Abstract
Polypharmacy increases the risk of drug–drug interactions that may disturb treatment effects. The aim of this study was to investigate the frequency of codispensing of potentially interacting or contraindicated drugs related to PH‐specific treatment in the Swedish pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) population. All prescribed drugs, on an individual level, dispensed 2016–2017 at pharmacies to patients with PAH or CTEPH were obtained from The National Board of Health and Welfare's pharmaceutical registry. Potential drug–drug interactions were investigated using the Drug Interaction tool in the IBM Micromedex® database. There were 4785 different dispensed drugs from 572 patients (mean age 61 ± 16 years, 61% female, mean number of drugs per patient 8.4 ± 4.2) resulting in 1842 different drug combinations involving a PH‐specific treatment. Of these drug combinations, 67 (3.5%) had a potential drug–drug interaction considered clinically relevant and it affected 232 patients (41%). The PH‐specific drugs with the highest number of potential drug–drug interactions was bosentan (n = 23, affected patients = 171) while the most commonly codispensed, potentially interacting drug combination was sildenafil/furosemide (119 patients affected). Other common codispensed and potentially interacting drugs were anticoagulants (n = 11, affected patients = 100) and antibiotic treatment (n = 12, affected patients = 26). In conclusion, codispensing of PH‐specific therapy and potentially interacting drugs was common, but codispensing of potentially contraindicated drugs was rare.
Keywords: clinical relevance, lexicomp, micromedex, patient safety, polypharmacy
INTRODUCTION
Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare and serious cardiopulmonary diseases that frequently require lifelong pharmacological treatment. 1 Disease‐specific treatment includes endothelin receptor antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE‐5i), soluble guanylate cyclase stimulators (SGCs) as well as selective prostacyclin receptor agonists and prostacyclin analogs. Combination therapy is recommended to improve quality of life and outcome but monotherapy is not uncommon. 2 , 3 , 4 , 5
An improved survival and an older population being diagnosed have increased the presence of comorbidities and thus, polypharmacy is common in this population. 6 , 7 , 8 , 9 , 10 Further, side effects from pulmonary hypertension (PH)‐specific drugs such as headache, nausea, diarrhea, or constipation often require additional medical treatment.
With polypharmacy, the potential of a drug–drug interaction causing adverse effects on treatment outcomes increases. 9 Drug–drug interactions can be caused by pharmacokinetic (PK) changes such as altered drug metabolism, or by pharmacodynamic (PD) changes such as additive effects. Combination of drugs that use the same metabolizing enzymes, for example, cytochrome P450, may cause reduced or enhanced systemic drug concentrations. 11 , 12 To avoid unwanted treatment effects, identification and understanding the risk of potential drug–drug interactions are important. The primary aim of this study was to investigate the frequency of codispensing of potentially interacting combinations of drugs or contraindicated drugs related to PH‐specific drugs in the Swedish PAH and CTEPH population. A secondary aim was to increase the awareness outside the PH specialist clinics of potential drug–drug interactions related to PH‐specific drugs.
METHODS
Study population
In Sweden, individual‐level data for all residents can be linked across national databases. The current study was a retrospective observational study including all drug prescriptions registered by the Swedish prescribed drug registry and dispensed by patients with PAH or CTEPH, aged ≥18 years, alive January 2016 through December 2017 and registered in the Swedish PAH & CTEPH registry (SPAHR 13 ).
The National Board of Health and Welfare's (Socialstyrelsen) pharmaceutical registry (Swedish Prescribed Drug Registry 14 ) covers all medicines that have been dispensed at pharmacies in Sweden on an individual level.
SPAHR 13 constitutes an open continuous registry of patients diagnosed with PAH or CTEPH. All Swedish PAH/CTEPH‐expert centers participate in SPAHR and the national coverage of patients diagnosed with PAH or CTEPH in the registry is >90%. SPAHR is approved by the National Board of Health and Welfare and by the Swedish Data Protection Authority. All patients were informed about their participation in SPAHR and had the right to decline.
The study was approved by the Regional Ethics Committee in Lund, Sweden (LU 2016/766), and performed in accordance with the Declaration of Helsinki.
