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Mavyret (Glecaprevir and Pibrentasvir) - Uses, Dose, Side effects, MOA

Mavyret is a regimen used to treat patients with chronic hepatitis C or HIV and chronic hepatitis C co-infected patients. It is a combination of direct-acting agents of NS5A inhibitor pibrentasvir and NS3/4A protease inhibitor glecaprevir.

Mavyret (Glecaprevir and pibrentasvir) Uses:

Chronic hepatitis C: In adults and children >12 years or weight ≥45 kg
- It is indicated in the treatment of patients with chronic hepatitis HCV genotype 1-6, without cirrhosis or with compensated cirrhosis (Child-Pugh class A)
- HCV genotype 1 infection: Previously treated with HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both.

Mavyret (Glecaprevir and pibrentasvir) Dose in Adults

Mavyret (Glecaprevir and pibrentasvir) Dose in the treatment of chronic hepatitis C (HCV mono-infected or HCV/HIV co-infected patients):

Without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Oral:
- Treatment-naive patients:
  - Genotype 1-6:
    - 3 tablets once a day for 8 weeks without cirrhosis or 12 weeks with compensated cirrhosis (Child-Pugh class A).
- Treatment-experienced patients:
  - Genotype 1: Previously treated with an NS5A inhibitor-containing regimen without an NS3/4A protease inhibitor:
    - 3 tablets once a day for 16 weeks
  - Genotype 1: Previously treated with an NS3/4A protease inhibitor-containing regimen without an NS5A inhibitor:
    - 3 tablets once a day for 12 weeks
  - Genotype 1, 2, 4, 5, or 6: Previously treated with interferons (including pegylated formulations) and/or ribavirin but no prior treatment with an NS3/4A or NS5A inhibitor:
    - 3 tablets once a day for 8 weeks without cirrhosis or 12 weeks with compensated cirrhosis (Child-Pugh class A)
  - Genotype 1 or 2: Previously treated with sofosbuvir, but no prior treatment with an NS3/4A or NS5A inhibitor:
    - 3 tablets once a day for 12 weeks without cirrhosis or with compensated cirrhosis (Child-Pugh class A)
  - Genotype 3: Previously treated with interferon (including pegylated formulations), ribavirin, and/or sofosbuvir, but no prior treatment with an NS3/4A or NS5A inhibitor:
    - 3 tablets once a day for 16 weeks
- Liver or kidney transplant recipients:
  - Genotypes 1-6: Treatment-naive:
    - 3 tablets once a day for 12 weeks
  - Genotype 1: Previously treated with an NS5A inhibitor without an NS3/4A protease inhibitor:
    - 3 tablets once a day for 16 weeks
  - Genotype 1: Previously treated with an NS3/4A protease inhibitor without an NS5A inhibitor:
    - 3 tablets once a day for 12 weeks
  - Genotype 1, 2, 4, 5, or 6: Previously treated with interferon (including pegylated formulations), ribavirin, and/or sofosbuvir but no prior treatment with an NS3/4A or NS5A inhibitor:
    - 3 tablets once a day for 12 weeks.
  - Genotype 3: Previously treated with interferon (including pegylated formulations), ribavirin, and/or sofosbuvir, but no prior treatment with an NS3/4A or NS5A inhibitor:
    - 3 tablets once a day for 16 weeks
- Missed dose:
  - If less than18 hours from the usual dose time, take the dose as soon as possible, then next doses according to schedule
  - If more than18 hours from the usual dose time, skip the missed dose and take the next doses according to schedule

Use in Children:

Not indicated.

Mavyret (Glecaprevir and pibrentasvir) Pregnancy Category: N

Studies on animal reproduction have not shown adverse effects of glecaprevir and pibrentasvir, as individuals.
Hepatitis C treatment during pregnancy is not recommended at the moment.
If HCV detected during pregnancy, postpone treatment until after delivery
Postpone pregnancy for non-pregnant women until you have received complete treatment to lower the risk of HCV transmission

Use of pibrentasvir and glecaprevir during breastfeeding

It is unknown whether breastmilk contains glecaprevir and pibrentasvir. It is important to consider the risks of infant exposure as well as the benefits for the mother.
Breastfeeding is not associated with the spread of HCV. However, breastfeeding is not recommended if the nipples become cracked or bleeding.
It is not recommended that you breastfeed HIV co-infection patients.

Dose in Kidney disease:

No dose adjustment required.

Dose in Liver disease:

Mild impairment (Child-Pugh class A):
- No dose adjustment required.
Moderate impairment (Child-Pugh class B):
- Not recommended.
Severe impairment (Child-Pugh class C):
- Contraindicated.

