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Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir

Pronunciation

(om BIT as vir, par i TA pre vir, ri TOE na vir, & da SA bue vir)

Index Terms

  • Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir
  • Paritaprevir, Ombitasvir, Ritonavir, and Dasabuvir
  • Ritonavir, Ombitasvir, Paritaprevir, and Dasabuvir
  • Viekira XR

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Combination package:

Viekira Pak [28 day supply]:

Tablet, oral: Ombitasvir 12.5 mg, paritaprevir 75 mg, and ritonavir 50 mg (56s)

Tablet, oral: Dasabuvir 250 mg (56s)

Tablet Extended Release, Oral:

Viekira XR: Ombitasvir 8.33 mg, paritaprevir 50 mg, ritonavir 33.33 mg, and dasabuvir 200 mg

Brand Names: U.S.

  • Viekira Pak
  • Viekira XR

Pharmacologic Category

  • Antihepaciviral, NS5A Inhibitor
  • Antihepaciviral, Polymerase Inhibitor (Anti-HCV)
  • Antihepaciviral, Protease Inhibitor (Anti-HCV)
  • Cytochrome P-450 Inhibitor
  • NS3/4A Inhibitor
  • NS5A Inhibitor
  • NS5B RNA Polymerase Inhibitor

Pharmacology

Combines 3 direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action. Ombitasvir inhibits HCV NS5A, and interferes with viral RNA replication and virion assembly. Paritaprevir inhibits HCV NS3/4A protease and interferes with HCV coded polyprotein cleavage necessary for viral replication. Dasabuvir inhibits HCV RNA-dependent RNA polymerase (encoded by the NS5B gene) which is also necessary for viral replication.

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 (ie, AUC).

Distribution

Ombitasvir: Vdss: 173 L

Paritaprevir: Vdss: 103 L

Ritonavir: Vdss: 21.5 L

Dasabuvir: Vdss: 149 L

Metabolism

Ombitasvir: Metabolized by amide hydrolysis and oxidative metabolism

Paritaprevir: Metabolized by CYP3A4 and to a lesser extent CYP3A5

Ritonavir: Metabolized by CYP3A and to a lesser extent CYP2D6

Dasabuvir: Metabolized by CYP2C8 and to a lesser extent CYP3A

Excretion

Ombitasvir: Feces (90.2%, mainly as unchanged drug) and urine (1.91%)

Paritaprevir: Feces (88%, mainly as metabolites) and urine (8.8%)

Ritonavir: Feces (86.4%) and urine (11.3%)

Dasabuvir: Feces (94.4%, mainly as metabolites) and urine (~2%)

Time to Peak

Ombitasvir: ~5 hours

Paritaprevir: ~4 to 5 hours

Ritonavir: ~4 to 5 hours

Dasabuvir: ~4 hours (immediate release); 8 hours (ER)

Half-Life Elimination

Ombitasvir: 21 to 25 hours; Paritaprevir: 5.5 hours; Ritonavir: 4 hours; Dasabuvir 5.5 to 6 hours

Protein Binding

Ombitasvir: 99.9%; Paritaprevir: 97 to 98.6%; Ritonavir: >99%; Dasabuvir: >99.5%

Use: Labeled Indications

Chronic hepatitis C: Treatment of adults with chronic hepatitis C virus (HCV) infection genotype 1a and genotype 1b without cirrhosis or with compensated cirrhosis.

Contraindications

Hypersensitivity (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome) to any component of the formulation, including ritonavir; moderate to severe hepatic impairment (Child-Pugh class B or C); concurrent use of drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events; concurrent use of moderate or strong inducers of CYP3A, strong inducers of CYP2C8, or strong inhibitors of CYP2C8. Concurrent use of drugs that are contraindicated include, but are not necessarily limited to: alfuzosin, carbamazepine, cisapride, colchicine, dronedarone, ergot derivatives (ergonovine, ergotamine, dihydroergotamine, methylergonovine), ethinyl estradiol-containing products, efavirenz, gemfibrozil, lovastatin, lurasidone, midazolam (oral), phenobarbital, phenytoin, pimozide, ranolazine, rifampin, sildenafil (when used for the treatment of pulmonary arterial hypertension [eg, Revatio]), simvastatin, St. John's wort, triazolam. If used with ribavirin, contraindications of ribavirin also apply. See ribavirin prescribing information.