Drug interactions
The Swedish Prescribed Drug Registry use the anatomical therapeutic chemical (ATC) classification system. The drug interaction tool in the IBM Micromedex® database 15 was used to search for known interacting combinations of drugs or contraindicated drug combinations. If drugs could not be found in the Micromedex® database, the Lexicomp® Interactions database was used. 16 Seven drugs were not found in either database. Using the Swedish interaction database Janusmed Interaktioner, 17 these seven drugs were determined not to have any recorded drug–drug interaction in combinations found in the present study. The classifications of drug–drug interactions from Micromedex® and Lexicomp® Interactions can be found in Table 1. Micromedex® classifications moderate, major, and contraindicated correspond to Lexicomp® classifications C, D, and X, respectively. Interactions were considered clinically relevant if moderate to severe in Micromedex® (C in Lexicomp®). Drugs that did not have a systemic uptake were excluded from the study. The reliability and quality of documentation that formed basis on the potential drug–drug interactions that was found ranged between fair, good, and excellent. 15 , 16
Table 1.
Classification of drug–drug interactions in Micromedex® and Lexicomp® interaction tools
| Micromedex® drug interactions | ||
| Unknown | Unknown (none found) | |
| Minor | Limited clinical effects, where interactions may include an increase in the frequency or severity of the side effects but generally would not require a major alteration in therapy | |
| Moderate | Interaction may result in exacerbation of the patient's condition and/or require an alteration in therapy | |
| Major | Interaction could prove life‐threatening and/or require medical intervention to minimize or prevent serious adverse effects | |
| Contraindicated | Drugs contraindicated for concurrent use | |
| Lexicomp® interactions | ||
| A | No known interaction | No demonstrated pharmacodynamic or pharmacokinetic interactions |
| B | No action needed | Potential interaction, with little to no evidence of clinical concern from concomitant use |
| C | Monitor therapy | Potential interaction in a clinically significant manner. Benefits of concomitant use usually outweigh risks. Appropriate monitoring plan should be implemented to identify potential negative effects. Dosage adjustments may be needed in minority of patients |
| D | Consider therapy modification | Potential interaction in a clinically significant manner. Patient‐specific assessment must be conducted to determine if benefits of concomitant therapy outweigh the risks. Actions (e.g., aggressive monitoring, empiric dosage changes, or choosing alternative agents) must be taken to realize the benefits and/or minimize the toxicity resulting from concomitant use |
| X | Avoid combination | Potential interaction in a clinically significant manner. Risks associated with concomitant use usually outweigh benefits. Generally considered contraindicated |
Note: Micromedex® classifications moderate, major and contraindicated correspond to Lexicomp® classifications C, D, and X, respectively.
PH‐specific treatment
All PH‐specific treatments approved in Sweden at the time of the study were included in the analyses 18 and are listed here by ATC code and generic name in parenthesis; B01AC09 (epoprostenol), B01AC11 (iloprost), B01AC21 (treprostinil), B01AC27 (selexipag), C02KX01 (bosentan), C02KX02 (ambrisentan), C02KX04 (macitentan), C02KX05 (riociguat), G04BE03 (sildenafil), and G04BE08 (tadalafil).
Statistical analyses and data management
Lists of drug combinations were exported from the SAS statistical software to Microsoft Excel® (Microsoft 365) and potential drug–drug interactions were analyzed with using the drug interaction tools described earlier. Descriptive statistics were used to characterize the data. The SAS statistical software (The SAS system for Windows 9.4. SAS Institute Inc.) was used for all analyses.
RESULTS
Study population
There were 4785 different drugs with filled prescriptions from 572 patients included in the analyses. Of those, 433 patients were treated with a PH‐specific treatment. The average number of drugs per patient was 8.4 ± 4.2, including PH‐specific treatment (Table 2). Mean age of the study cohort was 61 ± 16 years and 61% were female (Table 2). A prescription of ERA was filled by 61% of the patients, PDE‐5i by 60%, SGCs by 6%, and PRO by 12% (Table 3). The most common combinations of PH‐specific treatments were macitentan/sildenafil (17%) and macitentan/tadalafil (14%). There were no potential drug–drug interactions related to these drug combinations.
