Viekirax 12.5 mg/75 mg/50 mg film-coated tablets
Each film-coated tablet contains 12.5 mg of ombitasvir, 75 mg of paritaprevir and 50 mg of ritonavir.
For the full list of excipients, see section 6.1.
Film-coated tablet (tablet).
Pink, oblong, biconvex, film-coated tablets of dimensions 18.8 mm x 10.0 mm, debossed on one side with 'AV1'.
Viekirax is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults (see sections 4.2, 4.4, and 5.1).
For hepatitis C virus (HCV) genotype specific activity, see sections 4.4 and 5.1.
Treatment with Viekirax should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.
Posology
The recommended oral dose of Viekirax is two 12.5 mg / 75 mg / 50 mg tablets once daily with food.
Viekirax should be used in combination with other medicinal products for the treatment of HCV (see Table 1).
Table 1. Recommended co-administered medicinal product(s) and treatment duration for Viekirax by patient population
|
Patient population
|
Treatment*
|
Duration
|
|
Genotype 1b, without cirrhosis
|
Viekirax + dasabuvir
|
12 weeks
|
|
Genotype 1b, with compensated cirrhosis
|
Viekirax + dasabuvir + ribavirin
|
12 weeks
|
|
Genotype 1a, without cirrhosis
|
Viekirax + dasabuvir + ribavirin*
|
12 weeks
|
|
Genotype 1a, with compensated cirrhosis
|
Viekirax + dasabuvir + ribavirin*
|
24 weeks (see section 5.1.)
|
|
Genotype 4, without cirrhosis
|
Viekirax + ribavirin
|
12 weeks
|
|
Genotype 4, with compensated cirrhosis
|
Viekirax + ribavirin
|
24 weeks
|
|
*Note: Follow the genotype 1a dosing recommendations in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.
|
For specific dosage instructions for dasabuvir and ribavirin, including dose modification, refer to the respective Summaries of Product Characteristics.
Missed doses
In case a dose of Viekirax is missed, the prescribed dose can be taken within 12 hours. If more than 12 hours have passed since Viekirax is usually taken, the missed dose should NOT be taken and the patient should take the next dose per the usual dosing schedule. Patients should be instructed not to take a double dose.
Special populations
HIV-1 Co-infection
Follow the dosing recommendations in Table 1. For dosing recommendations with HIV antiviral agents, refer to section 4.4 (Treatment of patients with HIV co-infection) and section 4.5. See section 5.1 for additional information.
Liver transplant recipients
Viekirax and dasabuvir in combination with ribavirin is recommended for 24 weeks in liver transplant recipients with genotype 1 HCV infection. Viekirax in combination with ribavirin is recommended in genotype 4 infection. Lower ribavirin dose at initiation may be appropriate. In the post-liver transplant study, ribavirin dosing was individualized and most subjects received 600 to 800 mg per day (see section 5.1). For dosing recommendations with calcineurin inhibitors see section 4.5.
Elderly
No dose adjustment of Viekirax is warranted in elderly patients (see section 5.2).
Renal impairment
No dose adjustment of Viekirax is required for patients with mild, moderate, or severe renal impairment (see section 5.2).
Hepatic impairment
No dose adjustment of Viekirax is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of Viekirax have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B); however, no dose adjustment is expected to be required based on pharmacokinetic studies. Viekirax is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.3 and 5.2).
Paediatric population
The safety and efficacy of Viekirax in children less than 18 years of age have not been established. No data are available.
Method of administration
The film-coated tablets are for oral use. Patients should be instructed to swallow the tablets whole (i.e. patients should not chew, break or dissolve the tablet). To maximise absorption, Viekirax tablets should be taken with food, without regard to fat and calorie content (see section 5.2).
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Patients with severe hepatic impairment (Child-Pugh C) (see section 5.2).
Use of ethinylestradiol-containing medicinal products such as those contained in most combined oral contraceptives or contraceptive vaginal rings (see section 4.4 and 4.5).
Medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma levels are associated with serious events must not be co-administered with Viekirax (see section 4.5). Examples are provided below.
