9. 0.5 mg tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 2 mg tacrolimus was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.


NA: not available/not applicable; CI: Confidence interval.

Doses of ombitasvir, paritaprevir and ritonavir were 25 mg, 150 mg and 100 mg, respectively.

For studies conducted with ombitasvir/paritaprevir/ritonavir plus dasabuvir, doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).

Ombitasvir, paritaprevir and ritonavir were dosed once daily (and where applicable, dasabuvir was dosed twice daily) in all the above studies except studies with ketoconazole and carbamazepine that used single doses.

12.4 Microbiology
Mechanism of Action
TECHNIVIE combines two 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 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 a recombinant HCV genotype 4a NS3/4A protease enzyme with an IC50 value of 0.16 nM. Paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 1a, 1b, 2a, 2b, and 3a with IC50 values of 0.18 nM, 0.43 nM, 2.4 nM, 6.3 nM, and 14.5 nM, respectively.
Antiviral Activity
Ombitasvir
The EC50 values of ombitasvir against HCV replicons containing NS5A from a single isolate each of genotype 4a and genotype 4d were 1.7 pM and 0.38 pM, respectively. Ombitasvir had a median EC50 value of 0.21 pM (range 0.10 pM to 0.36 pM; n=9) against transient HCV replicons containing NS5A genes from a panel of genotype 4a isolates from treatment-naïve subjects. Ombitasvir had EC50 values of 14 pM, 5.0 pM, 12 pM, 4.3 pM, 19 pM, 3.2 pM, and 366 pM against replicon cell lines representing genotypes 1a-H77, 1b-Con1, 2a, 2b, 3a, 5a and 6a, respectively.
Paritaprevir
The EC50 values of paritaprevir against HCV replicons containing NS3 from a single isolate each of genotype 4a and genotype 4d were 0.09 nM and 0.015 nM, respectively. Paritaprevir had EC50 values of 1.0 nM, 0.21 nM, 5.3 nM, 19 nM and 0.68 nM against replicon cell lines representing genotypes 1a-H77, 1b-Con1, 2a-JFH1, 3a and 6a, respectively.
Ritonavir
In HCV replicon cell culture assays, ritonavir did not exhibit a direct antiviral effect and the presence of ritonavir did not affect the antiviral activity of paritaprevir.
Resistance
In Cell Culture
Exposure of HCV genotype 4a replicons to ombitasvir or paritaprevir resulted in the emergence of drug resistant replicons carrying amino acid substitutions in NS5A or NS3, respectively. Amino acid substitutions in NS5A or NS3 selected in cell culture or identified in clinical study PEARL-I were phenotypically characterized in genotype 4 replicons.
For ombitasvir, in an HCV genotype 4a replicon, NS5A substitution L28V reduced ombitasvir antiviral activity by 21-fold. In an HCV genotype 4d replicon, substitutions L28V alone and L28V in combination with T58S reduced ombitasvir antiviral activity by 310- and 760-fold, respectively. Ombitasvir activity against an HCV genotype 4d replicon was not reduced by a T58P polymorphism, which represents the consensus sequence observed at this position for HCV genotype 4a and 4d subjects in PEARL-I.
For paritaprevir, in an HCV genotype 4a replicon, NS3 substitutions R155C, A156T/V, and D168H/V reduced paritaprevir antiviral activity by 40- to 323-fold. In an HCV genotype 4d replicon, NS3 substitutions Y56H and D168V reduced paritaprevir antiviral activity by 8- and 313-fold, respectively, while a combination of Y56H and D168V reduced the activity of paritaprevir by 12,533-fold.
In Clinical Studies
In the clinical study PEARL-I, three subjects with HCV genotype 4 infection experienced virologic failure (2 post-treatment relapse, 1 on-treatment failure). All 3 virologic failures were observed in a regimen containing paritaprevir/ritonavir and ombitasvir without ribavirin. Treatment-emergent, resistance-associated substitutions were detected at the time of failure in all 3 subjects and included D168V (with or without Y56H) in NS3, and L28S and L28V (with or without M31I or T58S) in NS5A.
Persistence of Resistance-Associated Substitutions
The persistence of ombitasvir or paritaprevir resistance-associated amino acid substitutions in NS5A or NS3, respectively, in HCV genotype 4 has not been studied. In HCV genotype 1, persistence of ombitasvir and paritaprevir resistance-associated substitutions through 24 or 48 weeks post-treatment has been observed in subjects who experienced virologic failure with ombitasvir- and paritaprevir-containing regimens. The long-term clinical impact of the emergence or persistence of virus containing ombitasvir or paritaprevir resistance-associated substitutions is unknown.
Effect of Baseline HCV Polymorphisms on Treatment Response
Phylogenetic analysis of HCV sequences from genotype 4-infected subjects in the clinical study PEARL-I, identified 7 HCV genotype 4 subtypes (4a, 4b, 4c, 4d, 4f, 4g/4k, 4o). Most subjects were infected with either subtype 4a (38%) or 4d (52%); 1 to 7 subjects were infected with each of the other genotype 4 subtypes. Among subjects enrolled at U.S. study sites, 16/18 (89%) were infected with HCV subtype 4a; one subject each was infected with subtype 4c or 4d. Three subjects who experienced virologic failure with the regimen containing paritaprevir/ritonavir and ombitasvir without ribavirin were infected with HCV subtype 4d.
Baseline HCV polymorphisms are not expected to impact the likelihood of achieving SVR when TECHNIVIE is used as recommended to treat HCV genotype 4 infected patients, based on the low virologic failure rate observed in PEARL-I.
Cross-resistance
Cross-resistance may occur among NS5A inhibitors and among NS3/4A protease inhibitors within each individual class. The impact of prior ombitasvir or paritaprevir treatment experience on the efficacy of other NS5A inhibitors or NS3/4A protease inhibitors has not been studied. Similarly, the efficacy of TECHNIVIE has not been studied in subjects who have failed prior treatment with another NS5A inhibitor, NS3/4A protease inhibitor, or NS5B inhibitor.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Ombitasvir
Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (150 mg per kg per day).
The carcinogenicity study of ombitasvir in rats is ongoing.
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
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 11-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).
TECHNIVIE is administered with ribavirin. Refer to the prescribing information for ribavirin for information on carcinogenesis and mutagenesis.
Impairment of Fertility
Ombitasvir
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 26-fold the exposure in humans at the recommended clinical dose.
Paritaprevir, ritonavir
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 3- to 8-fold the exposure in humans at the recommended clinical dose.
TECHNIVIE is administered with ribavirin. Refer to the prescribing information for ribavirin for information on Impairment of Fertility.
14 CLINICAL STUDIES
14.1 Clinical Trial Results in Adults with Chronic GT4 HCV Infection without Cirrhosis
The efficacy and safety of TECHNIVIE was evaluated in a single clinical trial in subjects with genotype 4 (GT4) chronic hepatitis virus (HCV) infection. PEARL-I was a randomized, global, multicenter, open-label trial that enrolled 135 adults with HCV GT4 infection without cirrhosis who were either treatment-naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (pegIFN/RBV). Previous exposure to HCV direct-acting antivirals was prohibited. Treatment-naïve subjects were randomized in a 1:1 ratio to receive one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule once-daily with food with or without ribavirin for 12 weeks. PegIFN/RBV treatment-experienced subjects received one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule once-daily with food in combination with ribavirin for 12 weeks. The ribavirin dosage was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. The primary endpoint was sustained virologic response defined as HCV RNA below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12) using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System, which has an LLOQ of 25 IU per mL.
HCV GT4-infected subjects had a median age of 51 years (range: 19 to 70); 64% were treatment-naïve, 17% were prior pegIFN/RBV null responders; 7% were prior pegIFN/RBV partial responders, 13% were prior pegIFN/RBV relapsers; 65% were male; 9% were Black; 14% had a body mass index at least 30 kg/m2; 70% had baseline HCV RNA levels at least 800,000 IU/mL; 79% had IL28B (rs12979860) non-CC genotype; 7% had bridging fibrosis (F3).
Table 7 presents the SVR12 rates.
Table 7. SVR12 for HCV Genotype 4-Infected Subjects without Cirrhosis 