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use with astemizole, bosentan, colchicine (if concurrent renal and/or hepatic impairment), etravirine, fusidic acid (oral formulation), modafinil, nevirapine, salmeterol, terfenadine

Dosing: Adult

Chronic hepatitis C (monoinfected or HCV/HIV-1 coinfected): Oral: Note: Viekira Pak is a copackaged product; ombitasvir, paritaprevir, and ritonavir are a fixed-dose combination tablet; dasabuvir is an individual tablet. Viekira XR is a fixed dose bilayer tablet; the immediate release layer contains ombitasvir, paritaprevir, and ritonavir; the extended release layer contains dasabuvir.

Genotype 1a, without cirrhosis (with concomitant ribavirin):

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 12 weeks

Dasabuvir: 250 mg twice daily for 12 weeks

Extended release: Three tablets once daily for 12 weeks

Genotype 1a, with compensated cirrhosis (Child-Pugh class A) (with concomitant ribavirin):

Note: Based on prior treatment history, some patients may be considered for a duration of therapy of 12 weeks.

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 24 weeks

Dasabuvir: 250 mg twice daily for 24 weeks

Extended release: Three tablets once daily for 24 weeks

Genotype 1b, without cirrhosis:

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 12 weeks

Dasabuvir: 250 mg twice daily for 12 weeks

Extended release: Three tablets once daily for 12 weeks

Genotype 1b, with compensated cirrhosis (Child-Pugh class A):

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 12 weeks

Dasabuvir: 250 mg twice daily for 12 weeks

Extended release: Three tablets once daily for 12 weeks

Genotype 1 (unknown subtype) or Genotype 1 (mixed infection) without cirrhosis (with concomitant ribavirin):

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 12 weeks

Dasabuvir: 250 mg twice daily for 12 weeks

Extended release: Three tablets once daily for 12 weeks

Genotype 1 (unknown subtype) or Genotype 1 (mixed infection) with compensated cirrhosis (Child-Pugh class A) (with concomitant ribavirin):

Note: Based on prior treatment history, some patients may be considered for a duration of therapy of 12 weeks.

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 24 weeks

Dasabuvir: 250 mg twice daily for 24 weeks

Extended release: Three tablets once daily for 24 weeks

Genotype 1, liver transplant recipients, Metavir fibrosis score ≤2 (normal hepatic function, mild fibrosis) (regardless of genotype 1 subtype; with concomitant ribavirin): Note: If calcineurin inhibitor used concomitantly, calcineurin inhibitor dosage adjustment is needed.

Immediate release:

Ombitasvir/paritaprevir/ritonavir tablet: Two tablets every morning for 24 weeks

Dasabuvir: 250 mg twice daily for 24 weeks

Extended release: Three tablets once daily for 24 weeks

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

End-stage renal disease (ESRD) on dialysis: No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): Use is contraindicated.

Administration

Immediate release: Administer with a meal.

Extended release: Administer with a meal. Swallow whole; do not split, crush, or chew. Avoid consumption of alcohol within 4 hours before or after administration of ER tablet (may alter release of dasabuvir).

Dietary Considerations

Take with a meal.

Storage

Store at or below 30°C (86°F). Dispense in original carton.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Alcohol (Ethyl): May diminish the therapeutic effect of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Management: Avoid alcohol consumption within 4 hours of taking the extended-release ombitasvir/paritaprevir/ritonavir/dasabuvir product. This interaction does not apply to the immediate-release ombitasvir/paritaprevir/ritonavir/dasabuvir product. Consider therapy modification

Alfentanil: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Alfentanil. Management: Monitor for increased anesthetic and respiratory depressant effects of alfentanil if these agents are combined. Consider using lower initial doses of alfentanil or an alternative anesthetic. Canadian labeling recommends avoidance of this combination. Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of ALPRAZolam. Monitor therapy

Amiodarone: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Amiodarone. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

AmLODIPine: Antihepaciviral Combination Products may increase the serum concentration of AmLODIPine. Management: Reduce amlodipine dose by at least 50% and monitor for increased amlodipine effects (eg, hypotension) if an antihepaciviral combination product is initiated. Consider therapy modification

