Multiple drug prescriptions are very common for the treatment of various ailments and such therapy may be the potential source of drug-drug interactions (DDIs). DDIs can result in alteration of therapeutic response or increase untoward effects of many drugs. In hospitalized patients, the issue of DDIs deserves more attention due to severity of diseases, comorbid conditions, chronic diseases, polypharmacy, complex therapeutic regimens, and frequent modification in therapy. To the best of our knowledge, no data are available regarding the prevalence and nature of potential drug-drug interactions (pDDIs) in hospital settings in Pakistan. Studies are needed to explore pDDIs in hospital settings in Pakistan. This will help physicians and clinical pharmacists to identify and manage pDDIs. The objectives of the present study were to identify prevalence, levels and predictors of pDDIs in pulmonology, psychiatry, cardiology, pediatrics and internal medicine wards of tertiary care hospital settings in Khyber Pakhtunkhwa (KPK), Pakistan. This study involved evaluation of 2015 patients’ profiles from five different wards (at least 400 from each ward) of two major tertiary care hospitals of KPK, Pakistan (a) Ayub Teaching Hospital (b) Khyber Teaching Hospital. Micromedex Drug-Reax software (Thomson Reuters Healthcare Inc., Greenwood Village, Colorado, United States) was used to screen patients’ profiles for pDDIs. Logistic regression was applied to determine the odds ratio for specific risk factors of pDDIs such as patients’ age, number of prescribed medications, patients’ gender and duration of hospital stay. In pulmonology ward, 400 patients’ profiles were evaluated for pDDIs. Total 126 interacting drug-combinations were identified that encountered in 558 numbers of pDDIs. Overall, 45% patients were exposed to at least one pDDI regardless of type of severity, 24% to at least one major pDDIs and 36% patients to at least one moderate pDDIs. Among 558 pDDIs, most were of moderate (53.6%) or major severity (34%); good (74.2%) or fair (16.3%) type of scientific evidence; and delayed onset (70%). Thirteen interacting drug-pairs were considered potentially important interactions and included dexamethasone + rifampin (41 cases), isoniazid + rifampin (38), furosemide + captopril (38), rifampin + pyrazinamide (38), acetaminophen + isoniazid (20), spironolactone + captopril (18), digoxin + furosemide (16), potassium chloride + spironolactone (15), prednisolone + rifampin (15), furosemide + aspirin (13), potassium chloride + captopril (13), levofloxacin + prednisolone (12), and digoxin + spironolactone (10). There was significant association of the occurrence of pDDIs with patients’ age of 60 years or more (odds ratio (OR) = 3.85; 95% confidence interval (CI) = 2.17-6.83; p < 0.001), hospital stay of 7 days or longer (OR = 2.33; 95% CI = 1.23-4.43; p < 0.001), and 7 or more number of prescribed medications (OR = 27.63; 95% CI = 14.6-52.3; p < 0.001). Of 415 patients from psychiatry ward, 64.8% patients had at least one pDDI (overall prevalence), 27.2% patients at least one major pDDIs, and 58.5% patients at least one moderate pDDI. Total, 126 interacting drug-pairs were identified that presented in 825 numbers of pDDIs. Of 825 pDDIs, most were of moderate (75.6%) or major severity (20.8%); good (66.4%) or fair (29%) type of scientific evidence; and delayed onset (71%). Most frequent potentially important interactions included haloperidol + procyclidine (127 cases), haloperidol + olanzapine (49), haloperidol + promethazine (47), haloperidol + fluphenazine (41), diazepam + divalproex sodium (40), haloperidol + trihexyphenidyl (37), lorazepam + divalproex sodium (34), fluphenazine + procyclidine (33), olanzapine + divalproex sodium (32), promethazine + procyclidine (29), promethazine + trihexyphenidyl (25), trifluoperazine + procyclidine (17), haloperidol + chlorpromazine (14), alprazolam + fluoxetine (13), and divalproex sodium + risperidone (13). There was significant association of the occurrence of pDDIs with hospital stay of 7 days or longer (OR = 2.01; 95% CI = 1.23-3.28; p = 0.005), and 7 or more number of prescribed medications (OR = 3.33; 95% CI = 2.03-5.48; p < 0.001). In 400 