Liverpool HEP Interactions

Do Not Coadminister

Elbasvir/Grazoprevir

Carbamazepine

Summary:

Coadministration is contraindicated. Coadministration has not been studied but may significantly decrease elbasvir/grazoprevir concentrations due to induction of CYP3A4 and/or P-gp by carbamazepine; this may lead to reduced therapeutic effect and potential virological failure.

Description:

Coadministration of elbasvir/grazoprevir and CYP3A or P-gp inducers, such as carbamazepine, is contraindicated because it may significantly decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of elbasvir/grazoprevir. The interaction has not been studied but is expected to decrease exposure of elbasvir and grazoprevir due to CYP3A or P-gp induction.

Zepatier Summary of Product Characteristics, Merck Sharp & Dohme Ltd, January 2021.

Coadministration is contraindicated. May lead to loss of virologic response to elbasvir/grazoprevir due to significant decreases in elbasvir and grazoprevir plasma concentrations caused by strong CYP3A induction.

Zepatier US Prescribing Information, Merck & Co Inc., December 2021.

Potential Interaction

Elbasvir/Grazoprevir

Atorvastatin

Summary:

Coadministration of elbasvir + grazoprevir (50+ 200 mg once daily) with atorvastatin (10 mg single dose) increased atorvastatin AUC by 94% and increased Cmax by 4.34-fold. The dose of atorvastatin should not exceed a daily dose of 20 mg when coadministered with elbasvir/grazoprevir.

Description:

Coadministration of atorvastatin (20 mg single dose) and grazoprevir (200 mg once daily) increased atorvastatin AUC and Cmax by 3.00- and 5.66-fold (primarily due to BCRP inhibition). Grazoprevir AUC, Cmax and C24 increased by 26%, 26% and 11%, respectively. Coadministration of atorvastatin (10 mg single dose) and elbasvir/grazoprevir (50/200 mg once daily) increased atorvastatin AUC and Cmax by 94% and 334% but decreased C24 by 79%. The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with elbasvir/grazoprevir.

Zepatier Summary of Product Characteristics, Merck Sharp & Dohme Ltd, January 2021.

Coadministration of elbasvir and grazoprevir with atorvastatin increases the concentrations of atorvastatin. The dose of atorvastatin should not exceed a daily dose of 20 mg when co-administered with elbasvir/grazoprevir. Coadministration of atorvastatin (20 mg single dose) and grazoprevir (200 mg once daily) to 9 subjects increased grazoprevir AUC, Cmax and C24 by 26%, 26% and 11%, respectively. Coadministration of atorvastatin (10 mg single dose) and elbasvir + grazoprevir (50 + 200 mg once daily) to 16 subjects increased atorvastatin AUC and Cmax by 1.94-fold and 4.34-fold, but decreased Ctrough by 79%.

Zepatier US Prescribing Information, Merck & Co Inc., December 2021.

Coadministration of elbasvir/grazoprevir (50/200 mg, once daily) with atorvastatin (10 mg, single dose) was studied in 16 healthy volunteers in a two-period, fixed-sequence trial. Atorvastatin AIC and Cmax increased by 94% and 343%, respectively. Orthohydroxyatorvastatin AUC and Cmax increased by 91% and 634%, respectively. Dose adjustment of elbasvir/grazoprevir is not required. A dose reduction in atorvastatin is recommended, due to an increased risk of myopathy.

Evaluation of Pharmacokinetic Drug Interactions of the Direct-Acting Antiviral Agents Elbasvir and Grazoprevir with Pitavastatin, Rosuvastatin, Pravastatin, and Atorvastatin in Healthy Adults. L Caro, T Prueksaritanont, CM Fandozzi et al. Clin Drug Investig, 2021, 41(2):133-147.

No Interaction Expected

Elbasvir/Grazoprevir

Lactulose

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of lactulose to lactic acid occurs via gastro-intestinal microbial flora only.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Levetiracetam

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levetiracetam is not extensively metabolised in humans and production of the primary metabolite is not mediated by liver cytochrome P450 isoenzymes.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Levothyroxine

Summary:

Coadministration has not been studied and thyroid metabolism is complicated. The major pathway is sequential deiodination (but there are few published data on the enzymes involved) and conjugation with glucuronides and sulphates also occurs. A few individual case reports indicate some potential CYP involvement but this is unlikely to be clinically significant. Data suggest that endogenous T3 and T4 may be transported by OATP1B1 but no data that they cause inhibition. Monitor thyroid levels in the absence of further data.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Meloxicam

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meloxicam is a substrate of CYP2C9 (major) and CYP3A4 (minor). Grazoprevir is only a weak inhibitor of CYP3A4 and is unlikely to affect these pathways to any clinically significant extent.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Mirtazapine

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mirtazapine is metabolised by CYP2D6 and CYP1A2 which are not expected to be affected by elbasvir/grazoprevir.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Naltrexone

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies have shown that naltrexone is metabolised by UGTs which are not expected to be affected by elbasvir/grazoprevir.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Ramipril

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is metabolised by esterases and glucuronidation and these pathways are not expected to be affected by elbasvir/grazoprevir.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Senna

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Thiamine (Vitamin B1)

Summary:

Co-administration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as thiamine is predominantly eliminated unchanged by the kidneys.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Amlodipine

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amlodipine is metabolized by CYP3A4 and is a mild inhibitor of CYP3A4 and P-gp. Elbasvir/grazoprevir are metabolised by CYP3A4 and transported by P-gp. Although amlodipine may increase elbasvir and grazoprevir concentrations, this is unlikely to be of clinically significance. Concentrations of amlodipine may be increased due to weak inhibition of CYP3A4 by grazoprevir and mild inhibition of P-gp by elbasvir, but this is unlikely to be clinically significant.

Description:

(See Summary)

No Interaction Expected

Elbasvir/Grazoprevir

Baclofen

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Baclofen is mainly excreted in the urine or deaminated.

Description:

(See Summary)

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