Table 2.
Study population characteristics (n = 572), drug combinations including a PH‐specific drug and their drug–drug interaction severity
| Age (years) | 61 ± 16 |
| Sex (% women) | 61 |
| Time since diagnosis (years) | 5.3 ± 4.7 |
| Drugs per patient (polypharmacy, n) | 8.4 ± 4.2 |
| Drug combinations including PH‐specific drugs (n) | 1842 |
| Potential drug–drug interactions (n) | 65 |
| Moderate (n) | 23 |
| Major (n) | 41 |
| Contraindicated (n) | 1 |
| Patients that codispensing potentially interacting drugs or contraindicated drugs (n) | 232 |
| Moderate (n) | 183 |
| Major (n) | 97 |
| Contraindicated (n) | 2 |
| Patients with no potential drug–drug interaction (n) | 201 |
| Patients with 1 potential drug–drug interaction (n) | 132 |
| Patients with 2 potential drug–drug interaction (n) | 51 |
| Patients with 3 potential drug–drug interaction (n) | 32 |
| Patients with ≥4 potential drug–drug interaction (n) | 17 |
Note: Data are shown as mean ± SD, as number, or as proportion (%). PH indicates pulmonary hypertension.
Table 3.
Potential drug–drug interactions in shown by PH‐specific drugs
| PH‐drug (n = patients at risk, i.e., treated with the PH‐drug) | PH drug metabolism | Codispensed drug | ATC codispensed drug | Patients on combination treatment (n) | Severity | Probable mechanism (PK/PD) | Risk |
|---|---|---|---|---|---|---|---|
| Ambrisentan (n = 95) (C02KX02) | Hepatic metabolism by uridine 5′‐diphosphate glucuronosyltransferases (UGTs) UGT1A9S, ‐2B7S, ‐1A3S), and by CYP450 enzymes CYP3A4, ‐3A5, and ‐2C19 | Ciclosporin | L04AD01 | 1 | Moderate | Inhibition of ambrisentan metabolism by cyclosporine, a strong CYP3A4 inhibitor | ↑ Ambrisentan exposure |
| Bosentan (n = 87) (C02KX01) | Hepatic metabolism by CYP2C9, ‐3A4 and to lesser extent ‐2C19 | Oxycodone | N02AA05 | 13 | Major | Bosentan induces CYP3A4 which reduces oxycodone exposure | ↓ Oxycodone exposure |
| Tramadol | N02AX02 | 7 | Major | Bosentan induces CYP3A4 which reduces tramadol exposure | ↓ Tramadol exposure | ||
| Paracetamol + codeine | N02AJ06 | 5 | Major | Bosentan induces CYP3A4 which reduces codeine efficacy and may increase withdrawal | ↓ Opioid efficacy, risk opioid withdrawal | ||
| Medroxyprogest acetate | G03DA02 | 3 | Major | Bosentan induces CYP3A4 which reduces medroxyprogest. acetate exposure | ↓ Medroxyprogesterone concentrations | ||
| Estradiol | G03CA03 | 3 | Major | Bosentan induces CYP3A4 which reduces estradiol plasma levels | ↓ Hormonal contraceptive plasma levels | ||
| Buprenorphine | N02AE01 | 2 | Major | Bosentan induces CYP3A4 which reduces buprenorphine exposure | ↓ Buprenorphine plasma levels | ||
| Medroxyprogest acetate | G03AC06 | 1 | Major | Bosentan induces CYP3A4 which reduces medroxyprogest. acetate exposure | ↓Medroxyprogesterone concentrations | ||
| Desogestrel | G03AC09 | 1 | Major | Bosentan induces CYP3A4 which reduces desogestrel plasma levels | ↓ Hormonal contraceptive plasma levels | ||
| Estrogen + norethindrone | G03FB05 | 1 | Major | Bosentan induces CYP3A4 which reduces norethindrone plasma levels | ↓ Hormonal contraceptive plasma levels | ||
