Immunodeficiency Clinic > Drug Interaction Guide
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Sofosbuvir & Tranylcypromine (Parnate®) [class:green]
Summary/Recommendation:
Use standard doses of both drugs.
Data:
Interaction unlikely. Use standard doses of both drugs.
- Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203.
- The metabolic pathway for activation involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide binding protein 1 followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
- Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro.
- After a single 400 mg dose of 14C-sofosbuvir, sofosbuvir and GS-331007 accounted for approximately 4% and >90% of drug related material systemic exposure, respectively.
Sofosbuvir and GS-331007 are not inhibitors of any CYP450 isoenzymes or UGT1A1.
Sofosbuvir is a P-gp substrate and breast cancer resistance protein (BCRP) substrate whereas GS-331007 is not.
Effect of sofosbuvir’s on other drugs’ pharmacokinetics
Sofosbuvir and GS-331007 are not inhibitors of P-gp and/or BCRP and are not expected to increase exposure of drugs that are substrates of these transporters.
Effect of other drugs on sofosbuvir pharmacokinetics
- Drugs that are potent P-gp inducers such as rifampin or St. John’s wort may reduce sofosbuvir plasma concentration leading to a reduced therapeutic effect of sofosbuvir. Thus sofosbuvir should not be used with potent P-gp inducers.
- Co-administration of sofosbuvir with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration. Therefore sofosbuvir may be given with P-gp and BCRP inhibitors.
- The table below displays the potential effect of specific drug classes on the concentration of sofosbuvir and GS-331007.
Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
Analeptics: | Decreased sofosbuvir Decreased GS-331007 | Coadministration of sofosbuvir with modafinil is expected to decrease the concentration of sofosbuvir, leading to a reduced therapeutic effect of sofosbuvir. Coadministration is not recommended. |
Anticonvulsants: Carbamazepine | Decreased sofosbuvir Decreased GS-331007 | Coadministration of sofosbuvir and anticonvulsants is expected to decrease the concentration of sofosbuvir, leading to a decreased therapeutic effect. Coadministration is not recommended. |
Antimycobacterials: | Decreased sofosbuvir Decreased GS-331007 | Coadministration of sofosbuvir with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir leading to a reduced therapeutic effect. Coadministration is not recommended. Sofosbuvir should not be used with rifampin, a potent P-gp inducer. |
Herbal Supplements: | Decreased sofosbuvir Decreased GS-331007 | Sofosbuvir should not be used with St. John’s wort, a potent P-gp inducer |
HIV Protease Inhibitors: | Decreased sofosbuvir Decreased GS-331007 | Coadministration of sofosbuvir with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of sofosbuvir. Coadministration is not recommended. |
Interaction with antiretrovirals
No dose adjustments are required when sofosbuvir is used in combination with the following antiretrovirals based on results from clinical trials:
- Darunavir/ritonavir
- Efavirenz
- Emtricitabine
- Raltegravir
- Rilpivirine
- Tenofovir
Sofosbuvir monotherapy is not recommended for the treatment of CHC and should only be prescribed with ribavirin or in combination with both ribavirin and peginterferon alfa (refer to table below).
The recommended dose for sofosbuvir is one 400 mg tablet, taken orally, once daily with or without food. Dose reduction of sofosbuvir is not recommended.
The table below displays treatment regimen and duration based on viral genotype and patient population:
Treatment | Duration (Canadian Monograph) | Duration (American Monograph) | |
Treatment naïve patients with genotype 1 or 4 CHC | Sofosbuvir + peginterferon alfaa + ribavirinb | 12 weeks | 12 weeks |
Patients with genotype 2 CHC | Sofosbuvir + ribavirinb | 12 weeks | 12 weeks |
Patients with genotype 3 CHC | Sofosbuvir + ribavirinb | 16 weeks | 24 weeks |
a. See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC
b. Dose of ribavirin is weight based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). The daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require dose reduction; refer to ribavirin prescribing information.
Sofosbuvir in combination wit ribavirin for 24 weeks may be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon based regimen.
Patients with Hepatocellular Caricinoma Awaiting Liver Transplantation:
Sofosbuvir in combination with ribavirin is recommended for up to 24 weeks (48 weeks in the American monograph) or until the time of transplantation, whichever occurs first, to prevent post transplant HCV reinfection.
Patients Coinfected with Hepatitis B (HBV)/HCV:
The safety and efficacy of sofosbuvir has not been established in patients coinfected with HBV.
Patients Coinfected with HCV/HIV-1:
Genotype 2 and 3: sofosbuvir and ribavirin for 12 weeks have been evaluated in an open label clinical trial. 75% of patients with genotype 2 and 63% of patients with genotype 3 achieved sustained virologic response 4 weeks post treatment. The safety profile was similar in coinfected patients to that of monoinfected patients.
Dose Modification:
Genotype 1 and 4: if a patient experiences a serious reaction potentially related to peginterferon alfa and/or ribavirin, the peginteferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to peginterferon alfa and ribavirin prescribing information for dose modification or discontinuation information.
Genotype 2 and 3: if a patient experiences a serious reaction potentially related to ribavirin, the ribavirin dose should be modified or discontinued, until the adverse reaction abates or decreases in severity. Please refer to the ribavirin prescribing information for dose modification or discontinuation information.
Discontinuation:
If pegylated interferon/ribavirin or ribavirin are used in combination with sofosbuvir and are permanently discontinued sofosbuvir should also be discontinued.
The table below displays population pharmacokinetic data for subjects with genotype 1 to 6 HCV infection who were co-administered ribavirin (with or without pegylated interferon), the geometric mean steady state:
| Sofosbuvir | GS-331007 | |
| Genotype 1-6 HCV infection, AUC0-24 | 860 ng.hr/mL | 7200 mg.hr/mL |
In subjects infected with HCV the sofosbuvir AUC0-24 was 36% higher whereas the GS-331007 AUC0-24 was 39% lower when compared with healthy subjects administered sofosbuvir alone.
The steady state Cmax, based on population pharmacokinetics for GS-331007 in patients with genotype 1 to 6 HCV infection was 582 ng/mL. Relative to healthy volunteers the Cmax was 49% lower than in HCV-infected patients.
Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200-1200 mg.
Hepatic metabolism.
Alternative Options: Interaction Check with Drugs from Similar Classes
HCV antivirals with tranylcypromine
[green] 3
Sofosbuvir with MAOI
[green] 3
- Sofosbuvir (Sovaldi®) & moclobemide (Manerix®)[class:green]
- Sofosbuvir (Sovaldi®) & phenelzine (Nardil®)[class:green]
- Sofosbuvir (Sovaldi®) & selegiline (Eldepryl®)[class:green]
HCV antivirals with tranylcypromine [green] 3
Sofosbuvir with MAOI [green] 3
- Sofosbuvir (Sovaldi®) & moclobemide (Manerix®)[class:green]
- Sofosbuvir (Sovaldi®) & phenelzine (Nardil®)[class:green]
- Sofosbuvir (Sovaldi®) & selegiline (Eldepryl®)[class:green]
Interaction Classification
- These Drugs should not be coadministered[class:red]
- Potential interaction - may require close monitoring, alteration of drug dosage or timing of administration[class:yellow]
- No clinically significant interaction expected[class:green]
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