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the paritaprevir component may increase significantly. Management: These agents can be combined if the atazanavir dose is 300 mg daily, atazanavir is administered in the morning at the same time as the ombitasvir/paritaprevir/ritonavir/dasabuvir combination product, and atazanavir is given without additional ritonavir. Consider therapy modification

AtorvaSTATin: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of AtorvaSTATin. Management: Monitor for increased atorvastatin toxicities (eg, myopathy) if these agents are combined. Consider using lower initial doses of atorvastatin. Canadian labeling recommends avoidance of this combination. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Benperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol. Monitor therapy

Bepridil: Antihepaciviral Combination Products may increase the serum concentration of Bepridil. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Buprenorphine: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Buprenorphine. Monitor therapy

BuPROPion: Antihepaciviral Combination Products may decrease the serum concentration of BuPROPion. Monitor therapy

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

Candesartan: Antihepaciviral Combination Products may increase the serum concentration of Candesartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the candesartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Consider therapy modification

Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Carisoprodol: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may decrease the serum concentration of Carisoprodol. Monitor therapy

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cisapride: Antihepaciviral Combination Products may increase the serum concentration of Cisapride. Avoid combination

Clarithromycin: Antihepaciviral Combination Products may increase the serum concentration of Clarithromycin. Management: Avoid clarithromycin doses greater than 1000 mg/day when used with an antihepaciviral combination product. Further dose reductions may be needed in patients with impaired renal function. Consider an alternative antimicrobial for any non-MAC infection. Consider therapy modification

CloZAPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: Antihepaciviral Combination Products may increase the serum concentration of Colchicine. Avoid combination

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

Cyclobenzaprine: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may decrease the serum concentration of Cyclobenzaprine. Monitor therapy

CycloSPORINE (Systemic): Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of CycloSPORINE (Systemic). Management: Reduce cyclosporine dose 80% when initiating therapy with ombitasvir/paritaprevir/ritonavir/dasabuvir and monitor cyclosporine blood levels closely. Consider therapy modification

CYP2C8 Inducers (Strong): May decrease the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may decrease significantly. Avoid combination

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may increase significantly. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); AmLODIPine; Buprenorphine; Gefitinib; HYDROcodone; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Darunavir: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may decrease the serum concentration of Darunavir. Avoid combination

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Delamanid: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Delamanid. Management: Increase electrocardiogram (ECG) monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors because the risk for QTc interval prolongation may be increased. Continue frequent ECG assessments throughout the full delamanid treatment period. Consider therapy modification

DiazePAM: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may decrease the serum concentration of DiazePAM. Monitor therapy

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Monitor therapy

DOCEtaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Monitor therapy

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eluxadoline: Antihepaciviral Combination Products may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with antihepaciviral combination products. Monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergot Derivatives: Antihepaciviral Combination Products may increase the serum concentration of Ergot Derivatives. Exceptions: Nicergoline. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Consider therapy modification

Ethinyl Estradiol: May enhance the hepatotoxic effect of Antihepaciviral Combination Products. Avoid combination

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

FentaNYL: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of FentaNYL. Management: Monitor for increased opioid effects/toxicities if these agents are combined. Consider using lower initial doses of fentanyl. Canadian labeling recommends avoidance of this combination. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Flecainide: Antihepaciviral Combination Products may increase the serum concentration of Flecainide. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fluvastatin: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Fluvastatin. Management: Canadian product labeling recommends use of the lowest fluvastatin dose with this combination. Monitor therapy

Fosamprenavir: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Management: Use of ritonavir-boosted fosamprenavir with ombitasvir/paritaprevir/ritonavir/dasabuvir is not recommended. Consider a reduced dose of fosamprenavir 1400 mg once daily (unboosted) when used with ombitasvir/paritaprevir/ritonavir/dasabuvir. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

HYDROcodone: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of HYDROcodone. Management: Reduce the hydrocodone dose by 50% during concurrent use of ombitasvir, paritaprevir, ritonavir, and dasabuvir; monitor closely for both analgesic effectiveness and for signs of toxicity or withdrawal. Consider therapy modification

HydrOXYzine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HydrOXYzine. Management: This combination is specifically contraindicated in some non-U.S. labeling. Consider therapy modification

