Chemical formula: C₂₆H₂₇N₃O₅S Molecular mass: 493.58 g/mol PubChem compound: 56640146
Dasabuvir interacts in the following cases:
Co-administration of dasabuvir with medicinal productsthat inhibit CYP2C8 (e.g. teriflunomide, deferasirox) may increase dasabuvir plasma concentrations.
Dasabuvir is an inhibitor of UGT1A1 in vivo. Co-administration of 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).
Dasabuvir is an inhibitor of BCRP in vivo. Co-administration of dasabuvir with ombitasvir/paritaprevir/ritonavir 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.
Exposures of cyclobenzaprine, a CYP1A2 substrate, were decreased. Clinical monitoring and dose adjustment may be needed for other CYP1A2 substrates (e.g. ciprofloxacin, cyclobenzaprine, theophylline and caffeine).
Co-administration of dasabuvir with ombitasvir/paritaprevir/ritonavir can decrease exposures of medicinal products that are metabolized by CYP2C19 (e.g. lansoprazole, esomeprazole, smephenytoin), which may require dose adjustment/clinical monitoring. CYP2C19 substrates evaluated in drug interaction studies include omeprazole and escitalopram.
While dasabuvir is an in vitro inhibitor of P-gp, no significant change was observed in the exposure of the P-gp substrate, digoxin, when administered with dasabuvir with ombitasvir/paritaprevir/ritonavir. It may not be excluded that the systemic exposure of dabigatran etexilate is increased by dasabuvir due to inhibition of P-gp in the intestine.
While no change in the pharmacokinetics of warfarin is expected, close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Alprazolam 0.5 mg single dose:
| ↑ alprazolam | 1.09 (1.03-1.15) | 1.34 (1.15-1.55) | NA |
| ↔ dasabuvir | 0.93 (0.83-1.04) | 0.98 (0.87-1.11) | 1.00 (0.87-1.15) |
| ↔ 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) |
Clinical comments:
Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Amlodipine 5 mg single dose:
| Cmax | AUC | Cthrough | |
| ↑ amlodipine | 1.26 (1.11-1.44) | 2.57 (2.31-2.86) | ΝΑ |
| ↔ dasabuvir | 1.05 (0.97-1.14) | 1.01 (0.96-1.06) | 0.95 (0.89-1.01) |
| ↔ 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) |
Clinical effects: Decrease in amlodipine dose by 50% and monitor patients for clinical effects.
Mechanism: Increase in paritaprevir exposures may be due to inhibition of OATPs by atazanavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Atazanavir 300 mg once daily (given at the same time):
| Cmax | AUC | Cthrough | |
| ↔ atazanavir | 0.91 (0.84-0.99) | 1.01 (0.93-1.10) | 0.90 (0.81-1.01) |
| ↔ dasabuvir | 0.83 (0.71-0.96) | 0.82 (0.71-0.94) | 0.79 (0.66-0.94) |
| ↓ ombitasvir | 0.77 (0.70-0.85) | 0.83 (0.74-0.94) | 0.89 (0.78-1.02) |
| ↑ paritaprevir | 1.46 (1.06-1.99) | 1.94 (1.34-2.81) | 3.26 (2.06-5.16) |
Mechanism: Increase in paritaprevir exposures may be due to inhibition of OATP1B1/B3 and CYP3A by atazanavir and CYP3A inhibition by the additional dose of ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Atazanavir/ritonavir 300/100 mg once daily (administered in the evening):
| Cmax | AUC | Cthrough | |
| ↔ atazanavir | 1.02 (0.92-1.13) | 1.19 (1.11-1.28) | 1.68 (1.44-1.95) |
| ↔ dasabuvir | 0.81 (0.73-0.91) | 0.81 (0.71-0.92) | 0.80 (0.65-0.98) |
| ↓ ombitasvir | 0.83 (0.72-0.96) | 0.90 (0.78-1.02) | 1.00 (0.89-1.13) |
| ↑ paritaprevir | 2.19 (1.61-2.98) | 3.16 (2.40-4.17) | 11.95 (8.94-15.98) |
The recommended dose of atazanavir is 300 mg, without ritonavir, in combination with dasabuvir + ombitasvir/paritaprevir/ritonavir. Atazanavir must be administered at the same time as
dasabuvir + ombitasvir/paritaprevir/ritonavir. Ritonavir dose in ombitasvir/paritaprevir/ritonavir will provide atazanavir pharmacokinetic enhancement.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
The combination of atazanavir and ombitasvir/paritaprevir/ritonavir + dasabuvir increase bilirubin levels, in particular when ribavirin is part of the hepatitis C regimen.