CYP3A4 substrates:
• alfuzosin hydrochloride
• amiodarone
• astemizole, terfenadine
• cisapride
• colchicine in patients with renal or hepatic impairment
• ergotamine, dihydroergotamine, ergonovine, methylergometrine
• fusidic acid
• lovastatin, simvastatin, atorvastatin
• oral midazolam, triazolam
• pimozide
• quetiapine
• quinidine
• salmeterol
• sildenafil (when used for the treatment of pulmonary arterial hypertension)
• ticagrelor
Co-administration of Viekirax with or without dasabuvir with medicinal products that are strong or moderate enzyme inducers is expected to decrease ombitasvir, paritaprevir, and ritonavir plasma concentrations and reduce their therapeutic effect and must not be co-administered (see section 4.5). Examples of contraindicated strong or moderate enzyme inducers are provided below.
Enzyme inducers:
• carbamazepine, phenytoin, phenobarbital
• efavirenz, nevirapine, etravirine
• enzalutamide
• mitotane
• rifampicin
• St. John's Wort (Hypericum perforatum)
Co-administration of Viekirax with or without dasabuvir with medicinal products that are strong inhibitors of CYP3A4 is expected to increase paritaprevir plasma concentrations and must not be co-administered with Viekirax (see section 4.5). Examples of contraindicated strong CYP3A4 inhibitors are provided below.
CYP3A4 inhibitors:
• cobicistat
• indinavir, lopinavir/ritonavir, saquinavir, tipranavir,
• itraconazole, ketoconazole, posaconazole, voriconazole
• clarithromycin, telithromycin
• conivaptan
General
Viekirax is not recommended for administration as monotherapy and must be used in combination with other medicinal products for the treatment of hepatitis C infection (see sections 4.2 and 5.1).
Genotype-specific activity
Concerning recommended regimens with different HCV genotypes, see section 4.2. Concerning genotype-specific virological and clinical activity, see section 5.1.
The efficacy of Viekirax has not been established in patients with HCV genotypes 2, 3, 5 and 6; therefore Viekirax should not be used to treat patients infected with these genotypes.
There are no data on the use of Viekirax and ribavirin in patients with HCV genotype 4 infection with compensated cirrhosis and therefore the optimal treatment duration has not been established. Based on in vitro antiviral activity and available clinical data in HCV genotype 1, a conservative treatment duration of 24 weeks is recommended for patients with HCV genotype 4 and compensated cirrhosis.
Co-administration with other direct-acting antivirals against HCV
Viekirax safety and efficacy have been established in combination with dasabuvir and/or ribavirin. Co-administration of Viekirax with other antivirals has not been studied and therefore cannot be recommended.
Retreatment
The efficacy of Viekirax in patients previously exposed to Viekirax, or to medicinal products of the same classes as those of Viekirax (NS3/4A- or NS5A inhibitors), has not been demonstrated. Concerning cross-resistance, see also section 5.1.
Pregnancy and concomitant use with ribavirin
When Viekirax is used in combination with ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and for 6 months after the treatment as recommended in the Summary of Product Characteristics for ribavirin. Refer to the Summary of Product Characteristics for ribavirin for additional information.
ALT elevations
During clinical trials with Viekirax and dasabuvir with or without ribavirin, transient elevations of ALT to greater than 5 times the upper limit of normal occurred in approximately 1% of subjects (35 of 3,039). ALT elevations were asymptomatic and generally occurred during the first 4 weeks of treatment, without concomitant elevations of bilirubin, and declined within approximately two weeks of onset with continued dosing of Viekirax and dasabuvir with or without ribavirin.
These ALT elevations were significantly more frequent in the subgroup of subjects who were using ethinylestradiol-containing medicinal products such as combined oral contraceptives or contraceptive vaginal rings (6 of 25 subjects); (see section 4.3). In contrast, the rate of ALT elevations in subjects using other types of estrogens as typically used in hormonal replacement therapy (i.e., oral and topical estradiol and conjugated estrogens) was similar to the rate observed in subjects who were not using estrogen-containing products (approximately 1% in each group).
Patients who are taking ethinylestradiol-containing medicinal products (i.e. most combined oral contraceptives or contraceptive vaginal rings) must switch to an alternative method of contraception (e.g., progestin only contraception or non-hormonal methods) prior to initiating Viekirax and dasabuvir therapy (see sections 4.3 and 4.5).
Although ALT elevations associated with Viekirax and dasabuvir have been asymptomatic, patients should be instructed 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 discoloured faeces, and to consult a doctor without delay if such symptoms occur. Routine monitoring of liver enzymes is not necessary. Early discontinuation may result in drug resistance, but implications for future therapy are not known.
