Table 1.
Class-class interactions identified in Twosides and corroborated by EMRs. Forty-seven class-class interactions were corroborated by two retrospective analyses of EMRs: (i) short-term combination effects observed in the 36 days after combination treatment and (ii) long-term incidence of abnormal laboratory values associated with combination treatment. The posttreatment lab changes and long-term risk values shown are all statistically significant (P < 0.05) as determined by a paired t test and Cox proportional hazards model, respectively (see the Supplementary Methods). CA, calcium; MCH, mean corpuscular hemoglobin; MCHC, MCH concentration; PLT, platelets; RDW, red cell distribution width; K, potassium; Mg, magnesium; QTC, corrected QT interval; Na, sodium; PCO2A, arterial CO2; PTT, partial thromboplastin time; ALB, albumin; CR, creatine; GLOB, globulin; RBC, red blood cells; TP, total protein; AST, aspartate aminotransferase; TBIL, total bilirubin; BUN, blood urea nitrogen; ALKP, alkaline phosphatase.
| Drug class A (#Rx in millions) |
Drugs (A) | Drug class B (#Rx in millions) |
Drugs (B) | Effect category |
Lab marker |
Posttreatment lab change ± SEM |
Long-term risk versus A (95% CI) |
Long-term risk versus B (95% CI) |
|---|---|---|---|---|---|---|---|---|
| A01AB (13) | Doxycycline, minocycline, metronidazole tabs |
G01AF (6) | Ketoconazole topical, metronidazole tabs |
Cardiovascular | CA | −0.227 ± 0.013 mg/dl | 1.570 (1.658–1.486) |
1.107 (1.211–1.012) |
| Pulmonary | CO2 | −0.200 ± 0.056 mM | 1.837 (1.981–1.703) |
1.359 (1.541–1.198) |
||||
| A01AB (13) | Doxycycline, minocycline, metronidazole tabs |
N05CF (30) | Zolpidem tartrate | Hemorrhage | MCH | −0.015 ± 0.017 g/dl | 1.671 (1.781–1.567) |
2.129 (2.257–2.008) |
| MCHC | −0.001 ± 0.010 g/dl | 2.178 (2.396–1.980) |
2.523 (2.745–2.319) |
|||||
| PLT | 14.113 ± 2.036 k/μl | 2.362 (2.563–2.178) |
3.179 (3.419–2.956) |
|||||
| A02BC (38) | Omeprazole, pantoprazole |
N05CD (9) | Temazepam | Metabolic | K | −0.029 ± 0.007 mEq/liter | 1.434 (1.511–1.361) |
3.037 (3.303–2.793) |
| RDW | 0.444 ± 0.024% | 1.317 (1.376–1.261) |
2.701 (2.889–2.526) |
|||||
| A07AA (2) | Nystatin topical, nystatin systemic |
N02AA (27) | Morphine sulfate ER, oxycodone with APAP, hydromorphone HCl, oxycodone |
Cardiovascular | CA | −0.234 ± 0.010 mg/dl | 1.131 (1.195–1.072) |
1.718 (1.782–1.656) |
| Mg | −0.002 ± 0.006 mg/dl | 1.784 (1.991–1.598) |
7.407 (8.065–6.803) |
|||||
| A07AA (2) | Nystatin topical, nystatin systemic |
N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
Cardiovascular | CA | −0.162 ± 0.020 mg/dl | 1.149 (1.238–1.066) |
1.506 (1.623–1.398) |
| QTC | 3.853 ± 2.661 ms | 1.476 (1.676–1.299) |
3.009 (3.446–2.628) |
|||||
| A07EA (26) | Dexamethasone oral, hydrocortisone top. Rx, prednisone oral |
S03AA (19) | Ciprofloxacin HCl | Cardiovascular | CA | −0.086 ± 0.016 mg/dl | 1.081 (1.138–1.028) |