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Ketoconazole (Systemic): Antihepaciviral Combination Products may increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Antihepaciviral Combination Products. Specifically, ketoconazole may increase serum concentrations of paritaprevir. Management: Limit the dose of ketoconazole to 200 mg per day in patients taking antihepaciviral combination products. Additionally, monitor for increased ketoconazole effects/toxicities and for increased paritaprevir effects/toxicities. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Linagliptin: Antihepaciviral Combination Products may increase the serum concentration of Linagliptin. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lopinavir: May increase the serum concentration of Antihepaciviral Combination Products. Specifically, the serum concentrations of the paritaprevir component may increase significantly. Avoid combination

Losartan: Antihepaciviral Combination Products may increase the serum concentration of Losartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the losartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Consider therapy modification

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy

MetFORMIN: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Mexiletine: Antihepaciviral Combination Products may increase the serum concentration of Mexiletine. Monitor therapy

Midazolam: Antihepaciviral Combination Products may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with antihepaciviral combination products. When used with intravenous midazolam, monitor for increased midazolam effects (eg, sedation, respiratory depression) and consider using a reduced midazolam dose. Avoid combination

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 300 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

OLANZapine: Antihepaciviral Combination Products may decrease the serum concentration of OLANZapine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Omeprazole: Antihepaciviral Combination Products may decrease the serum concentration of Omeprazole. Monitor therapy

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Pitavastatin. Management: Canadian product labeling recommends use of the lowest pitavastatin dose with this combination. Monitor therapy

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Pravastatin: Antihepaciviral Combination Products may increase the serum concentration of Pravastatin. Management: Limit the pravastatin dose to a maximum of 40 mg per day when used with antihepaciviral combination products and monitor patients for evidence of pravastatin toxicities (eg, myopathy). Consider therapy modification

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy

Proguanil: Antihepaciviral Combination Products may decrease the serum concentration of Proguanil. Monitor therapy

Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Propafenone: Antihepaciviral Combination Products may increase the serum concentration of Propafenone. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce the quetiapine dose to one sixth of the regular dose following strong CYP3A4 inhibitor initiation. In patients receiving strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and up-titrate as needed. Consider therapy modification

QuiNIDine: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of QuiNIDine. Management: Canadian labeling recommends avoiding this combination. Monitor therapy

QuiNINE: Antihepaciviral Combination Products may increase the serum concentration of QuiNINE. Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Rilpivirine: Antihepaciviral Combination Products may increase the serum concentration of Rilpivirine. Avoid combination

Riociguat: Antihepaciviral Combination Products may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times daily. Patients receiving such a combination should also be monitored closely for signs or symptoms of hypotension. Consider therapy modification

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Rosuvastatin: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Rosuvastatin. Management: Limit the rosuvastatin dose to a maximum of 10 mg per day when used with the ombitasvir/paritaprevir/ritonavir/dasabuvir combination product. Canadian labeling recommends limiting the rosuvastatin dose to 5 mg per day. Consider therapy modification

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sirolimus: Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Sirolimus. Management: Monitor for increased sirolimus effects/toxicities and sirolimus serum concentrations after initiation of ombitasvir/paritaprevir/ritonavir/dasabuvir. Consider empiric sirolimus dose reductions. Canadian labeling recommends avoiding this combination. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Tacrolimus (Systemic). Management: Do not administer tacrolimus on the day the ombitasvir/paritaprevir/ritonavir/dasabuvir product is initiated. Beginning the day after initiation, restart tacrolimus at a reduced dose. Typical tacrolimus dose is 0.5 mg every 7 days. Consider therapy modification

Tacrolimus (Topical): Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir may increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Consider therapy modification

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Triamcinolone (Systemic): Antihepaciviral Combination Products may increase the serum concentration of Triamcinolone (Systemic). Monitor therapy

Triazolam: Antihepaciviral Combination Products may increase the serum concentration of Triazolam. Avoid combination

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Valsartan: Antihepaciviral Combination Products may increase the serum concentration of Valsartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the valsartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Consider therapy modification

Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Antihepaciviral NS5B RNA Polymerase Inhibitors may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Voriconazole: Antihepaciviral Combination Products may decrease the serum concentration of Voriconazole. Management: Concurrent use of voriconazole with antihepaciviral combination products should be avoided unless the patient-specific benefit/risk ratio justifies the use of voriconazole. Decreased efficacy of voriconazole is possible. Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Adverse Reactions

Also see individual agents.