Use with glucocorticoids metabolised by CYP3A (e.g. fluticasone)
Caution should be used when administering Viekirax with fluticasone or other glucocorticoids that are metabolised by CYP3A4. Concomitant use of inhaled glucocorticoids metabolised with CYP3A can increase systemic exposures of the glucocorticoids, and cases of Cushing's syndrome and subsequent adrenal suppression have been reported with ritonavir-containing regimens. Concomitant use of Viekirax and glucocorticoids, particularly long-term use, should only be initiated if the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.5).
Use with colchicine
The interaction between Viekirax with or without dasabuvir and colchicine has not been eva luated. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with Viekirax with or without dasabuvir is required (see section 4.5). In patients with renal or hepatic impairment, use of colchicine with Viekirax with or without dasabuvir is contraindicated (see section 4.3 and 4.5).
Use with statins
Simvastatin, lovastatin and atorvastatin are contraindicated (see section 4.3 and 4.5).
Rosuvastatin
Viekirax with dasabuvir is expected to increase the exposure to rosuvastatin more than 3-fold. If rosuvastatin treatment is required during the treatment period, the maximum daily dose of rosuvastatin should be 5 mg (see section 4.5, Table 2).The increase in rosuvastatin when combined with Viekirax without dasabuvir is less pronounced. In this combination, the maximum daily dose of rosuvastatin should be 10 mg (see section 4.5, Table 2).
Pitavastatin and fluvastatin
The interactions between pitavastatin and fluvastatin and Viekirax have not been investigated. Theoretically, Viekirax with and without dasabuvir is expected to increase the exposure to pitavastatin and fluvastatin. A temporary suspension of pitavastatin/fluvastatin is recommended for the duration of treatment with Viekirax. If statin treatment is required during the treatment period, a switch to a reduced dose of pravastatin/rosuvastatin is possible (see section 4.5, Table 2).
Treatment of patients with HIV co-infection
Low dose ritonavir, which is part of the fixed dose combination Viekirax, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with Viekirax.
Drug interactions need to be carefully taken into account in the setting of HIV co-infection (for details see section 4.5, Table 2).
Atazanavir can be used in combination with Viekirax and dasabuvir, if administered at the same time. To be noted, atazanavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of Viekirax. The combination carries an increased risk for hyperbilirubinemia (including ocular icterus), in particular when ribavirin is part of the hepatitis C regimen.
Darunavir, dosed 800 mg once daily, if administered at the same time as Viekirax and dasabuvir, can be used in the absence of extensive PI resistance (darunavir exposure lowered). To be noted, darunavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of Viekirax.
HIV protease inhibitors other than atazanavir and darunavir (e.g., indinavir, saquinavir, tipranavir, lopinavir/ritonavir) are contraindicated (see section 4.3).
Raltegravir exposure is substantially increased (2-fold). The combination was not linked to any particular safety issues in a limited set of patients treated for 12-24 weeks.
Rilpivirine exposure is substantially increased (3-fold) when rilpivirine is given in combination with Viekirax and dasabuvir, with a consequent potential for QT-prolongation. If an HIV protease inhibitor is added (atazanavir, darunavir), rilpivirine exposure may increase even further and is therefore not recommended. Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.
NNRTIs other than rilpivirine (efavirenz, etravirine and nevirapine) are contraindicated (see section 4.3).
Hepatic impairment
No dose adjustment for Viekirax is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of Viekirax have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B); however, no dose adjustment is expected to be required based on pharmacokinetic studies.
Viekirax is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see sections 4.3 and 5.2).
HCV/HBV (Hepatitis B Virus) co-infection
The safety and efficacy of Viekirax have not been established in patients with HCV/HBV co-infection.
Paediatric population
The safety and efficacy of Viekirax in children below 18 years have not been established. No data are available.
Viekirax may be administered with or without dasabuvir. When co-administered, they exert mutual effects on each other (see section 5.2). Therefore, the interaction profile of the compounds must be considered as a combination.
Pharmacodynamic interactions
Coadministration with enzyme inducers may increase the risk of adverse events and ALT elevations (see Table 2). Coadministration with ethinylestradiol may increase the risk of ALT elevations (see sections 4.3 and 4.4). Examples of contraindicated enzyme inducers are provided in section 4.3.