1.417 (1.497–1.341) |
| Mg | −0.006 ± 0.008 mg/dl | 4.708 (5.131–4.322) |
6.653 (7.413–5.970) |
|||||
| A10BB (9) | Glipizide ER, glipizide, glimepiride, glyburide |
S03AA (19) | Ciprofloxacin HCl | Metabolic | Na | −0.375 ± 0.161 mEq/liter | 1.578 (1.761–1.413) |
1.560 (1.725–1.411) |
| B05XA (10) | Ferrous sulfate, potassium chloride |
N05CF (30) | Zolpidem tartrate | Cardiovascular | CA | −0.265 ± 0.013 mg/dl | 1.299 (1.377–1.226) |
1.155 (1.215–1.097) |
| C03AA (46) | Hydrochlorothiazide | H02AB (26) | Triamcinolone acet. top, hydrocortisone top. Rx, prednisone oral, methylprednisolone tabs, dexamethasone oral |
Pulmonary | PCO2A | 2.194 ± 0.698 mmHg | 3.077 (3.776–2.506) |
1.955 (2.351–1.626) |
| C03AA (46) | Hydrochlorothiazide | N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
Cardiovascular | QTC | 15.349 ± 5.675 ms | 1.609 (1.883–1.375) |
1.605 (1.878–1.372) |
| C09AA (74) | Lisinopril, ramipril, benazepril, enalapril, quinapril, fosinopril sodium |
J02AC (13) | Fluconazole | Cardiovascular | Mg | −0.005 ± 0.019 mg/dl | 6.803 (8.143–5.685) |
1.630 (1.967–1.351) |
| C10AA (72) | Simvastatin, Pravastatin, Lovastatin |
S02AA (19) | Ciprofloxacin HCl | Cardiovascular | K | −0.022 ± 0.009 mEq/liter | 1.838 (1.966–1.719) |
1.087 (1.167–1.013) |
| D01AC (13) | Fluconazole, ketoconazole topical |
A02BC (38) | Omeprazole, pantoprazole |
Metabolic disorders |
CA | −0.038 ± 0.017 mg/dl | 1.144 (1.226–1.068) |
1.471 (1.553–1.393) |
| D06AX (4) | Mupirocin | N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
Cardiovascular | K | −0.079 ± 0.037 mEq/liter | 1.652 (2.036–1.340) |
2.271 (2.775–1.859) |
| Mg | −0.078 ± 0.029 mg/dl | 2.195 (2.912–1.655) |
3.975 (5.203–3.035) |
|||||
| D07AB (8) | Triamcinolone acet. top, dexamethasone oral |
R03BA (18) | Triamcinolone acet. top, dexamethasone oral, fluticasone nasal |
Cardiovascular | CA | −0.390 ± 0.011 mg/dl | 1.262 (1.433–1.111) |
1.158 (1.200–1.117) |
| D07AC (18) | Fluocinonide, dexamethasone oral, fluticasone nasal |
S03AA (19) | Ciprofloxacin HCl | Cardiovascular | K | −0.027 ± 0.010 mEq/liter | 1.982 (2.160–1.818) |
1.773 (1.936–1.624) |
| D10AA (12) | Dexamethasone oral, methylprednisolone tabs |
N06AX (17) | Mirtazapine, bupropion SR, bupropion ER, bupropion XL, venlafaxine, trazodone HCl |
Cardiovascular | PTT | 0.158 ± 0.897 s | 1.210 (1.380–1.061) |
1.828 (2.092–1.598) |
| D10AF (7) | Clindamycin topical, clindamycin systemic |
N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
Cardiovascular | ALB | −0.353 ± 0.048 g/dl | 1.217 (1.427–1.039) |
1.647 (1.919–1.413) |
| G01AA (7) | Nystatin topical, clindamycin topical, nystatin systemic, clindamycin systemic |
N03AX (23) | Gabapentin, lamotrigine, levetiracetam, topiramate |
Pulmonary | CO2 | 0.672 ± 0.110 mM | 1.311 (1.463–1.175) |
1.764 (1.965–1.583) |
