Drug Interactions between Avastin and sunitinib

GENERALLY AVOID: Coadministration of bevacizumab and sunitinib in patients with solid tumors has been associated with microangiopathic hemolytic anemia (MAHA), a rare type of hemolytic anemia primarily caused by thrombotic lesions in the microvessels. The mechanism of interaction is unknown. In a phase I dose-escalation study, 25 patients with metastatic renal cell carcinoma received a fixed dose of bevacizumab (10 mg/kg) intravenously every 2 weeks and escalating doses of sunitinib (25 to 50 mg) orally daily in a 4 weeks on, 2 weeks off schedule. Five of 12 patients at the highest sunitinib dosage exhibited laboratory findings consistent with MAHA. Two of the cases were considered severe, with findings of thrombocytopenia, anemia, reticulocytosis, reduced serum haptoglobin, schistocytes on peripheral smear, modestly increased serum creatinine levels, severe (grade 3 to 4) hypertension, reversible posterior leukoencephalopathy syndrome (RPLS), and proteinuria--all of which were reversible within three weeks after discontinuing both drugs without additional interventions. In a phase 2 trial, two of seven patients receiving the same combination for the first-line treatment of metastatic renal cell carcinoma were also found to have MAHA, which resulted in closure of the trial. Overall, the seven patients who developed MAHA in the two trials ranged in age from 41 to 76. Time of onset was reported in five cases and ranged from 14 to 196 days. Two additional phase 2 studies of bevacizumab in combination with sunitinib and chemotherapy in patients with solid tumors have also been closed due to poor tolerability primarily related to myelosuppression, fatigue, and gastrointestinal complications such as diarrhea, anorexia, dehydration, and stomatitis. However, no cases of MAHA were reported in these studies.

MANAGEMENT: Based on existing data, the use of bevacizumab in combination with sunitinib is not recommended.

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