Pharmacokinetic interactions
Potential for Viekirax to affect the pharmacokinetics of other medicinal products
In vivo drug interaction studies eva luated the net effect of the combination treatment, including ritonavir.
The following section describes the specific transporters and metabolizing enzymes that are affected by Viekirax with or without dasabuvir. See Table 2 for guidance regarding potential interactions with other medicinal products and dosing recommendations.
Medicinal products metabolised by CYP3A4
Ritonavir is a strong inhibitor of CYP3A. Co-administration of Viekirax with or without dasabuvir with medicinal products primarily metabolized by CYP3A may result in increased plasma concentrations of these medicinal products. Medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma levels are associated with serious events are contraindicated (see section 4.3 and Table 2).
CYP3A substrates eva luated in drug interaction studies which may require dose adjustment and/or clinical monitoring include (see Table 2) cyclosporine, tacrolimus, amlodipine, rilpivirine and alprazolam. Examples of other CYP3A4 substrates which may require dose adjustment and/or clinical monitoring include calcium channel blockers (e.g. nifedipine), and trazodone. Although buprenorphine and zolpidem are also metabolized by CYP3A, drug interaction studies indicate that no dose adjustment is needed when co-administering these medicinal products with Viekirax with or without dasabuvir (see Table 2).
Medicinal products transported by the OATP family and OCT1
Paritaprevir is an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3, and paritaprevir and ritonavir are inhibitors of OATP2B1. Ritonavir is an in vitro inhibitor of OCT1, but the clinical relevance is unknown. Co-administration of Viekirax with or without dasabuvir with medicinal products that are substrates of OATP1B1, OATP1B3, OATP2B1 or OCT1 may increase plasma concentrations of these transporter substrates, potentially requiring dose adjustment/clinical monitoring. Such medicinal products include some statins (see Table 2), fexofenadine, repaglinide and angiotensin II receptor antagonists (e.g., valsartan).
OATP1B1/3 substrates eva luated in drug interaction studies include pravastatin and rosuvastatin (see Table 2).
Medicinal products transported by BCRP
Paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP in vivo. Co-administration of Viekirax with or without dasabuvir together with medicinal products that are substrates of BCRP may increase plasma concentrations of these transporter substrates, potentially requiring dose adjustment/clinical monitoring. Such medicinal products include sulfasalazine, imatinib and some of the statins (see Table 2).
BCRP substrates eva luated in drug interaction studies include rosuvastatin (see Table 2).
Medicinal products transported by P-gp in the intestine
While paritaprevir, ritonavir and dasabuvir are in vitro inhibitors of P-gp, no significant change was observed in the exposure of the P-gp substrate digoxin when administered with Viekirax and dasabuvir. However, co-administration of digoxin with Viekirax without dasabuvir may result in increased plasma concentrations (see Table 2). Viekirax may increase the plasma exposure to medicinal products that are sensitive for changed intestinal P-gp activity (such as dabigatran etexilate).
Medicinal products metabolised by glucuronidation (UGT1A1)
Paritaprevir, ombitasvir and dasabuvir are inhibitors of UGT1A1. Co-administration of Viekirax with or without dasabuvir with medicinal products that are primarily metabolized by UGT1A1 result in increased plasma concentrations of such medicinal products; routine clinical monitoring is recommended for narrow therapeutic index medicinal products (i.e. levothyroxine). See also Table 2 for specific advice on raltegravir and buprenorphine, which have been eva luated in drug interaction studies.
Medicinal products metabolised by CYP2C19
Co-administration of Viekirax with or without dasabuvir can decrease exposures of medicinal products that are metabolized by CYP2C19 (e.g. lansoprazole, esomeprazole, s-mephenytoin), which may require dose adjustment/clinical monitoring. CYP2C19 substrates eva luated in drug interaction studies include omeprazole and escitalopram (see Table 2).
Medicinal products metabolised by CYP2C9
Viekirax administered with or without dasabuvir did not affect the exposures of the CYP2C9 substrate, warfarin. Other CYP2C9 substrates (NSAIDs (e.g. ibuprofen), antidiabetics (e.g. glimepiride, glipizide) are not expected to require dose adjustments.
Medicinal products metabolised by CYP2D6 or CYP1A2
Viekirax administered with or without dasabuvir did not affect the exposures of the CYP2D6/CYP1A2 substrate, duloxetine. Other CYP1A2 substrates (e.g. ciprofloxacin, theophylline and caffeine) and CYP2D6 substrates (e.g. desipramine, metoprolol and dextromethorphan) are not expected to require dose adjustments.