| G01AF (6) | Metronidazole tabs, ketoconazole topical |
N05CF (30) | Zolpidem tartrate | Gastrointestinal | ALB | −0.272 ± 0.015 g/dl | 2.105 (2.256–1.964) |
3.059 (3.253–2.877 |
| G02CC (25) | Ibuprofen, naproxen | C08CA (10) | Nifedipine ER, felodipine ER, amlodipine besyl. benz. |
Gastrointestinal | ALB | −0.308 ± 0.034 g/dl | 1.349 (1.498–1.214) |
1.237 (1.374–1.115) |
| H03AA (63) | Levothyroxine | A02BC (38) | Omeprazole, pantoprazole |
Gastrointestinal | PTT | 3.867 ± 0.573 s | 2.538 (2.770–2.325) |
1.085 (1.157–1.018) |
| J01DB (21) | Cephalexin | C09AA (74) | Benazepril, enalapril, lisinopril, ramipril, quinapril, fosinopril sodium |
Metabolic | Na | −0.624 ± 0.075 mEq/liter | 1.127 (1.217–1.044) |
1.162 (1.253–1.078) |
| J01DB (21) | Cephalexin | N05CD (9) | Temazepam | Cardiovascular | K | 0.015 ± 0.010 mEq/liter | 1.280 (1.407–1.165) |
1.215 (1.336–1.105) |
| Mg | −0.009 ± 0.015 mg/dl | 1.575 (1.822–1.360) |
1.640 (1.903–1.413) |
|||||
| Gastrointestinal | PTT | 1.792 ± 0.584 s | 1.353 (1.485–1.233) |
1.419 (1.559–1.290) |
||||
| J01DD (8) | Cefdinir | R03BA (18) | Triamcinolone acet. top, dexamethasone oral, fluticasone nasal |
Gastrointestinal | PTT | −0.857 ± 0.316 s | 1.410 (1.625–1.224) |
2.353 (2.666–2.077) |
| J01FF (7) | Clindamycin systemic, clindamycin topical |
C05AA (8) | Triamcinolone acet. top, dexamethasone oral, hydrocortisone top. Rx, fluocinonide |
Pulmonary | CO2 | 0.291 ± 0.125 mM | 1.211 (1.389–1.055) |
1.137 (1.286–1.005) |
| Cardiovascular | K | −0.036 ± 0.017 mEq/liter | 1.817 (2.093–1.578) |
1.558 (1.761–1.378) |
||||
| J01MA (19) | Ciprofloxacin HCl | A07AA (2) | Nystatin systemic, nystatin topical |
Metabolic | CR | −0.001 ± 0.010 mg/dl | 1.565 (1.639–1.495) |
1.853 (1.969–1.745) |
| GLOB | −0.020 ± 0.015 g/dl | 1.573 (1.659–1.491) |
1.853 (1.988–1.726) |
|||||
| MCH | −0.059 ± 0.014 g/dl | 1.727 (1.818–1.642) |
1.984 (2.121–1.855) |
|||||
| MCHC | −0.012 ± 0.009 g/dl | 2.211 (2.389–2.047) |
2.386 (2.643–2.153) |
|||||
| RBC | −0.183 ± 0.007 ×106/μl | 2.287 (2.411–2.170) |
2.118 (2.269–1.977) |
|||||
| RDW | 0.347 ± 0.028% | 2.144 (2.251–2.042) |
2.180 (2.324–2.045) |
|||||
| TP | −0.340 ± 0.017 g/dl | 2.039 (2.165–1.920) |
2.275 (2.466–2.098) |
|||||
| J01MA (19) | Ciprofloxacin HCl | S03AA (19) | Ciprofloxacin HCl | Gastrointestinal | AST | 6.204 ± 7.721 U/liter | 1.690 (1.816–1.573) |
2.841 (3.273–2.466) |
| TBIL | 0.139 ± 0.057 mg/dl | 1.418 (1.499–1.342) |
2.549 (2.843–2.286) |
|||||
| J02AB (3) | Ketoconazole topical | S03AA (19) | Ciprofloxacin HCl | Cardiovascular | K | −0.026 ± 0.013 mEq/liter | 2.035 (2.284–1.813) |
2.768 (3.002–2.552) |
| J05AB (5) | Acyclovir | B05XA (10) | Ferrous sulfate, potassium chloride |
Metabolic | BUN | 1.000 ± 0.602 mg/dl | 1.246 (1.352–1.149) |
1.949 (2.108–1.802) |
| Na | −0.388 ± 0.132 mEq/liter | 4.002 (4.348–3.682) |
4.717 (5.084–4.378) |