Mechanism: CYP2C19 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Carisoprodol 250 mg single dose:
| Cmax | AUC | Cthrough | |
| ↓ carisoprodol | 0.54 (0.47-0.63) | 0.62 (0.55-0.70) | NA |
| ↔ dasabuvir | 0.96 (0.91-1.01) | 1.02 (0.97-1.07) | 1.00 (0.92-1.10) |
| ↔ ombitasvir | 0.98 (0.92-1.04) | 0.95 (0.92-0.97) | 0.96 (0.92-0.99) |
| ↔ paritaprevir | 0.88 (0.75-1.03) | 0.96 (0.85-1.08) | 1.14 (1.02-1.27) |
Clinical comments: No dose adjustment required for carisoprodol; increase dose if clinically indicated.
Mechanism: Effect on ciclosporin is due to CYP3A4 inhibition by ritonavir and increase in paritaprevir exposures may be due to OATP/BCRP/P-gp inhibition by ciclosporin.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Ciclosporin 30 mg once daily single dose1:
| Cmax | AUC | Cthrough | |
| ↑ ciclosporin | 1.01 (0.85-1.20) | 5.82 (4.73-7.14) | 15.8 (13.8-18.09) |
| ↓ dasabuvir | 0.66 (0.58-0.75) | 0.70 (0.65-0.76) | 0.76 (0.71-0.82) |
| ↔ ombitasvir | 0.99 (0.92-1.07) | 1.08 (1.05-1.11) | 1.15 (1.08-1.23) |
| ↑ paritaprevir | 1.44 (1.16-1.78) | 1.72 (1.49-1.99) | 1.85 (1.58-2.18) |
1 Ciclosporin 100 mg dosed alone and 30 mg administered with dasabuvir + ombitasvir/paritaprevir/ritonavir. Dose normalized cyclosporine ratios are shown for interaction with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Clinical comments:
When starting coadministration with dasabuvir and ombitasvir/paritaprevir/ritonavir, give one fifth of the total daily dose of ciclosporin once daily with ombitasvir/paritaprevir/ritonavir.
Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: decrease possibly due to CYP1A2 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Cyclobenzaprine 5 mg single dose:
| Cmax | AUC | Cthrough | |
| ↓ cyclobenzaprine | 0.68 (0.61-0.75) | 0.60 (0.53-0.68) | NA |
| ↔ dasabuvir | 0.98 (0.90-1.07) | 1.01 (0.96-1.06) | 1.13 (1.07-1.18) |
| ↔ ombitasvir | 0.98 (0.92-1.04) | 1.00 (0.97-1.03) | 1.01 (0.98-1.04) |
| ↔ paritaprevir | 1.14 (0.99-1.32) | 1.13 (1.00-1.28) | 1.13 (1.01-1.25) |
Clinical studies: No dose adjustment for cyclobenzaprine required; increase dose if clinically indicated.
Mechanism: Intestinal P-gp inhibition by paritaprevir and ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not Studied.
Expected: ↑ dabigatran etexilate
Clinical comments: dasabuvir + ombitasvir/paritaprevir/ritonavir may increase the plasma concentrations of dabigatran etexilate. Use with caution.