Medicinal products renally excreted via transport proteins
Ombitasvir, paritaprevir, and ritonavir do not inhibit organic anion transporter (OAT1) in vivo as shown by the lack of interaction with tenofovir (OAT1 substrate). In vitro studies show that ombitasvir, paritaprevir, and ritonavir are not inhibitors of organic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.
Therefore, Viekirax with or without dasabuvir is not expected to affect medicinal products which are primarily excreted by the renal route via these transporters (see section 5.2).
Potential for other medicinal products to affect the pharmacokinetics of ombitasvir, paritaprevir, and dasabuvir
Medicinal products that inhibit CYP3A4
Co-administration of Viekirax with or without dasabuvir with strong inhibitors of CYP3A may increase paritaprevir concentrations (see section 4.3 and Table 2).
Enzyme inducers
Co-administration of Viekirax and dasabuvir with medicinal products that are moderate or strong enzyme inducers is expected to decrease ombitasvir, paritaprevir, ritonavir and dasabuvir plasma concentrations and reduce their therapeutic effect. Contraindicated enzyme inducers are provided in section 4.3 and Table 2.
Medicinal products that inhibit CYP3A4 and transport proteins
Paritaprevir is eliminated via CYP3A4 mediated metabolism and biliary excretion (substrate of the hepatic transporters OATP1B1, P-gp and BCRP). Caution is advised if co-administering Viekirax with medicinal products that are both moderate inhibitors of CYP3A4 and inhibitors of multiple transporters (P-gp, BCRP and/or OATP1B1/ OATP1B3). These medicinal products may show clinically relevant increases in exposures of paritaprevir (e.g., ritonavir with atazanavir, erythromycin, diltiazem or verapamil).
Medicinal products that inhibit transport proteins
Potent inhibitors of P-gp, BCRP, OATP1B1 and/or OATP1B3 have the potential to increase the exposure to paritaprevir. Inhibition of these transporters is not expected to show clinically relevant increases in exposures of ombitasvir and dasabuvir.
Drug interaction studies
Recommendations for co-administration of Viekirax with and without dasabuvir for a number of medicinal products are provided in Table 2.
If a patient is already taking medicinal product(s) or initiating a medicinal product while receiving Viekirax with or without dasabuvir for which potential for drug interaction is expected, dose adjustment of the concomitant medicinal product(s) or appropriate clinical monitoring should be considered (Table 2).
If dose adjustments of concomitant medicinal products are made due to treatment with Viekirax or Viekirax with dasabuvir, doses should be re-adjusted after administration of Viekirax or Viekirax with dasabuvir is completed.
Table 2 provides the Least Squares Means Ratio (90% Confidence Interval) effect on concentration of Viekirax with or without dasabuvir and concomitant medicinal products.
The magnitude of interaction when administered with medicinal products listed in Table 2 are similar (≤25% difference in the Least Square Means ratio) for Viekirax with or without dasabuvir, unless otherwise noted. Drug interactions were eva luated for the Viekirax and dasabuvir regimen, but not for the Viekirax without dasabuvir, with carbamazepine, furosemide, zolpidem, darunavir twice daily, darunavir (evening administration), atazanavir (evening administration) or rilpivirine. Thus, for these medicinal products, results and dosing recommendations of the Viekirax and dasabuvir regimen can be extrapolated to Viekirax without dasabuvir.
The direction of the arrow indicates the direction of the change in exposures (Cmax, and AUC) in paritaprevir, ombitasvir, dasabuvir and the co-administered medicinal product (↑ = increase (more than 20%), ↓ = decrease (of more than 20%), ↔ = no change or change less than 20%). This is not an exclusive list.