Common Side Effects of Mavyret (Glecaprevir and pibrentasvir):

Central nervous system:
- Headache
- Fatigue
Gastrointestinal:
- Nausea

Less Common Side Effects of Mavyret (Glecaprevir and pibrentasvir):

Dermatologic:
- Pruritus
Gastrointestinal:
- Diarrhea
Hepatic:
- Increased serum bilirubin

Infection:
- Reactivation of HBV

Contraindications to Mavyret (Glecaprevir and pibrentasvir):

Severe hepatic impairment (Child Puugh class C).
Use atazanavir and rifampin in combination

Additional contraindications for Canadian labeling (not US labeling)

Hypersensitivity to pibrentasvir or glecaprevir
Coadministration with atorvastatin, dabigatran, Ethinyl estradiol, or simvastatin.

Warnings and precautions

Diabetes:
- Diabetes patients may experience hypoglycemia after receiving direct-acting antiviral therapy (DAA) for hepatitis C.
- This is due to an improvement in glucose metabolism following rapid reductions in viral load.
- Monitor blood sugar levels, especially in the first three months.
Hepatic impairment
- Avoid moderate impairment (Childugh class B).
- In severe impairment (Child Puugh class C), contraindicated
Hepatitis B virus activation: [US-Boxed Warning]
- Patients infected by HCV/HBV while receiving HCV DAA (directly-acting antivirals), but not receiving antiviral treatment for hepatitis B, may develop fulminant liver disease, hepatic failure and even death.
- Before starting treatment, test for HBV infection.
- Monitor for HBV reactivation or hepatitis flare in HBV coinfected patients during treatment. Followup
- If HBV infection is diagnosed clinically, start treatment immediately.
- HBV reactivation was also reported.

Glecaprevir and pibrentasvir: Drug Interaction

Risk Factor C (Monitor therapy)
Antidiabetic Agents	Direct Acting Antiviral Agents (HCV) may enhance the hypoglycemic effect of Antidiabetic Agents.
ARIPiprazole	CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Brentuximab Vedotin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Celiprolol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.
CloZAPine	CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Cobicistat	May increase the serum concentration of Glecaprevir and Pibrentasvir.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
Dofetilide	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide.
Eltrombopag	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Eltrombopag	May increase the serum concentration of BCRP/ABCG2 Substrates.
Everolimus	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus.
Flibanserin	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin.
Gemfibrozil	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates. See separate drug interaction monographs for agents listed as exceptions.
Larotrectinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.
Naldemedine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Naloxegol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol.
NiMODipine	CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine.
Osimertinib	May increase the serum concentration of BCRP/ABCG2 Substrates.
P-glycoprotein/ABCB1 Inducers	: May decrease the serum concentration of Glecaprevir and Pibrentasvir.
P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide.
Prucalopride	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
Ranolazine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine.
Regorafenib	May increase the serum concentration of BCRP/ABCG2 Substrates.
RifAXIMin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
Rolapitant	May increase the serum concentration of BCRP/ABCG2 Substrates. Management: Monitor patients receiving rolapitant for increased exposure to and/or effects of BCRP/ABCG2 substrates. Use the lowest effective rosuvastatin dose when used in combination with rolapitant.
Silodosin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.
Tacrolimus (Systemic)	Glecaprevir and Pibrentasvir may increase the serum concentration of Tacrolimus (Systemic).
Talazoparib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs.
Talazoparib	BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib.
Tedizolid	May increase the serum concentration of BCRP/ABCG2 Substrates.
Teriflunomide	May increase the serum concentration of BCRP/ABCG2 Substrates.
Teriflunomide	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Risk Factor D (Consider therapy modification)
Afatinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
Betrixaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor.
Bilastine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors.
Cladribine	BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration.
Colchicine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
Dabigatran Etexilate	P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling.
Digoxin	Glecaprevir and Pibrentasvir may increase the serum concentration of Digoxin. Management: Measure serum digoxin concentrations before initiating glecaprevir/pibrentasvir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 50% or by modifying the dosing frequency; continue monitoring during concomitant therapy.
DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Edoxaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation.
HMG-CoA Reductase Inhibitors (Statins)	Glecaprevir and Pibrentasvir may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with glecaprevir/pibrentasvir and monitor for increased statin effects/toxicities. Avoid concomitant use with atorva-, simva-, or lovastatin. Limit rosuvastatin to 10 mg daily and reduce pravastatin dose 50%
Lomitapide	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day.
TiZANidine	CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions.
Tolvaptan	May increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates.
Tolvaptan	May increase the serum concentration of BCRP/ABCG2 Substrates.
Venetoclax	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors.
Risk Factor X (Avoid combination)
Asunaprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir.
Atazanavir	May increase the serum concentration of Glecaprevir and Pibrentasvir.
AtorvaSTATin	Glecaprevir and Pibrentasvir may increase the serum concentration of AtorvaSTATin.
CarBAMazepine	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
CycloSPORINE (Systemic)	May increase the serum concentration of Glecaprevir and Pibrentasvir.
Darunavir	May increase the serum concentration of Glecaprevir and Pibrentasvir.
Efavirenz	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
Elagolix	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix.
Ethinyl Estradiol	May enhance the adverse/toxic effect of Glecaprevir and Pibrentasvir. Specifically, the risk for ALT elevation may be increased with this combination.
Fosphenytoin-Phenytoin	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
Grazoprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Grazoprevir.
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.
Lopinavir	May increase the serum concentration of Glecaprevir and Pibrentasvir.
Lovastatin	Glecaprevir and Pibrentasvir may increase the serum concentration of Lovastatin.
PAZOPanib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
PAZOPanib	BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib.
Pimozide	CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide.
Revefenacin	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin.
RifAMPin	May decrease the serum concentration of Glecaprevir and Pibrentasvir. RifAMPin may increase the serum concentration of Glecaprevir and Pibrentasvir. Specifically, a single dose of rifampin may increase glecaprevir/pibrentasvir concentrations, while chronic daily use of rifampin may decrease glecaprevir/pibrentasvir concentrations.
Simvastatin	Glecaprevir and Pibrentasvir may increase the serum concentration of Simvastatin.
St John's Wort	May decrease the serum concentration of Glecaprevir and Pibrentasvir.
Topotecan	BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan.
Topotecan	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
VinCRIStine (	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).
Liposomal)	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir.
Voxilaprevir	May increase the serum concentration of BCRP/ABCG2 Substrates.