Mechanism: unknown.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Darunavir 800 mg once daily (given at the same time):
| Cmax | AUC | Cthrough | |
| ↓ darunavir | 0,92 (0,87-0,98) | 0,76 (0,71-0,82) | 0,52 (0,47-0,58) |
| ↔ dasabuvir | 1,10 (0,88-1,37) | 0,94 (0,78-1,14) | 0,90 (0,76-1,06) |
| ↔ ombitasvir | 0,86 (0,77-0,95) | 0,86 (0,79-0,94) | 0,87 (0,82-0,92) |
| ↑ paritaprevir | 1,54 (1,14-2,09) | 1,29 (1,04-1,61) | 1,30 (1,09-1,54) |
Mechanism: unknown.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Darunavir/ritonavir 600/100 mg twice daily:
| Cmax | AUC | Cthrough | |
| ↔ darunavir | 0,87 (0,79-0,96) | 0,80 (0,74-0,86) | 0,57 (0,48-0,67) |
| ↓ dasabuvir | 0,84 (0,67-1,05) | 0,73 (0,62-0,86) | 0,54 (0,49-0,61) |
| ↓ ombitasvir | 0,76 (0,65-0,88) | 0,73 (0,66-0,80) | 0,73 (0,64-0,83) |
| ↓ paritaprevir | 0,70 (0,43-1,12) | 0,59 (0,44-0,79) | 0,83 (0,69-1,01) |
Mechanism: unknown
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Darunavir/ritonavir 800/100 mg once daily (administered in the evening):
| Cmax | AUC | Cthrough | |
| ↑ darunavir | 0,79 (0,70-0,90) | 1,34 (1,25-1,43) | 0,54 (0,48-0,62) |
| ↓ dasabuvir | 0,75 (0,64-0,88) | 0,72 (0,64-0,82) | 0,65 (0,58-0,72) |
| ↔ ombitasvir | 0,87 (0,82-0,93) | 0,87 (0,81-0,93) | 0,87 (0,80-0,95) |
| ↓ paritaprevir | 0,70 (0,50-0,99) | 0,81 (0,60-1,09) | 1,59 (1,23-2,05) |
The recommended dose of darunavir is 800 mg once daily, without ritonavir, when administered at the same time as ombitasvir/paritaprevir/ritonavir + dasabuvir (ritonavir dose in ombitasvir/paritaprevir/ritonavir will provide darunavir pharmacokinetic enhancement). This regimen can be used in the absence of extensive PI resistance (i.e. lack of darunavir associated RAMs).
Darunavir combined with ombitasvir/paritaprevir/ritonavir + dasabuvir is not recommended in patients with extensive PI resistance.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected: ↑ dasabuvir
Clinical comments: Deferasirox may increase dasabuvir exposures and should be used with caution.
Mechanism: CYP2C19 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Diazepam 2 mg single dose:
| Cmax | AUC | Cthrough | |
| ↓diazepam | 1.18 (1.07-1.30) | 0.78 (0.73-0.82) | NA |
| ↓ nordiazepam | 1.10 (1.03-1.19) | 0.56 (0.45-0.70) | NA |
| ↔ dasabuvir | 1.05 (0.98-1.13) | 1.01 (0.94-1.08) | 1.05 (0.98-1.12) |
| ↔ ombitasvir | 1.00 (0.93-1.08) | 0.98 (0.93-1.03) | 0.93 (0.88-0.98) |
| ↔ paritaprevir | 0.95 (0.77-1.18) | 0.91 (0.78-1.07) | 0.92 (0.82-1.03) |
Clinical comments: No dose adjustment required for diazepam; increase dose if clinically indicated.
Mechanism: P-gp inhibition by dasabuvir, paritaprevir, and ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Digoxin 0.5 mg single dose:
| Cmax | AUC | Cthrough | |
| ↔ digoxin | 1.15 (1.04-1.27) | 1.16 (1.09-1.23) | 1.01 (0.97-1.05) |
| ↔ dasabuvir | 0.99 (0.92-1.07) | 0.97 (0.91-1.02) | 0.99 (0.92-1.07) |
| ↔ 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) |
Clinical comments: While no dose adjustment is necessary for digoxin, appropriate monitoring of serum digoxin levels is recommended.
Mechanism: CYP2C19 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected: ↓ esomeprazole, lansoprazole
Clinical comments: If clinically indicated, higher doses of esomeprazole/lansoprazole may be needed.