|||||
| M01AB (5) | Diclofenac sodium SR, etodolac, indomethacin |
B05XA (10) | Ferrous sulfate, potassium chloride |
Cardiovascular | CA | −0.227 ± 0.020 mg/dl | 1.230 (1.351–1.120) |
1.215 (1.334–1.106) |
| M03BX (21) | Cyclobenzaprine, baclofen, tizanidine HCl |
G01AA (7) | Clindamycin systemic, nystatin topical, clindamycin topical, nystatin systemic |
Pulmonary | CO2 | 0.656 ± 0.143 mM | 1.501 (1.745–1.290) |
1.439 (1.671–1.239) |
| N02AB (4) | Fentanyl transdermal | B05XA (10) | Ferrous sulfate, potassium chloride |
Cardiovascular | CA | −0.419 ± 0.012 mg/dl | 1.097 (1.151–1.045) |
1.116 (1.185–1.050) |
| K | −0.001 ± 0.007 mEq/liter | 1.841 (1.964–1.726) |
1.303 (1.409–1.204) |
|||||
| N02AB (4) | Fentanyl transdermal | C05AA (8) | Triamcinolone acet. top, dexamethasone oral, hydrocortisone top. Rx, fluocinonide |
Cardiovascular | K | −0.012 ± 0.008 mEq/liter | 1.949 (2.078–1.827) |
1.590 (1.701–1.486) |
| N02AB (4) | Fentanyl transdermal | G04BD (2) | Oxybutynin chloride ER, oxybutynin chloride |
Cardiovascular | Mg | −0.061 ± 0.031 mg/dl | 1.389 (1.882–1.025) |
2.717 (3.942–1.872) |
| N05BA (44) | Diazepam, lorazepam, alprazolam |
N05AB (2) | Prochlorperazine maleate |
Cardiovascular | CA | −0.202 ± 0.013 mg/dl | 2.024 (2.112–1.940) |
2.583 (2.768–2.411) |
| N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
A07AA (2) | Nystatin systemic, nystatin topical |
Metabolic | CA | −0.162 ± 0.020 mg/dl | 1.427 (1.537–1.325) |
1.187 (1.280–1.101) |
| CO2 | CO2 0.139 ± 0.102 mM | 1.866 (2.046–1.702) |
1.304 (1.430–1.189) |
|||||
| GLOB | 0.016 ± 0.029 g/dl | 2.005 (2.194–1.833) |
1.209 (1.322–1.106) |
|||||
| MCHC | −0.015 ± 0.017 g/dl | 2.729 (3.116–2.390) |
1.223 (1.390–1.076) |
|||||
| QTC | 3.853 ± 2.661 ms | 2.608 (2.976–2.284) |
1.513 (1.720–1.330) |
|||||
| RDW | 0.383 ± 0.048% | 2.924 (3.173–2.695) |
1.313 (1.421–1.213) |
|||||
| N06AB (30) | Citalopram HBR, paroxetine, sertraline, fluoxetine |
S02AA (19) | Ciprofloxacin HCl | Metabolic | GLOB | −0.028 ± 0.026 g/dl | 1.665 (1.810–1.531) |
1.144 (1.239–1.056) |
| RDW | 0.356 ± 0.043% | 2.376 (2.566–2.201) |
1.368 (1.469–1.274) |
|||||
| MCHC | 0.004 ± 0.018 g/dl | 2.076 (2.396–1.799) |
1.208 (1.387–1.052) |
|||||
| RDW | 0.395 ± 0.049% | 2.157 (2.351–1.978) |
1.320 (1.436–1.214) |
|||||
| N06AX (17) | Mirtazapine, bupropion SR, bupropion ER, bupropion XL, venlafaxine, trazodone HCl |
A07AA (2) | Nystatin systemic, nystatin topical |
Cardiovascular | CA | −0.101 ± 0.019 mg/dl | 1.401 (1.509–1.301) |
1.249 (1.345–1.160) |
| N06AX (17) | Mirtazapine, bupropion SR, bupropion ER, bupropion XL, venlafaxine, trazodone HCl |
S01AX (19) | Ciprofloxacin HCl | Cardiovascular | CA | −0.067 ± 0.016 mg/dl | 1.308 (1.399–1.222) |
1.198 (1.277–1.123) |
| N06AX (17) | Mirtazapine, bupropion SR, bupropion ER, bupropion XL, venlafaxine, trazodone HCl |