patients’ profiles from cardiology ward, 100 interacting drug-combinations were identified that encountered in 1120 pDDIs. Overall, 77.5% patients were exposed to at least one pDDI of any severity, 36.75% to at least one major pDDI, and 69.75% to at least one moderate pDDI. Of 1120 identified-pDDIs, most were of moderate (56.3%) or major severity (25.4%); fair (45.3%) or good (42%) type of scientific evidence; and delayed onset (50.4%). Sixteen interacting drug-pairs, eight each of major and moderate severity, were considered potentially important interactions and included ramipril + aspirin (129 cases), nitroglycerin + aspirin (100), furosemide + aspirin (59), digoxin + furosemide (41), heparin + aspirin (39), digoxin + spironolactone (35), spironolactone + aspirin (34), warfarin + spironolactone (34), furosemide + ramipril (29), spironolactone + ramipril (23), lisinopril + aspirin (22), warfarin + aspirin (17), heparin + nitroglycerin (14), warfarin + amiodarone (14), digoxin + amiodarone (13), and clopidogrel + omeprazole (11). There was significant association of the occurrence of pDDIs with patients’ age of 65 years or more (OR = 2.32; 95% CI = 1.26-4.28; p = 0.007), male gender (OR = 1.94; 95% CI = 1.07-3.53; p = 0.03), hospital stay of 4 days or longer (OR = 3.51; 95% CI = 1.60-7.70; p = 0.002), and 7 or more number of prescribed medications (OR = 26.84; 95% CI = 11.11-64.83; p < 0.001). In pediatrics ward, pDDIs of any severity were identified in 25.8% patients, major pDDIs in 10.75% patients, and moderate pDDIs in 15.25% patients. Total 86 interacting drug- combinations were recorded that presented in 260 pDDIs, of which, most were of moderate severity (41.5%); good (76.9%) or fair (16.5%) type of scientific evidence; and delayed onset (46.5%). Eleven interacting drug-pairs (4 major and 7 moderate) were considered potentially important interactions and included rifampin + pyrazinamide (14 cases), phenobarbital + diazepam (14), dexamethasone + rifampin (8), amikacin + furosemide (7), furosemide + captopril (7), dexamethasone + phenobarbital (6), phenobarbital + divalproex sodium (6), isoniazid + rifampin (5) amikacin + ibuprofen (5), digoxin + furosemide (4), and acetaminophen + phenytoin sodium (4). There was significant association of the occurrence of pDDIs with 5 or more number of prescribed medications (OR = 6.82; 95% CI = 4.0-11.59; p < 0.001). In internal medicine wards, 188 interacting drug-combinations were identified that contributed to 675 pDDIs. Of 400 patients, 52.8% patients were presented with at least one pDDI (overall prevalence), 21.25% with at least one major pDDI, and 44.25% with at least one moderate pDDI. Among 675 pDDIs, most were of moderate (63.6%) or major severity (23%); good (61.2%) or fair (25.5%) type of scientific evidence; and delayed onset (50.2%). Twenty interacting drug-pairs (9 major and 11 moderate) were considered potentially clinically important interactions and included furosemide + aspirin (38 cases), rifampin + pyrazinamide (37), isoniazid + rifampin (35), furosemide + ramipril (21), acetaminophen + isoniazid (20), furosemide + captopril (17), furosemide + lisinopril (16), insulin + aspirin (15), dexamethasone + rifampin (15), captopril + aspirin (14), aspirin + ramipril (14), nitroglycerin + aspirin (14), lisinopril + aspirin (14), heparin + aspirin (10), warfarin + aspirin (5), and spironolactone + ramipril (5). There was significant association of the occurrence of pDDIs with patients’ age of 60 years or more (OR = 2.06; 95% CI = 1.27-3.33; p = 0.003), hospital stay of 6 days or longer (OR = 2.58; 95% CI = 1.50-4.45; p = 0.001), and 7 or more number of prescribed medications (OR = 5.88; 95% CI = 3.62-9.55; p < 0.001). In conclusion, the present study has recorded a high prevalence of pDDIs in pulmonology, psychiatry, cardiology and internal medicine wards. Most of the interactions were of moderate severity, however, major pDDIs were also recorded in considerable number. Patients with old age, longer hospital stay and increased number of prescribed drugs were more exposed to pDDIs. Close monitoring of patients is recommended to manage and prevent negative clinical outcomes of these interactions." xml:lang="en_US