Mechanism: Effect on everolimus is due to CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Everolimus 0.75 mg single dose:
| Cmax | AUC | Cthrough | |
| ↑ everolimus | 4.74 (4.29-5.25) | 27.1 (24.5-30.1) | 16.1 (14.5-17.9)1 |
| ↔ dasabuvir | 1.03 (0.90-1.18) | 1.08 (0.98-1.20) | 1.14 (1.05-1.23) |
| ↔ ombitasvir | 0.99 (0.95-1.03) | 1.02 (0.99-1.05) | 1.02 (0.99-1.06) |
| ↔ paritaprevir | 1.22 (1.03-1.43) | 1.26 (1.07-1.49) | 1.06 (0.97-1.16) |
1 C12:= concentration at 12 hours following single dose of everolimus.
Clinical comments: Co-administration of dasabuvir + ombitasvir/paritaprevir/ritonavir with everolimus is not recommended because of a significant increase in everolimus exposures which cannot be properly dose adjusted with available dose strengths.
Mechanism: OATP1B inhibition by paritaprevir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected:
↑ fluvastatin
↑ pitavastatin
↔ dasabuvir
↔ ombitasvir
↔ paritaprevir
Clinical comments:
Concomitant use with fluvastatin and pitavastatin is not recommended.
A temporary suspension of fluvastatin and pitavastatin is recommended for the duration of treatment. If statin treatment is required during the treatment period, a switch to dose reduced pravastatin or rosuvastatin is possible.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: possibly due to UGT1A1 inhibition by paritaprevir, ombitasvir and dasabuvir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Furosemide 20 mg single dose:
| Cmax | AUC | Cthrough | |
| ↑ furosemide | 1.42 (1.17-1.72) | 1.08 (1.00-1.17) | ΝΑ |
| ↔ dasabuvir | 1.12 (0.96-1.31) | 1.09 (0.96-1.23) | 1.06 (0.98-1.14) |
| ↔ ombitasvir | 1.1.4 (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) |
Clinical comments: Monitor patients for clinical effects; a decrease in furosemide dose of up to 50% may be required. No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Hydrocodone (as given in a fixed-dose hydrocodone/paracetamol) 5 mg single dose:
| Cmax | AUC | Cthrough | |
| ↑ hydrocodone | 1.27 (1.14-1.40) | 1.90 (1.72-2.10) | NA |
| ↔ dasabuvir | 1.13 (1.01-1.26) | 1.12 (1.05-1.19) | 1.16 (1.08-1.25) |
| ↔ ombitasvir | 1.01 (0.93-1.10) | 0.97 (0.93-1.02) | 0.93 (0.90-0.97) |
| ↔ paritaprevir | 1.01 (0.80-1.27) | 1.03 (0.89-1.18) | 1.10 (0.97-1.26) |
Clinical comments: A reduction of hydrocodone dose by 50% and/or clinical monitoring should be considered when administered with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: BCRP inhibition by paritaprevir, ritonavir and dasabuvir.
Diven with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not Studied.
Expected: ↑ imatinib
Clinical comments: Clinical monitoring and lower doses of imatinib are recommended.
Mechanism: UGT1A1 inhibition by paritaprevir, ombitasvir and dasabuvir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected: ↑ levothyroxine
Clinical comments: Clinical monitoring and dose adjustment may be required for levothyroxine.
