Table 5.

Drug–drug interactions involving high-alert medications and subsequent symptoms observed within 24 h after the administration of the respective drug–drug interaction

pDDI		Classification		Associated symptom	Patient days with/without pDDI and symptom, N
Drug 1	Drug 2	UpToDateb	drugs.comc		pDDI	Yes	Yes	No	No	Odds ratio [95% CI]	p value
					Symptom	Yes	No	Yes	No
Potassium saltsa	Furosemide	B	n/a	Hyponatremia		163	667	341	2617	1.88 [1.5; 2.3]	< 0.001*
Fentanyla	Furosemide	C	Moderate	Decreased blood pressure		43	275	104	3366	5.06 [3.5; 7.4]	< 0.001*
				Urinary retention		86	232	541	2929	2.01 [1.5; 2.6]	< 0.001*
				Increased heart rate		76	242	521	2949	1.78 [1.3; 2.3]	< 0.001*
Vancomycina	Furosemide	n/a	Moderate	Edema		83	150	490	3065	3.46 [2.6; 4.6]	< 0.001*
				Decreased diuresis		42	191	575	2980	1.14 [0.8; 1.6]	0.459
				Vomiting		36	197	502	3053	1.11 [0.8; 1.6]	0.573
Digoxina	Furosemide	n/a	Moderate	Hypokalemia		89	134	523	3042	3.86 [2.9; 5.1]	< 0.001*
				Nausea		10	213	177	3388	0.90 [0.5; 1.7]	0.748
				Increased heart rate		35	188	562	3003	0.99 [0.7; 1.4]	0.978
				Hypomagnesemia		12	211	238	3327	0.80 [0.4; 1.4]	0.451
Digoxina	HCT	n/a	Moderate	Hypokalemia		86	120	526	3056	4.16 [3.1; 5.6]	< 0.001*
				Increased heart rate		29	177	568	3014	0.87 [0.6; 1.3]	0.496
Fentanyla	Phenobarbitala	D	Major	Restlessness		80	59	961	2688	3.79 [2.7; 5.4]	< 0.001*
				Sweating		30	109	480	3169	1.82 [1.2; 2.8]	0.005*
Potassium saltsa	HCT	B	n/a	Hyponatremia		85	229	419	3055	2.71 [2.1; 3.5]	< 0.001*
Midazolama	HCT	n/a	Moderate	Decreased blood pressure		20	168	127	3473	3.26 [2.0; 5.3]	< 0.001*
				Increased heart rate		56	132	541	3059	2.40 [1.7; 3.3]	< 0.001*

For each drug combination and observed symptom, the frequencies of patient days on which the respective potential drug–drug interaction was or was not administered and whether the symptom was observed is shown. From those numbers, the odds ratios, 95% confidence intervals, and p-values were calculated using a univariate logistic regression

HCT hydrochlorothiazide, n/a not applicable (not listed in the respective database), pDDI potential drug–drug interaction

*Significant

^aCategorized as high-alert medication for hospitalized pediatric patients according to Schilling et al. [6]

^bClassification used in UpToDate: “D—Consider therapy modification; C—Monitor therapy; B—No action needed. Agents may interact with each other”

^cClassification used in Drugs.com: “Major—Avoid combinations; Moderate—Usually avoid combination. Use it only under special circumstances; Minor—Take steps to circumvent the interaction risk and/or establish a monitoring plan”