Table 3.

Dose interruption and modifications guidelines for common adverse events related to cabozantinib & vandetanib (defined by common terminology criteria for adverse events).

Grade	Hypertension	Diarrhea†	Dermatologic AEs (acne, drug rash, HFSR)	Fatigue, weight loss	Proteinuria (confirmed by 24-h urinalysis)	QTcF prolongation	Liver transaminase elevation	Decreased potassium, magnesium, corrected calcium	Hematologic AEs (neutropenia, thrombocytopenia, anemia)‡
1	No dose change; manage hypertension	No dose change; manage diarrhea	No dose change; manage symptoms	No dose change	(<1 g/24 h); no dose change; monitor	(450-480 ms); monitor closely	No dose change; monitor labs	No dose change; correct abnormalities	No dose change
2	1st occurrence: continue drug; manage hypertension	Tolerable: manage diarrhea	1st occurrence: hold drug until grade ≤1; manage symptoms; resume at same dose level	Tolerable: manage symptoms	(1-3.4 g/24 h); hold drug for 1 week; manage proteinuria medically, then repeat 24-h urinalysis	(481-500 ms); monitor closely; correct electrolyte levels	Monitor labs closely; search for other causes; −1 dose reduction may be considered	Correct abnormalities	No dose change
	2nd or 3rd occurrence: hold drug; manage hypertension; resume drug at −1 dose level	Intolerable: 1st occurrence: hold drug, manage diarrhea, resume at same dose level 2nd occurrence: hold drug, manage diarrhea, resume at −1 dose level	2nd occurrence: hold drug; manage symptoms; resume at −1 dose level	Intolerable: hold drug; resume at −1 dose level when grade ≤1	If <1 g/24 h, resume drug at same dose level If >1 g/24 h, resume at −1 dose level			If caused by diarrhea: control diarrhea; consider a −1 dose reduction upon correction of abnormality
3	Hold drug; manage hypertension; resume at −1 dose level	Hold drug, manage diarrhea, resume at −1 dose level	1st or 2nd occurrence: hold drug; manage symptoms; resume at −1 dose level	Hold drug; manage symptoms; resume at −1 dose level when grade ≤1	(≥3.5 g/24 h); hold drug for at least 1 week; manage proteinuria medically; repeat 24 h urinalysis	(≥500 ms); hold drug until QTcF normalizes; review electrolytes and medication list; resume drug at −1 dose level when QTc ≤450 ms	Hold drug; search for other causes; resume at −1 dose level when labs decrease to grade ≤2	Hold drug; correct abnormalities	Dose reduction for neutropenia and thrombocytopenia
			3rd occurrence: consider discontinuation		If <1 g/24 h, resume at −1 dose level. If persistently >1 g/24 h, consider discontinuation			If caused by diarrhea: control diarrhea and resume at −1 dose level
								If caused by non-compliance: consider discontinuation of drug
4	Discontinue drug unless adequate control can be achieved: consider reduction of -2 dose levels under close supervision	Discontinue drug	Discontinue drug	Discontinue drug		Discontinue drug	Discontinue drug	Discontinue drug	Dose reduction for anemia, neutropenia and thrombocytopenia

^†Grade ≥2 diarrhea may cause electrolyte abnormalities and therefore, laboratory evaluations should be performed.

^‡Grade 3-4 hematologic AEs should trigger a search for causes not related to the drug.

AE: Adverse event; HFSR: Hand-foot skin reaction; QTcF: Correct QT interval by Fridericia formula.