Mechanism: CYP2C19 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Omeprazole 40 mg once daily:
| ↓ omeprazole | 0.62 (0.48-0.80) | 0.62 (0.51-0.75) | NA |
| ↔ dasabuvir | 1.13 (1.03-1.25) | 1.08 (0.98-1.20) | 1.05 (0.93-1.19) |
| ↔ ombitasvir | 1.02 (0.95-1.09) | 1.05 (0.98-1.12) | 1.04 (0.98-1.11) |
| ↔ paritaprevir | 1.19 (1.04-1.36) | 1.18 (1.03-1.37) | 0.92 (0.76-1.12) |
Clinical comments:
If clinically indicated, higher doses of omeprazole should be used.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: OATP1B1 inhibition by paritaprevir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Pravastatin 10 mg once daily:
| Cmax | AUC | Cthrough | |
| ↑ pravastatin | 1.37 (1.11-1.69) | 1.82 (1.60-2.08) | - |
| ↔ dasabuvir | 1.00 (0.87-1.14) | 0.96 (0.85-1.09) | 1.03 (0.91-1.15) |
| ↔ ombitasvir | 0.95 (0.89-1.02) | 0.94 (0.89-0.99) | 0.94 (0.89-0.99) |
| ↑ paritaprevir | 0.96 (0.69-1.32) | 1.13 (0.92-1.38) | 1.39 (1.21-1.59) |
Clinical comments: Reduce pravastatin dose by 50%. No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: CYP3A inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Rilpivirine1 25 mg once daily administered in the morning, with food:
| Cmax | AUC | Cthrough | |
| ↑ rilpivirine | 2.55 (2.08-3.12) | 3.25 (2.80-3.77) | 3.62 (3.12-4.21) |
| ↔ dasabuvir | 1.18 (1.02-1.37) | 1.17 (0.99-1.38) | 1.10 (0.89-1.37) |
| ↔ 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) |
1 Rilpivirine was also administered with food in the evening and 4 hours after dinner with dasabuvir + ombitasvir/paritaprevir/ritonavir in the study. The effect on rilpivirine exposures was similar to that observed when rilpivirine was administered in the morning with food with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Clinical comments: Co-administration of dasabuvir and ombitasvir/paritaprevir/ritonavir with rilpivirine once daily should only be considered in patients without known QT-prolongation, and without other QT-prolongation coadministered medicinal products. If the combination is used, repeated ECG-monitoring should be done.
No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: OATP1B inhibition by paritaprevir and BCRP inhibition by dasabuvir paritaprevir, and ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Rosuvastatin 5 mg once daily:
| Cmax | AUC | Cthrough | |
| ↑ rosuvastatin | 7.13 (5.11-9.96) | 2.59 (2.09-3.21) | 0.59 (0.51-0.69) |
| ↔ dasabuvir | 1.07 (0.92-1.24) | 1.08 (0.92-1.26) | 1.15 (1.05-1.25) |
| ↔ ombitasvir | 0.92 (0.82-1.04) | 0.89 (0.83-0.95) | 0.88 (0.83-0.94) |
| ↑ paritaprevir | 1.59 (1.13-2.23) | 1.52 (1.23-1.90) | 1.43 (1.22-1.68) |
Clinical comments: The maximum daily dose of rosuvastatin should be 5 mg. No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: Effect on sirolimus is due to CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Sirolimus 0.5 mg single dose1:
| Cmax | AUC | Cthrough | |
| ↑ sirolimus | 6.40 (5.34-7.68) | 38.0 (31.5-45.8) | 19.6 (16.7-22.9)2 |
| ↔ dasabuvir | 1.04 (0.89-1.22) | 1.07 (0.95-1.22) | 1.13 (1.01-1.25) |
| ↔ ombitasvir | 1.03 (0.93-1.15) | 1.02 (0.96-1.09) | 1.05 (0.98-1.12) |
| ↔ paritaprevir | 1.18 (0.91-1.54) | 1.19 (0.97-1.46) | 1.16 (1.00-1.34) |
1 Sirolimus 2 mg was dosed alone, 0.5 mg administered with dasabuvir + ombitasvir/paritaprevir/ritonavir. Dose normalized sirolimus ratios are shown for interaction with ombitasvir/paritaprevir/ritonavir + dasabuvir.
2 C24:= concentration at 24 hours following single dose of cyclosporine, tacrolimus or sirolimus.
Clinical comments:
Concomitant use of sirolimus with dasabuvir + ombitasvir/paritaprevir/ritonavir is not recommended unless the benefits outweigh the risks. If sirolimus is used together with dasabuvir + ombitasvir/paritaprevir/ritonavir, administer sirolimus 0.2 mg twice a week (every 3 or 4 days on the same two days each week). Sirolimus blood concentrations should be monitored every 4 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus. Sirolimus dose and/or dosing frequency should be adjusted as needed.
5 days after completion of dasabuvir + ombitasvir/paritaprevir/ritonavir treatment, the sirolimus dose and dosing frequency prior to receiving dasabuvir + ombitasvir/paritaprevir/ritonavir should be resumed, along with routine monitoring of sirolimus blood concentrations.
