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| ==Drug Interactions== | | ==Drug Interactions== |
| ===Drugs Metabolized by Cytochrome P450===
| | Roferon-A has been reported to reduce the clearance of theophylline.10,11 The clinical relevance of this interaction is presently unknown. Caution should be exercised when administering Roferon-A in combination with other potentially myelosuppressive agents. Synergistic toxicity has been observed when Roferon-A is administered in combination with zidovudine (AZT) (see WARNINGS: Bone Marrow Toxicity). |
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| There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.
| | In transplant recipients, therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action. |
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| Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC.
| | Alpha-interferons may affect the oxidative metabolic process by reducing the activity of hepatic microsomal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this should be taken into account when prescribing concomitant therapy with drugs metabolized by this route. |
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| ===Theophylline===
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| Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS.
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| ===Methadone===
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| In a PK study of HCV subjects concomitantly receiving methadone, treatment with PEGASYS once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.
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| The pharmacokinetics of concomitant administration of methadone and PEGASYS were evaluated in 24 PEGASYS naïve chronic hepatitis C (CHC) subjects (15 male, 9 female) who received 180 mcg PEGASYS subcutaneously weekly. All subjects were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving PEGASYS. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of PEGASYS treatment as compared to baseline. Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C subjects not receiving methadone.
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| ===Nucleoside Analogues===
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| In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HCV/HIV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected subjects.
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| ====NRTIs====
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| In Study 7 among the CHC/HIV coinfected cirrhotic subjects receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.9)].
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| Patients receiving PEGASYS/COPEGUS and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3, 5.9) and Dosage and Administration (2.5, 2.6)].
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| ====Didanosine====
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| Co-administration of COPEGUS and didanosine is contraindicated. In vitro, didanosine and its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4)].
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| ====Zidovudine====
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| In Study 7, subjects who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC less than 500 cells/mm3) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar subjects not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
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| ====Azathioprine====
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| The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.1)].
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| Please refer to the Full Prescribing Information for ribavirin for full details on ribavirin's drug interaction potential.<ref>{{Cite web | last = | first =|title = http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103964s5204lbl.pdf| url =http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103964s5204lbl.pdf | publisher = |date = | accessdate = }}</ref>
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| | The neurotoxic, hematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs. Use of Roferon-A in conjunction with interleukin-2 may potentiate risks of renal failure.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = ROFERON-A (INTERFERON ALFA-2A) INJECTION, SOLUTION [ROCHE PHARMACEUTICALS] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4c918b02-f158-4f7c-8ecc-fd49574ec228#nlm34090-1 | publisher = | date = | accessdate = 9 January 2014 }}</ref> |
| ==References== | | ==References== |
| {{Reflist}} | | {{Reflist}} |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Drug Interactions
Roferon-A has been reported to reduce the clearance of theophylline.10,11 The clinical relevance of this interaction is presently unknown. Caution should be exercised when administering Roferon-A in combination with other potentially myelosuppressive agents. Synergistic toxicity has been observed when Roferon-A is administered in combination with zidovudine (AZT) (see WARNINGS: Bone Marrow Toxicity).
In transplant recipients, therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action.
Alpha-interferons may affect the oxidative metabolic process by reducing the activity of hepatic microsomal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this should be taken into account when prescribing concomitant therapy with drugs metabolized by this route.
The neurotoxic, hematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs. Use of Roferon-A in conjunction with interleukin-2 may potentiate risks of renal failure.[1]
References
Adapted from the FDA Package Insert.