Treatment outcome Ombitasvir + Paritaprevir
+ Ritonavir
with RBV
for 12 weeks
Ombitasvir + Paritaprevir
+ Ritonavir
for 12 weeks
Treatment-naïve Treatment-experienced Treatment-naïve
% (n/N) % (n/N) % (n/N)
Overall SVR12 100 % (42/42) 100% (49/49) 91% (40/44)
Outcome for subjects without SVR12      
On-treatment VFa 0% (0/42) 0% (0/49) 2% (1/44)
Relapseb 0% (0/42) 0% (0/49) 5% (2/42)
Otherc 0% (0/42) 0% (0/49) 2% (1/44)
VF = virologic failure
a. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed increase from nadir in HCV RNA > 1 log10 IU/mL during treatment, or HCV RNA ≥ 25 IU/mL persistently during treatment with at least 6 weeks of treatment.
b. Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA less than 25 IU/mL at last observation during at least 11 weeks of treatment.
c. Other includes subjects not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. lost to follow-up).
Among 131 HCV GT4 infected subjects in PEARL-I who achieved SVR12, virologic response data at post-treatment week 24 were available from 129 subjects, and 129/129 (100%) subjects maintained their response through 24 weeks post-treatment (SVR24). 
16 HOW SUPPLIED/STORAGE AND HANDLING
TECHNIVIE 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 two TECHNIVIE tablets. The NDC number is NDC-0074-3082-28.
TECHNIVIE is a pink-colored, film-coated, oblong, biconvex-shaped tablet debossed with “AV1” on one side. Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.
Store at or below 30°C (86°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients to review the Medication Guide for ribavirin [see Warnings and Precautions (5.2)].
Risk of ALT Elevations
Inform patients to watch for early warning signs of liver inflammation, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
Pregnancy
Advise patients to avoid pregnancy during treatment with TECHNIVIE with ribavirin.Inform patients to notify their health care provider immediately in the event of a pregnancy [see Use in Specific Populations (8.1)].
Drug Interactions
Inform patients that TECHNIVIE may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products [see Contraindications (4), Warnings and Precautions (5.3) and Drug Interactions (7)].
Inform patients that contraceptives containing ethinyl estradiol are contraindicated with TECHNIVIE [see Contraindications (4) and Warnings and Precautions (5.1)].
Hepatitis C Virus Transmission
Inform patients that the effect of treatment of hepatitis C virus infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment should be taken.
Missed Dose
Inform patients that in case a dose of TECHNIVIE is missed, the prescribed dose can be taken within 12 hours.
If more than 12 hours has passed since TECHNIVIE is usually taken, the missed dose should NOT be taken and the patient should take the next dose as per the usual dosing schedule.
Instruct patients not to take more than their prescribed dose of TECHNIVIE to make up for a missed dose.
TECHNIVIE is manufactured by AbbVie Inc., North Chicago, IL 60064.
TECHNIVIE and NORVIR are trademarks of AbbVie Inc. All other brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products.

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