4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for sickle cell disease products are summarized in Table 3. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| Hydroxyurea (Droxia®, Siklos®) | Live Vaccines (MMR*, Varicella, Zoster, Smallpox, Typhoid, Yellow fever, Rotavirus+) | May increase risk of infection by live vaccine | Avoid use until at least 3 months after discontinuation of immunosuppressive drugs unless benefits clearly outweigh potential risks | Contraindicated (DrugReax) 1 – severe (CP) |
| Hydroxyurea (Droxia®, Siklos®) | Stavudine | May increase risk of severe peripheral neuropathy, fatal pancreatitis, and hepatotoxicity | Avoid concurrent use | Major (DrugReax) 2 – major (CP) |
| Hydroxyurea (Droxia®, Siklos®) | Didanosine | May result in fatal pancreatitis and hepatotoxicity | Avoid concurrent use | Major (DrugReax) 2 – major (CP) |
| Voxelotor (Oxbryta®) | Strong or moderate CYP3A4 inducers (e.g. phenytoin, nafcillin, carbamazepine) | May reduce voxelotor plasma concentration and result in reduced efficacy | Avoid concurrent use or increase voxelotor dosage to 2000-2500 mg daily | Major (DrugReax) 2 – major (CP) |
| Voxelotor (Oxbryta®) | Fluconazole | May increase voxelotor plasma concentration and result in increased toxicity | Avoid concurrent use, replace with alternative drugs, or decrease voxelotor dosage to 1000 mg daily | Major (DrugReax) 2 – major (CP) |
| Voxelotor (Oxbryta®) | Strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole) | May increase voxelotor plasma concentration and result in increased toxicity | Avoid concurrent use, replace with alternative drug, or Decrease voxelotor dosage to 1000 mg daily | Major (DrugReax) 2 – major (CP) |
| Voxelotor (Oxbryta®) | CYP 3A4 substrates with narrow therapeutic indices (e.g. oxycodone, cyclosporine, fentanyl, tacrolimus) | May result in increased concentration of sensitive CYP3A4 substrates | Avoid concurrent use or consider dose reduction of sensitive CYP3A4 substrates with narrow therapeutic index | Major (DrugReax) 3 – moderate (CP) |
Legend:
- * MMR-Measles, mumps, rubella
- + Rotavirus vaccination is indicated up to 24 months of age; because hydroxyurea (Siklos®) is indicated for use in pediatric patients 2 years and older, there is a small chance that a patient might be considered for both treatments; this combination should be avoided.