Mechanism: increase in dasabuvir possibly due to CYP2C8 inhibition by trimethoprim.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Sulfamethoxazole, trimethoprim 800/160 mg twice daily:
| Cmax | AUC | Cthrough | |
| ↑ sulfamethoxazole | 1.21 (1.15-1.28) | 1.17 (1.14-1.20) | 1.15 (1.10-1.20) |
| ↑ trimethoprim | 1.17 (1.12-1.22) | 1.22 (1.18-1.26) | 1.25 (1.19-1.31) |
| ↑ dasabuvir | 1.15 (1.02-1.31) | 1.33 (1.23-1.44) | NA |
| ↔ ombitasvir | 0.88 (0.83-0.94) | 0.85 (0.80-0.90) | NA |
| ↓ paritaprevir | 0.78 (0.61-1.01) | 0.87 (0.72-1.06) | NA |
Clinical comments: No dose adjustment needed for dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: BCRP inhibition by paritaprevir, ritonavir and dasabuvir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not Studied.
Expected: ↑ sulfasalazine
Clinical comments: Caution should be used when sulfasalazine is co-administered with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Mechanism: Effect on tacrolimus is due to CYP3A4 inhibition by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect:
Tacrolimus 2 mg single dose1:
| Cmax | AUC | Cthrough | |
| ↑ tacrolimus | 3.99 (3.21-4.97) | 57.1 (45.5-71.7) | 16.6 (13.0-21.2) |
| ↔ dasabuvir | 0.85 (0.73-0.98) | 0.90 (0.80-1.02) | 1.01 (0.91-1.11) |
| ↔ ombitasvir | 0.93 (0.88-0.99) | 0.94 (0.89-0.98) | 0.94 (0.91-0.96) |
| ↓ paritaprevir | 0.57 (0.42-0.78) | 0.66 (0.54-0.81) | 0.73 (0.66-0.80) |
1 Tacrolimus 2 mg was dosed alone and 2 mg was administered with dasabuvir + ombitasvir/paritaprevir/ritonavir. Dose normalized tacrolimus ratios are shown for interaction with dasabuvir + ombitasvir/paritaprevir/ritonavir.
Clinical comments:
Concomitant use of tacrolimus with dasabuvir and ombitasvir/paritaprevir/ritonavir is not recommended unless the benefits outweigh the risks.
If tacrolimus with dasabuvir and ombitasvir/paritaprevir/ritonavir are used concomitantly, tacrolimus should not be administered on the day dasabuvir and ombitasvir/paritaprevir/ritonavir are initiated. Beginning the day after dasabuvir and ombitasvir/paritaprevir/ritonavir are initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus blood concentrations. The recommended tacrolimus dosing is 0.5 mg every 7 days.
Tacrolimus whole blood concentrations should be monitored upon initiation and throughout coadministration with dasabuvir and ombitasvir/paritaprevir/ritonavir and the dose and/or dosing frequency should be adjusted as needed. Upon completion of dasabuvir and ombitasvir/paritaprevir/ritonavir treatment, the appropriate dose and dosing frequency of tacrolimus should be guided by assessment of tacrolimus blood concentrations.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected: ↑ dasabuvir
Clinical comments: Teriflunomide may increase dasabuvir exposures and should be used with caution.
Cases of depression and more rarely of suicidal ideation and suicide attempt have been reported with dasabuvir with or without ombitasvir/paritaprevir/ritonavir treatment in combination with ribavirin in the majority of the cases. Although some cases had previous history of depression, psychiatric illness and/or substance abuse, a causal relation with dasabuvir with or without ombitasvir/paritaprevir/ritonavir treatment cannot be excluded. Caution should be used in patients with a pre-existing history of depression or psychiatric illness. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation.
Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported post-marketing in patients treated with dasabuvir with ombitasvir/paritaprevir/ritonavir with and without ribavirin. Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosis prior to initiating therapy. Although causality is difficult to establish due to background advanced liver disease, a potential risk cannot be excluded.
Dasabuvir should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C).
For patients with cirrhosis:
Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines.
Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicinal products modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated.
Dasabuvir is recommended in combination with paritaprevir/ombitasvir/ritonavir, and ritonavir may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV coinfected patients without suppressive antiretroviral therapy should not be treated with dasabuvir. Drug interactions need to be carefully taken into account in the setting of HIV co-infection.