Monitoring parameters:

Baseline (within 12 weeks before starting therapy):
- CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), and calculated GFR. Repeat these test after 4 weeks or according to clinical indications
HCV - genotype and subtype and quantitative HCV viral load before starting the therapy repeat quantitative viral load after 4 weeks of therapy and at 12 weeks after completion of therapy.
If the quantitative viral load is detectable at treatment week 4, repeat testing after 2 additional weeks of treatment (treatment week 6)
HBsAg and anti-HBc before starting therapy:
- If the patient has serologic evidence of hepatitis B virus infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during treatment and follow-up
- Monitor blood sugar level in diabetics ( to avoid the risk of symptomatic hypoglycemia).

How to administer Mavyret (Glecaprevir and pibrentasvir)?

Oral: can be taken with food.

Mechanism of action of Mavyret (Glecaprevir and pibrentasvir):

Glecaprevir

It inhibits HCV NS3/4A protease, which is necessary for the proteolytic cleavage (into mature forms the NS4A and NS4B, NS5A and NS5A proteins) and is vital for viral replication.

Pibrentasvir:

It blocks HCV NS5A, which is essential for viral RNA replication.

Protein binding:

Glecaprevir: 97.5%
Pibrentasvir: >99.9%

Metabolism:

Glecaprevir: Secondary to CYP3A

Half-life elimination:

Glecaprevir: 6 hours
Pibrentasvir: 13 hours

Time to peak: 5 hours Excretion:

Glecaprevir: Feces (92.1%), urine (0.7%)
Pibrentasvir: Feces (96.6%)

International Brand Names of Glecaprevir and pibrentasvir:

Mavyret

Glecaprevir and pibrentasvir Brand Names in Paksitan:

No Brands Available in Pakistan.

Mavyret (Glecaprevir and Pibrentasvir) - Uses, Dose, Side effects, MOA

Mavyret (Glecaprevir and pibrentasvir) Uses:

Chronic hepatitis C: In adults and children >12 years or weight ≥45 kg

Mavyret (Glecaprevir and pibrentasvir) Dose in Adults

Mavyret (Glecaprevir and pibrentasvir) Dose in the treatment of chronic hepatitis C (HCV mono-infected or HCV/HIV co-infected patients):

Without cirrhosis or with compensated cirrhosis (Child-Pugh class A): Oral:

Use in Children:

Mavyret (Glecaprevir and pibrentasvir) Pregnancy Category: N

Use of pibrentasvir and glecaprevir during breastfeeding

Dose in Kidney disease:

Dose in Liver disease:

Common Side Effects of Mavyret (Glecaprevir and pibrentasvir):

Central nervous system:

Gastrointestinal:

Less Common Side Effects of Mavyret (Glecaprevir and pibrentasvir):

Dermatologic:

Gastrointestinal:

Hepatic:

Infection:

Contraindications to Mavyret (Glecaprevir and pibrentasvir):

Warnings and precautions

Diabetes:

Hepatic impairment

Hepatitis B virus activation: [US-Boxed Warning]

Monitoring parameters:

How to administer Mavyret (Glecaprevir and pibrentasvir)?

Mechanism of action of Mavyret (Glecaprevir and pibrentasvir):

International Brand Names of Glecaprevir and pibrentasvir:

Glecaprevir and pibrentasvir Brand Names in Paksitan:

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