Table 1.
Disproportionality signals considering time of co-exposure
| AE | DDI | Event/non-event | ROR (95% CI) | Pharmacological actions | Type of interaction | UpToDate reliability rate |
|---|---|---|---|---|---|---|
| Acute kidney injury | Losartan ± ramipril | 9/32 | 2.91 (1.37–6.15) | ARB ± ACE inhibitor | PD | Excellent |
| Lisinopril ± valsartan | 8/23 | 3.42 (1.52–7.68) | ACE inhibitor ± ARB | PD | Excellent | |
| Bradycardia | Digoxin ± bisoprolol | 76/152 | 3.73 (2.70–5.18) | Cardiac glycoside ± β-blocker | PD | Good |
| Confusional state | Amitriptyline ± duloxetine | 14/71 | 3.87 (2.12–7.07) | TCA ± SNRI | Synergic effect | Good |
| QT prolonged | Paroxetine ± escitalopram | 9/26 | 32.27 (13.98–74.49) | SSRI ± SSRI | Synergic effect | Good |
| Clomipramine ± quetiapine | 20/71 | 4.51 (2.42–8.40) | TCA ± antipsychotic | Synergic effect | Fair | |
| Haloperidol ± fluoxetine | 4/39 | 4.38 (1.52–12.66) | Antipsychotic ± SSRI | Synergic effect | Fair | |
| Clomipramine ± venlafaxine | 12/64 | 2.39 (1.18–4.81) | TCA ± SNRI | Synergic effect | NA | |
| GI haemorrhage | Methylprednisolone ± dexketoprofen | 3/15 | 15.10 (4.33–52.59) | Corticosteroid ± NSAID | Synergic effect | Fair |
| Celecoxib ± dexamethasone | 6/115 | 3.30 (1.38–7.91) | NSAID ± corticosteroid | Synergic effect | Fair | |
| Haemorrhage | Ticagrelor ± escitalopram | 6/0.5 | 54.47 (3.04–976.58) | Platelet inhibitor ± SSRI | PD | Fair |
| Paroxetine ± clopidogrel | 3/9 | 21.97 (5.75–83.92) | SSRI ± platelet inhibitor | PD | Fair | |
| Duloxetine ± clopidogrel | 9/3 | 137.13 (36.40–516.58) | SNRI ± platelet inhibitor | PD | Fair | |
| Acenocoumarol ± paroxetine | 4/1 | 11.05 (1.22–99.74) | Anticoagulant ± SSRI | PD/PK | Fair | |
| Tinzaparin ± clopidogrel | 3/1 | 27.93 (2.87–271.52) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Enoxaparin ± ticagrelor | 34/50 | 5.51 (3.55–8.56) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Ticagrelor ± heparin | 45/69 | 3.11 (2.11–4.58) | Platelet inhibitor ± anticoagulant | Synergic effect | Fair | |
| Enoxaparin ± clopidogrel | 104/200 | 4.49 (3.51–5.75) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Apixaban ± ticagrelor | 13/3 | 12.10 (3.44–42.52) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Apixaban ± prasugrel | 11/5 | 6.14 (2.13–17.68) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Fondaparinux ± ticagrelor | 30/11 | 9.10 (4.46–18.57) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Fondaparinux ± clopidogrel | 23/14 | 5.17 (2.60–10.28) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Urokinase ± heparin | 5/5 | 26.00 (2.48–272.83) | Fibrinolytic agent ± anticoagulant | Synergic effect | Fair | |
| Alteplase ± heparin | 19/23 | 2.09 (1.12–3.88) | Fibrinolytic agent ± anticoagulant | Synergic effect | Fair | |
| Warfarin ± clopidogrel | 106/114 | 1.85 (1.41–2.42) | Anticoagulant ± platelet inhibitor | Synergic effect | Good | |
| Warfarin ± rivaroxaban | 48/64 | 1.47 (1.01–2.15) | Anticoagulant ± platelet inhibitor | Synergic effect | Fair | |
| Ticagrelor ± ibuprofen | 6/5 | 5.43 (1.66–17.87) | Platelet inhibitor ± NSAID | Synergic effect | Fair | |
| Ibuprofen ± clopidogrel | 11/31 | 6.19 (3.10–12.37) | NSAID ± platelet inhibitor | Synergic effect | Fair | |
| Diclofenac ± clopidogrel | 5/27 | 2.79 (1.07–7.30) | NSAID ± platelet inhibitor | Synergic effect | Fair | |
| Diclofenac ± paroxetine | 4/15 | 3.99 (1.32–12.09) | NSAID ± SSRI | Synergic effect | Good | |
| Naproxen ± clopidogrel | 5/17 | 4.06 (1.49–11.07) | NSAID ± platelet inhibitor | Synergic effect | Fair | |
| Celecoxib ± venlafaxine | 4/4 | 18.36 (4.55–74.13) | NSAID ± SNRI | PD | NA | |