Mechanism: CYP2C19 induction by ritonavir.
Given with: dasabuvir + ombitasvir/paritaprevir/ritonavir
Effect: Not studied.
Expected: ↓ S-mephenytoin
Clinical comments: Clinical monitoring and dose adjustment maybe needed for s-mephenytoin.
There are very limited data from the use of dasabuvir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of dasabuvir during pregnancy.
If ribavirin is co-administered with dasabuvir and ombitasvir/paritaprevir/ritonavir, the contraindications regarding use of ribavirin during pregnancy apply.
It is not known whether dasabuvir and metabolites are excreted in human breast milk. Available pharmacokinetic data in animals have shown excretion of dasabuvir and metabolites in milk. Because of the potential for adverse reactions from the medicinal product in breastfed infants, a decision must be made whether to discontinue breastfeeding or discontinue treatment with dasabuvir, taking into account the importance of the therapy to the mother.
Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when dasabuvir is used with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Refer to the Summary of Product Characteristics for ribavirin for additional information.
Female patients: Women of childbearing potential should not receive ribavirin unless they are using an effective form of contraception during treatment with ribavirin and for 4 months after treatment.
Male patients and their female partners: Either male patients or their female partners of childbearing potential must use a form of effective contraception during treatment with ribavirin and for 7 months after treatment.
Ethinyloestradiol is contraindicated in combination with dasabuvir.
No human data on the effect of dasabuvir on fertility are available. Animal studies do not indicate harmful effects on fertility.
Dasabuvir has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue has been reported during treatment with dasabuvir in combination with ombitasvir/paritaprevir/ritonavir and ribavirin.
In subjects receiving dasabuvir and ombitasvir/paritaprevir/ritonavir with ribavirin, the most commonly reported adverse reactions (greater than 20% of subjects) were fatigue and nausea. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.2% (5/2,044) and 4.8% (99/2,044) of subjects had ribavirin dose reductions due to adverse reactions.
The safety summary is based on pooled data from phase 2 and 3 clinical trials in subjects who received dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin. The majority of adverse reactions presented in the table below were of grade 1 severity in dasabuvir- and ombitasvir/paritaprevir/ritonavir-containing regimens.
The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).
Adverse reactions identified with dasabuvir in combination with ombitasvir/paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir and ribavirin:
| Frequency | dasabuvir and ombitasvir/paritaprevir/ritonavir + ribavirin* N=2,044 | dasabuvir and ombitasvir/paritaprevir/ritonavir N=588 |
|---|---|---|
| Blood and lymphatic system disorders | ||
| Common | Anaemia | |
| Immune system disorders | ||
| Frequency unknown | Anaphylactic reactions | Anaphylactic reactions |
| Metabolism and nutrition disorders | ||
| Uncommon | Dehydration | |
| Psychiatric disorders | ||
| Very common | Insomnia | |
| Gastrointestinal disorders | ||
| Very common | Nausea, Diarrhoea | |
| Common | Vomiting | |
| Hepatobiliary disorders | ||
| Frequency unknown | Hepatic decompensation and hepatic failure | Hepatic decompensation and hepatic failure |
| Skin and subcutaneous tissue disorders | ||
| Very common | Pruritus | |
| Common | Pruritus | |
| Rare | Angioedema | Angioedema |
| General disorders and administration and administration site conditions | ||
| Very common | Asthenia, Fatigue | |
* Data set includes all genotype 1-infected subjects in Phase 2 and 3 trials including subjects with cirrhosis. Note: For laboratory abnormalities refer to the next table.
Compared to subjects without cirrhosis, in subjects with compensated cirrhosis there was an increased rate of indirect hyperbilirubinemia when ribavirin was part of the regimen.
Changes in selected laboratory parameters are described in the following table. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in trial designs.