1% to 10%:

Central nervous system: Insomnia (5%)

Dermatologic: Pruritus (7%), skin rash (7%)

Gastrointestinal: Nausea (8%)

Hepatic: Increased serum bilirubin (≥2 x ULN; 2%), increased serum ALT (>5 x ULN; 1%)

Neuromuscular & skeletal: Weakness (4%)

<1% (Limited to important or life-threatening): Angioedema, hepatic failure, hypersensitivity reaction, liver decompensation

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Hepatic decompensation and hepatic failure, including liver transplantation and fatal cases, have been reported with ombitasvir, paritaprevir, ritonavir, and dasabuvir; most patients experiencing these severe adverse events had advanced or decompensated cirrhosis prior to treatment initiation. Typically occurs between 1 and 4 weeks of treatment initiation; characterized by acute elevation of direct bilirubin, without ALT elevation, and signs and symptoms of hepatic decompensation (eg, ascites, hepatic encephalopathy, variceal hemorrhage). In patients with cirrhosis, monitor for signs and symptoms of hepatic decompensation and perform hepatic function testing (including direct bilirubin) at baseline, during the first 4 weeks of treatment initiation, and as indicated thereafter. Discontinue treatment in patients who develop signs/symptoms of hepatic decompensation.

• Hepatic enzyme elevations: Elevations of ALT (>5 times ULN) have been reported. Elevations are usually asymptomatic, occur within 4 weeks of treatment initiation, and decline within 2 to 8 weeks with continued dosing. Monitor hepatic enzymes during the first 4 weeks of treatment initiation and thereafter as clinically indicated. If ALT is elevated, repeat testing and continue to monitor closely; patients should contact their health care professional immediately if they experience onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice, or discolored feces. Consider discontinuation if ALT remains persistently >10 x ULN. Discontinue if ALT increase is accompanied by signs of hepatic inflammation, elevated direct bilirubin, alkaline phosphatase, or INR. Female patients taking ethinyl estradiol products are at increased risk. For management of women taking concomitant estrogen products, refer to Special Populations below.

Disease-related concerns:

• Hepatic impairment: Use is contraindicated in moderate to severe hepatic impairment (Child-Pugh class B or C).

Concurrent drug therapy issues:

• Concomitant therapy: If used with concomitant ribavirin, contraindications of ribavirin, particularly pregnancy avoidance warnings, also apply. See ribavirin prescribing information.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Women taking concomitant estrogen products: Concurrent use of ethinyl estradiol-containing products is contraindicated; these products may be restarted approximately 2 weeks following completion of HCV therapy. Alternative methods of contraception (eg, nonhormonal methods, progestin only contraception) are recommended during therapy. Women using other estrogens (eg, estradiol, conjugated estrogens) should have hepatic enzymes tested during the first 4 weeks of treatment and as clinically indicated thereafter.

Other warnings/precautions:

• Risk of HIV-1 protease inhibitor drug resistance: Ritonavir, a component of the product, is also an HIV-1 protease inhibitor. In HCV/HIV coinfected patients, ritonavir can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 coinfected patients should also be taking a suppressive antiretroviral regimen to reduce resistance risk.

Monitoring Parameters

Manufacturer’s labeling: Baseline hepatic function tests and during the first 4 weeks of therapy, then periodically during therapy, especially in women taking concomitant estrogen products; serum HCV-RNA at baseline and at the end of treatment, during treatment follow-up, and when clinically indicated. In patients with cirrhosis, monitor for clinical signs and symptoms of hepatic decompensation (eg, ascites, hepatic encephalopathy, variceal hemorrhage).

Alternate recommendations (AASLD/IDSA 2015):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Considerations

This combination product is contraindicated for use with ribavirin in pregnant women or males whose female partners are pregnant.

Adverse events were not observed in animal reproduction studies. If used in combination with ribavirin, all warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Mother-to-child transmission of HCV does not occur if the woman is not viremic, therefore, HCV-infected women of childbearing potential should postpone pregnancy until therapy is complete. Treatment of HCV is not recommended for women who are already pregnant (AASLD/IDSA 2015).

Health care providers are encouraged to enroll pregnant women who are HCV/HIV co-infected and exposed to antiretroviral medications in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience itching, nausea, or insomnia. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), skin irritation, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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