Table 2. Interactions between Viekirax with or without dasabuvir and other medicinal products
|
Medicinal Product/Possible Mechanism of Interaction
|
GIVEN WITH
|
EFFECT
|
Cmax
|
AUC
|
Cmin
|
Clinical Comments
|
|
ALPHA 1-ADRENORECEPTOR ANTAGONIST
|
|
Alfuzosin
Mechanism:
CYP3A inhibition by ritonavir
|
Viekirax with or without dasabuvir
|
Not studied. Expected
↑ alfuzosin
|
Concomitant use is contraindicated (see section 4.3).
|
|
AMINOSALICYLATE
|
|
Sulfasalazine
Mechanism:
BCRP inhibition by paritaprevir, ritonavir and dasabuvir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ sulfasalazine
|
Caution should be used when sulfasalazine is co-administered with Viekirax with or without dasabuvir.
|
|
ANGIOTENSIN RECEPTOR BLOCKER
|
|
Valsartan
Mechanism: OATP1B inhibition by paritaprevir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ valsartan
|
Clinical monitoring and dose reduction is recommended when Viekirax with or without dasabuvir is coadministered with valsartan.
|
|
ANTIARRYTHMICS
|
|
Digoxin
0.5 mg single dose
Mechanism: P-gp inhibition by paritaprevir, ritonavir and dasabuvir.
|
Viekirax + dasabuvir
|
↔ digoxin
|
1.15
(1.04-1.27)
|
1.16
(1.09-1.23)
|
1.01
(0.97-1.05)
|
While no dose adjustment is necessary for digoxin, appropriate monitoring of serum digoxin levels is recommended.
|
|
↔ ombitasvir
|
1.03
(0.97-1.10)
|
1.00
(0.98-1.03)
|
0.99
(0.96-1.02)
|
|
↔ paritaprevir
|
0.92
(0.80-1.06)
|
0.94
(0.81-1.08)
|
0.92
(0.82-1.02)
|
|
↔ dasabuvir
|
0.99
(0.92-1.07)
|
0.97
(0.91-1.02)
|
0.99
(0.92-1.07)
|
|
Viekirax without dasabuvir
|
↑ digoxin
|
1.58
(1.43-1.73)
|
1.36
(1.21-1.54)
|
1.24
(1.07-1.43)
|
Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended.
|
|
↔ ombitasvir r
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔
paritaprevir
|
|
Amiodarone
Quinidine
Mechanism: CYP3A4 inhibition by ritonavir.
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↑ amiodarone
↑ quinidine
|
Concomitant use is contraindicated (see section 4.3).
|
|
ANTIBIOTICS (SYSTEMIC ADMINISTRATION)
|
|
Clarithromycin
Telithromycin
Mechanism: CYP3A4/P-gp inhibition by clarithromycin and ritonavir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ clarithromycin
↑ telithromycin
↑ paritaprevir
↑ dasabuvir
|
Concomitant use is contraindicated (see section 4.3)
|
|
Erythromycin
Mechanism: CYP3A4/P-gp inhibition by erythromycin, paritaprevir, ritonavir and dasabuvir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ erythromycin
↑ paritaprevir
↑ dasabuvir
|
Administration of Viekirax with or without dasabuvir with erythromycin may result in increased concentrations of erythromycin and paritaprevir. Caution is advised.
|
|
Fusidic Acid
Mechanism: CYP3A4 inhibition by ritonavir.
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↑ fusidic acid
|
Concomitant use is contraindicated (see section 4.3).
|
|
ANTICANCER AGENTS
|
|
Enzalutamide
Mitotane
Mechanism: CYP3A4 induction enzalutamide or mitotane.
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↓ombitasvir
↓ paritaprevir
↓ dasabuvir
|
Concomitant use is contraindicated (see section 4.3).
|
|
Imatinib
Mechanism: BCRP inhibition by paritaprevir, ritonavir and dasabuvir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ imatinib
|
Clinical monitoring and lower doses of imatinib are recommended.
|
|
ANTICOAGULANTS
|
|
Warfarin
5 mg single dose
|
Viekirax + dasabuvir
|
↔
R-warfarin
|
1.05
(0.95-1.17)
|
0.88
(0.81-0.95)
|
0.94
(0.84-1.05)
|
While no dose adjustment is necessary for warfarin, appropriate monitoring of international normalised ratio (INR) is recommended.