Selected treatment emergent laboratory abnormalities
| Laboratory parameters | SAPPHIRE I and II | PEARL II, III, and IV | TURQUOISE II (subjects with cirrhosis) |
|---|---|---|---|
| dasabuvir and ombitasvir/paritaprevir/ritonavir + ribavirin 12 weeks N=770 n(%) | dasabuvir and ombitasvir/paritaprevir/ritonavir 12 weeks N=509 n(%) | dasabuvir and ombitasvir/paritaprevir/ritonavir + ribavirin 12 or 24 weeks N=380 n(%) | |
| ALT | |||
| >5-20 × ULN* (Grade 3) | 6/765 (0.8%) | 1/509 (0.2%) | 4/380 (1.1%) |
| >20 × ULN (Grade 4) | 3/765 (0.4%) | 0 | 2/380 (0.5%) |
| Haemoglobin | |||
| <100-80 g/L (grade 2) | 41/765 (5.4%) | 0 | 30/380 (7.9%) |
| <80-65 g/L (grade 3) | 1/765 (0.1%) | 0 | 3/380 (0.8%) |
| <65 g/L (Grade 4) | 0 | 0 | 1/380 (0.3%) |
| Total bilirubin | |||
| >3-10 × ULN (grade 3) | 19/765 (2.5%) | 2/509 (0.4%) | 37/380 (9.7%) |
| >10 × ULN (grade 4) | 1/765 (0.1%) | 0 | 0 |
* ULN: Upper Limit of Normal
In a pooled analysis of clinical trials with dasabuvir and ombitasvir/paritaprevir/ritonavir with and without ribavirin, 1% of subjects experienced serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. As the incidence of such elevations was 26% among women taking a concomitant ethinyloestradiol-containing medicine, such medicinal products are contraindicated with dasabuvir and ombitasvir/paritaprevir/ritonavir. No increase in incidence of ALT elevations was observed with other types of systemic oestrogens commonly used for hormone replacement therapy (e.g., oestradiol and conjugated oestrogens). ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8- 57 days) and most resolved with ongoing therapy. Two patients discontinued dasabuvir and ombitasvir/paritaprevir/ritonavir due to elevated ALT, including one on ethinyloestradiol. Three interrupted dasabuvir and ombitasvir/paritaprevir/ritonavir for one to seven days, including one on ethinyloestradiol. The majority of these ALT elevations were transient and assessed as related to dasabuvir and ombitasvir/paritaprevir/ritonavir. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.
Transient elevations in serum bilirubin (predominantly indirect) were observed in subjects receiving dasabuvir and ombitasvir/paritaprevir/ritonavir with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced haemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among subjects who did not receive ribavirin.
The overall safety profile in HCV-infected transplant recipients who were administered dasabuvir and ombitasvir/paritaprevir/ritonavir and ribavirin (in addition to their immunosuppressant medicinal products) was similar to subjects treated with dasabuvir and ombitasvir/paritaprevir/ritonavir and ribavirin in phase 3 clinical trials, although some adverse reactions were increased in frequency. 10 subjects (29.4%) had at least one post baseline haemoglobin value of less than 10 g/dL. 10 of 34 subjects (29.4%) dose modified ribavirin due to decrease in haemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact SVR rates. 5 subjects required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion.
The overall safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV mono-infected subjects. Transient elevations in total bilirubin >3 x ULN (mostly indirect) occurred in 17 (27.0%) subjects; 15 of these subjects were receiving atazanavir. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases.
Dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin were assessed in 68 subjects with genotype 1 infection with or without cirrhosis who have severe renal impairment or ESRD. The overall safety profile in subjects with severe renal impairment was similar to that seen in prior Phase 3 studies in subjects without severe renal impairment, except that a greater proportion of subjects required intervention due to ribavirin-associated decreases in serum haemoglobin. The mean baseline haemoglobin level was 12.1 g/dL and the mean decline in haemoglobin at the end of treatment for subjects taking RBV was 1.2 g/dL. Thirty-nine of the 50 subjects who received ribavirin required interruption of ribavirin, and 11 of these subjects were also treated with erythropoietin. Four subjects experienced a haemoglobin level <8 g/dL. Two subjects received a blood transfusion. Adverse events of anaemia were not seen in the 18 GT1b-infected subjects who did not receive ribavirin. Ombitasvir/paritaprevir/ritonavir with or without dasabuvir was also evaluated without ribavirin in 18 GT1a- and GT4-infected patients; no adverse events of anaemia were seen in these subjects.
The safety of dasabuvir in children and adolescents aged <18 years has not yet been established. No data are available.
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