S01AX (19) | Ciprofloxacin HCl | Cardiovascula | CA | −0.064 ± 0.016 mg/dl | 1.305 (1.397–1.220) |
1.181 (1.260–1.107) |
| R03CC (9) | Albuterol nebulizer sol. |
C10AA (72) | Simvastatin, pravastatin, lovastatin |
Cardiovascular | Mg | 0.063 ± 0.017 mg/dl | 1.754 (2.073–1.484) |
1.850 (2.135–1.603) |
| R06AE (5) | Meclizine HCl | S02AA (19) | Ciprofloxacin HCl | Metabolic | MCH | −0.128 ± 0.071 g/dl | 1.753 (2.146–1.432) |
1.255 (1.525–1.033) |
| S01AD (5) | Acyclovir | B05XA (10) | Ferrous sulfate, potassium chloride |
Cardiovascular | Mg | −0.057 ± 0.011 mg/dl | 7.087 (8.224–6.109) |
7.669 (8.584–6.854) |
| S01AD (5) | Acyclovir | N03AX (23) | Gabapentin, lamotrigine, levetiracetam, topiramate |
Cardiovascular | K | −0.064 ± 0.022 mEq/liter | 1.450 (1.689–1.245) |
2.611 (3.020–2.257) |
| S01AX (19) | Ciprofloxacin HCl | A07AA (2) | Nystatin systemic, nystatin topical |
Metabolic | ALB | −0.364 ± 0.010 g/dl | 1.744 (1.827–1.664) |
1.912 (2.042–1.789) |
| CR | 0.009 ± 0.010 mg/dl | 1.499 (1.567–1.433) |
1.685 (1.791–1.584) |
|||||
| MCH | −0.045 ± 0.013 g/dl | 1.653 (1.736–1.573) |
1.818 (1.947–1.698) |
|||||
| MCHC | −0.002 ± 0.008 g/dl | 2.111 (2.278–1.957) |
2.092 (2.325–1.883) |
|||||
| RDW | 0.394 ± 0.026% | 2.045 (2.144–1.952) |
2.018 (2.155–1.889) |
|||||
| TP | −0.417 ± 0.017 g/dl | 1.960 (2.079–1.849) |
2.094 (2.276–1.926) |
|||||
| S01AX (19) | Ciprofloxacin HCl | D06AX (4) | Mupirocin | Gastrointestinal | ALB | −0.135 ± 0.025 g/dl | 1.377 (1.514–1.253) |
2.399 (2.743–2.098) |
| TBIL | 1.017 ± 0.222 mg/dl | 1.425 (1.576–1.289) |
2.106 (2.420–1.833) |
|||||
| S01BA (8) | Dexamethasone oral, triamcinolone acet. top, hydrocortisone top. Rx |
N01AH (4) | Fentanyl transdermal | Cardiovascular | Mg | 0.031 ± 0.010 mg/dl | 2.796 (3.125–2.501) |
3.403 (3.923–2.951) |
| S01BC (5) | Diclofenac sodium SR, indomethacin |
B05XA (10) | Ferrous sulfate, potassium chloride |
Cardiovascula | CA | −0.222 ± 0.020 mg/dl | 1.226 (1.347–1.115) |
1.195 (1.313–1.088) |
| S01CB (2) | Hydrocortisone top. Rx, dexamethasone oral |
N01AH (4) | Fentanyl transdermal | Cardiovascular | Mg | 0.034 ± 0.010 mg/dl | 2.372 (2.657–2.118) |
3.360 (3.871–2.917) |
| S01EA (11) | Clonidine | A04AA (3) | Ondansetron | Cardiovascular | K | −0.055 ± 0.011 mEq/liter | 2.301 (2.595–2.040) |
2.054 (2.192–1.925) |
| S01XA (4) | Ferrous sulfate | N05CF (30) | Zolpidem tartrate | Cardiovascular | CA | −0.263 ± 0.009 mg/dl | 1.211 (1.258–1.165) |
1.419 (1.478–1.363) |
| S02BA (2) | Hydrocortisone top. Rx, dexamethasone oral |
N01AH (4) | Fentanyl transdermal | Cardiovascular | Mg | 0.034 ± 0.010 mg/dl | 2.356 (2.639–2.103) |
3.362 (3.873–2.919) |
| V03AB (4) | Ferrous sulfate | S01AX (19) | Ciprofloxacin HCl | Gastrointestinal | ALB | −0.365 ± 0.010 g/dl | 1.719 (1.800–1.641) |
1.668 (1.753–1.586) |
| ALKP | 7.739 ± 1.842 U/liter | 1.516 (1.583–1.452) |
1.316 (1.378–1.257) |