| Celecoxib ± fluoxetine | 3/11 | 4.96 (1.37–17.97) | NSAID ± SSRI | PD | NA | |
| Meloxicam ± venlafaxine | 5/8 | 5.34 (1.72–16.61) | NSAID ± SNRI | Synergic effect | Fair | |
| Hyperkalaemia | Ramipril ± irbesartan | 3/8 | 8.69 (2.29–33.00) | ACE inhibitor ± ARB | PD | Excellent |
| Enalapril ± valsartan | 7/44 | 2.65 (1.17–6.01) | ACE inhibitor ± ARB | PD | Excellent | |
| Trimethoprim ± lisinopril | 18/66 | 7.77 (4.56–13.21) | Antibiotic ± ACE inhibitor | Synergic effect | Good | |
| Enalapril ± trimethoprim | 11/49 | 3.86 (1.95–7.63) | ACE inhibitor ± Antibiotic | Synergic effect | Good | |
| Hyponatraemia | Desmopressin ± fluoxetine | 3/1 | 11.71 (1.20–114.51) | synthetic analogue of ADH ± SSRI | Synergic effect | Fair |
| Duloxetine ± escitalopram | 10/25 | 10.45 (4.92–22.22) | SNRI ± SSRI | Synergic effect | NA | |
| Hypotension | Lercanidipine ± propranolol | 16/0.5 | 240.24 (14.23–4056.14) | CCB ± β-blocker | Synergic effect | NA |
| Irbesartan ± perindopril | 10/1 | 75.48 (9.60–593.19) | ARB ± ACE inhibitor | PD | Excellent | |
| Irbesartan ± lisinopril | 3/0.5 | 43.63 (2.18–874.51) | ARB ± ACE inhibitor | PD | Excellent | |
| Ramipril ± losartan | 12/29 | 2.87 (1.46–5.65) | ACE inhibitor ± ARB | PD | Excellent | |
| Sildenafil ± furosemide | 10/58 | 4.87 (2.38–10.00) | PDE5 inhibitor ± diuretic | Synergic effect | Fair | |
| Enalapril ± clomipramine | 4/2 | 24.99 (4.54–137.54) | ACE inhibitor ± TCA | Synergic effect | Fair | |
| Clomipramine ± oxepine | 3/10 | 4.21 (1.11–15.94) | TCA ± antipsychotic | Synergic effect | NA | |
| Amitriptyline ± propranolol | 13/31 | 22.26 (10.93–45.36) | TCA ± β-blocker | Synergic effect | Fair | |
| Tamsulosin ± propranolol | 9/5 | 17.65 (5.87–53.11) | α1 antagonist ± β-blocker | Synergic effect | Fair | |
| Nebivolol ± doxazosin | 15/11 | 7.86 (3.51–17.62) | β-blocker ± α1 antagonist | Synergic effect | Fair | |
| Bisoprolol ± alfuzosin | 13/19 | 5.67 (2.78–11.54) | β-blocker ± α1 antagonist | Synergic effect | Fair | |
| Bisoprolol ± doxazosin | 33/61 | 4.61 (2.99–7.11) | β-blocker ± α1 antagonist | Synergic effect | Fair | |
| Carvedilol ± doxazosin | 8/27 | 2.33 (1.04–5.20) | β-blocker ± α1 antagonist | Synergic effect | Fair | |
| Nifedipine ± doxazosin | 4/40 | 3.11 (1.06–9.13) | Ca2+ antagonist ± α1 antagonist | Synergic effect | Fair | |
| Nebivolol ± tamsulosin | 11/4 | 15.42 (4.82–49.37) | β-blocker ± α1 antagonist | Synergic effect | Fair | |
| Bisoprolol ± terazosin | 8/2 | 32.96 (6.98–155.51) | β-blocker ± α1 antagonist | Synergic effect | Good | |
| Myopathy | Dexamethasone ± atracurium | 4/360 | 3.34 (1.23–9.08) | Corticosteroid ± muscle relaxant | Synergic effect | Excellent |
| Orthostatic hypotension | Amitriptyline ± propranolol | 3/41 | 29.61 (7.16–122.49) | TCA ± β-blocker | PK | NA |
| Ototoxicity | Vancomycin ± gentamicin | 7/537 | 6.12 (2.46–15.23) | Antibiotic ± antibiotic | Synergic effect | Fair |
| Syncope | Valsartan ± enalapril | 8/43 | 4.04 (1.88–8.67) | ARB ± ACE inhibitor | PD | Excellent |
| Ramipril ± olmesartan | 4/9 | 4.49 (1.38–14.64) | ACE inhibitor ± ARB | PD | Excellent |
Event is the n° of AEs with co-exposure; non-event is the n° of other AEs with co-exposure.
ACE angiotensin-converting enzyme; ADH anti-diuretic hormone; AE adverse event; ARB angiotensin II receptor blocker; CCB calcium-channel blocker; CI confidence interval; DDI drug–drug interaction; GI gastrointestinal; NA not available; NSAID non-steroidal anti-inflammatory drug; PD pharmacodynamic interaction; PDE5 phosphodiesterase-5; PK pharmacokinetic interaction; ROR reporting odds ratio; SNRI serotonin and norepinephrine reuptake inhibitor; SSRI selective serotonin reuptake inhibitor; TCA tricyclic antidepressant