|
|
↔
S-warfarin
|
0.96
(0.85-1.08)
|
0.88
(0.81-0.96)
|
0.95
(0.88-1.02)
|
|
↔
ombitasvir
|
0.94
(0.89-1.00)
|
0.96
(0.93-1.00)
|
0.98
(0.95-1.02)
|
|
↔
paritaprevir
|
0.98
(0.82-1.18)
|
1.07
(0.89-1.27)
|
0.96
(0.85-1.09)
|
|
↔
dasabuvir
|
0.97
(0.89-1.06)
|
0.98
(0.91-1.06)
|
1.03
(0.94-1.13)
|
|
Viekirax without dasabuvir
|
↔
R-warfarin
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔
S-warfarin
|
|
↔ paritaprevir
|
|
↔
ombitasvir
|
|
Dabigatran etexilate
Mechanism: Intestinal P-gp inhibition by paritaprevir and ritonavir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ dabigatran etexilate
|
Viekirax without dasabuvir may increase the plasma concentrations of dabigatran etexilate. Use with caution.
|
|
ANTICONVULSANTS
|
|
Carbamazepine
200 mg once daily followed by 200 mg twice daily
Mechanism: CYP3A4 induction by carbamazepine
|
Viekirax + dasabuvir
|
↔ carba-mazepine
|
1.10
(1.07-1.14)
|
1.17
(1.13-1.22)
|
1.35
(1.27-1.45)
|
Concomitant use is contraindicated (see section 4.3).
|
|
↓ carbamaze pine 10, 11-epoxide
|
0.84
(0.82-0.87)
|
0.75
(0.73-0.77)
|
0.57
(0.54-0.61)
|
|
↓
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
|
|
↓
dasabuvir
|
0.45
(0.41-0.50)
|
0.30
(0.28-0.33)
|
NA
|
|
Viekirax without dasabuvir
|
Not studied: similar effect expected as observed with Viekirax + dasabuvir.
|
|
Phenobarbital
Mechanism:
CYP3A4 induction by phenobarbital.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↓ ombitasvir
↓ paritaprevir
↓ dasabuvir
|
Concomitant use is contraindicated (see section 4.3).
|
|
Phenytoin
Mechanism:
CYP3A4 induction by phenytoin.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↓ ombitasvir
↓ paritaprevir
↓ dasabuvir
|
Concomitant use is contraindicated (see section 4.3).
|
|
S-mephenytoin
Mechanism: CYP2C19 induction by ritonavir.
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↓ S-mephenytoin
|
Clinical monitoring and dose adjustment maybe needed for s-mephenytoin.
|
|
ANTIDEPRESSANTS
|
|
Escitalopram
10 mg single dose
|
Viekirax + dasabuvir
|
↔ escitalopram
|
1.00
(0.96-1.05)
|
0.87
(0.80-0.95)
|
NA
|
No dose adjustment is necessary for escitalopram.
|
|
↑ S-Desmethyl citalopram
|
1.15
(1.10-1.21)
|
1.36
(1.03-1.80)
|
NA
|
|
↔
ombitasvir
|
1.09
(1.01-1.18)
|
1.02
(1.00-1.05)
|
0.97
(0.92-1.02)
|
|
↔ paritaprevir
|
1.12
(0.88-1.43)
|
0.98
(0.85-1.14)
|
0.71
(0.56-0.89)
|
|
↔
dasabuvir
|
1.10
(0.95-1.27)
|
1.01
(0.93-1.10)
|
0.89
(0.79-1.00)
|
|
Viekirax without dasabuvir
|
↓ escitalopram
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔ S-Desmethyl citalopram
|
1.17
(1.08-1.26)
|
1.07
(1.01-1.13)
|
NA
|
|
↔
ombitasvir
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔
paritaprevir
|
|
Duloxetine
60 mg single dose
|
Viekirax + dasabuvir
|
↓
duloxetine
|
0.79
(0.67-0.94)
|
0.75
(0.67-0.83)
|
NA
|
No dose adjustment is necessary for duloxetine.
No dose adjustment needed for Viekirax with or without dasabuvir.
|
|
↔
ombitasvir
|
0.98
(0.88-1.08)
|
1.00
(0.95-1.06)
|
1.01
(0.96-1.06)
|
|
↓ paritaprevir
|
0.79
(0.53-1.16)
|
0.83
(0.62-1.10)
|
0.77
(0.65-0.91)
|
|
↔
dasabuvir
|
0.94
(0.81-1.09)
|
0.92
(0.81-1.04)
|
0.88
(0.76-1.01)
|
|
Viekirax without dasabuvir
|
↔
duloxetine
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔
ombitasvir
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↔ paritaprevir
|
1.07
(0.63-1.81)
|
0.96
(0.70-1.32)
|
0.93
(0.76-1.14)
|
|
Trazodone
Mechanism: CYP3A4 inhibition by ritonavir.
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↑ trazodone
|
Trazodone should be used with caution and a lower dose of trazodone may be considered.
|
|
ANTI-DIURETIC HORMONE
|
|
Conivaptan
Mechanism: CYP3A4/P-gp inhibition by conivaptan and paritaprevir/ ritonavir/ombitasvir
|
Viekirax with or without dasabuvir
|
Not studied. Expected:
↑conivaptan
↑ paritaprevir
↑ dasabuvir
|
Concomitant use is contraindicated (see section 4.3)
|
|
ANTIFUNGALS
|
|
Ketoconazole
400 mg once daily
Mechanism: CYP3A4/P-gp inhibition by ketoconazole and paritaprevir/ ritonavir/ ombitasvir
|
Viekirax with dasabuvir
|
↑ keto-conazole
|
1.15
(1.09-1.21)
|
2.17
(2.05-2.29)
|
NA
|
Concomitant use is contraindicated (see section 4.3)
|
|
↔
ombitasvir
|
0.98
(0.90-1.06)
|
1.17
(1.11-1.24)
|
NA
|
|
↑
paritaprevir
|
1.37
(1.11-1.69)
|
1.98
(1.63-2.42)
|
NA
|
|
↑
dasabuvir
|
1.16
(1.03-1.32)
|
1.42
(1.26-1.59)
|
NA
|
|
Viekirax without dasabuvir
|
↑ keto-conazole
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↑
ombitasvir
|
The magnitude of interaction was similar to that observed with Viekirax + dasabuvir.
|
|
↑
paritaprevir
|
1.72
(1.32-2.26)
|
2.16
(1.76-2.66)
|
NA
|
|
Itraconazole
Posaconazole
Mechanism: CYP3A4 and/or P-gp inhibition by itraconazole, posaconazole and paritaprevir/ ritonavir/ombitasvir
|
Viekirax + dasabuvir
|
Not Studied. Expected:
↑ itraconazole
↑ posaconazole
↑ paritaprevir
↑ dasabuvir
|
Concomitant use is contraindicated (see section 4.3)
|
|
Viekirax without dasabuvir
|
|
Voriconazole
Mechanism: CYP2C19 induction and CYP3A4 inhibition by ritonavir
|
Viekirax with or without dasabuvir
|
Not studied. Expected in CYP2C19 Extensive Metabolisers:
↓ voriconazole
↑ paritaprevir
↑ dasabuvir
Not studied. Expected in CYP2C19 Poor Metabolisers:
↑ voriconazole
↑ dasabuvir
↑ paritaprevir
|
Concomitant use is contraindicated (see section 4.3).
|
|
ANTI-GOUT
|
|
Colchicine
Mechanism: CYP3A4 inhibition by ritonavir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ colchicine
|
A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with Viekirax with or without dasabuvir is required. Use of colchicine is contraindicated with Viekirax with or without dasabuvir in patients with renal or hepatic impairment (see sections 4.3 and 4.4)
|
|
ANTIHISTAMINES
|
|
Astemizole
Terfenadine
Mechanism: CYP3A4 inhibition by ritonavir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ astemizole/terfenadine
|
Concomitant use is contraindicated (see section 4.3).
|
|
Fexofenadine
Mechanism: OATP1B1 inhibition by paritaprevir.
|
Viekirax with or without dasabuvir
|
Not Studied. Expected:
↑ fexofenadine
|
Caution should be used when Viekirax with or without dasabuvir is coadministered with fexofenadine.
|
|
ANTIHYPERLIPIDAEMICS
|
|
Gemfibrozil
600 mg twice daily
Mechanism: Increase in dasabuvir exposure is possibly due to CYP2C8 inhibition and increase in paritaprevir possibly due to OATP1B1 inhibition by gemfibrozil.
|
Paritaprevir/ritonavir + dasabuvir
|
↑ paritaprevir
|
1.21
(0.94-1.57)
|
1.38
(1.18-1.61)
|
NA
|
Concomitant use of Viekirax with dasabuvir is contraindicated (see section 4.3).
|
|
↑ dasabuvir
|
2.01
(1.71-2.38)
|
11.25
(9.05-13.99)
|
NA
|
|
Viekirax without dasabuvir
|
Not studied;
No interaction expected when gemfibrozil is used in combinati |