| Codeine | N05DA04 | 1 | Major | Bosentan induces CYP3A4 which reduces codeine efficacy and may increase withdrawal | ↓ Opioid efficacy, opioid withdrawal | ||
| Aspirin + caffeine + codeine | N02AJ09 | 1 | Major | Bosentan induces CYP3A4 which reduces codeine efficacy and may increase withdrawal | ↓ Opioid efficacy, opioid withdrawal | ||
| Warfarin | B01AA03 | 55 | Moderate | Bosentan induces CYP3A4 (and possibly 2C9) which reduces warfarin exposure | ↓ Warfarin efficacy | ||
| Sildenafil | G04BE03 | 35 | Moderate | Sildenafil induces increased bosentan exposure due to CYP3A4 metabolism | ↑ Bosentan, ↓ sildenafil plasma levels | ||
| Tadalafil | G04BE08 | 19 | Moderate | Bosentan induces CYP3A4 which reduces tadalafil exposure | ↓ Tadalafil plasma levels | ||
| Atorvastatin | C10AA05 | 7 | Moderate | Bosentan induces CYP3A4 which reduces atorvastatin exposure | ↓ Atorvastatin plasma levels and efficacy | ||
| Simvastatin | C10AA01 | 7 | Moderate | Bosentan induces CYP3A4 which reduces simvastatin exposure | ↓ Simvastatin plasma levels and efficacy | ||
| Diclofenac | M02AA15 | 3 | Moderate | Bosentan induces CYP2C9 which reduces diclofenac exposure | ↓ Diclofenac exposure | ||
| Verapamil | C08DA01 | 2 | Moderate | Inhibition of CYP3A4‐mediated bosentan metabolism by verapamil | ↑ Bosentan plasma levels | ||
| Ebastin | R06AX22 | 1 | Moderate | Bosentan induces CYP3A4 which reduces ebastin exposure (increased ebastin metabolism) | ↓ Ebastin plasma levels | ||
| Fluconazole | J02AC01 | 1 | Moderate | Fluconazole is a CYP2C9 inhibitor which may reduce bosentan metabolism | ↑ Bosentan plasma levels | ||
| Diclofenac | M01AB05 | 1 | Moderate | Bosentan induces CYP2C9‐mediated diclofenac metabolism | ↓ Diclofenac plasma levels | ||
| Amiodarone | C01BD01 | 1 | Moderate | Bosentan induces CYP3A4 which reduces amiodarone exposure; reduced CYP3A4‐ and CYP2C9‐mediated bosentan metabolism | ↓ Amiodarone and/or ↓ bosentan exposure | ||
| Clarithromycin | J01FA09 | 1 | Moderate | Clarithromycin is a CYP2C9 inhibitor which may reduce bosentan metabolism | ↑ Bosentan plasma levels | ||
| Macitentan (n = 169) (C02KX04) | Hepatic metabolism by CYP3A4, ‐2C8, ‐2C9, ‐2C19 | Fluconazole | J02AC01 | 2 | Major | Fluconazole is a dual CYP3A4‐ and CYP2C9‐inhibitor and may inhibit macitentan metabolism | ↑ Macitentan plasma levels, toxicity |
| Esomeprazole + amoxicillin + clarithromycin | A02BD06 | 2 | Major | Clarithromycin is a strong CYP3A4 inhibitor and may inhibit macitentan metabolism | ↑ Macitentan plasma levels | ||
| Clarithromycin | J01FA09 | 1 | Major | Clarithromycin is a strong CYP3A4 inhibitor and may inhibit macitentan metabolism | ↑ Macitentan plasma levels | ||
| Carbamazepine | N03AF01 | 1 | Major | Carbamazepine is a strong CYP3A4 inducer and may increase macitentan metabolism | ↑ Macitentan plasma levels | ||
| Iloprost (n = 14) (B01AC11) | β‐oxidation | Warfarin | B01AA03 | 5 | Major | Additive effects on hemostasis combining antiplatelet agents (iloprost) and warfarin | Bleeding |
| Dalteparin | B01AB04 | 4 | Major | Additive effects on hemostasis combining antiplatelet agents (iloprost) and low molecular weight heparin (dalteparin) | Bleeding | ||
| Apixaban | B01AF02 | 2 | Major | Additive effects on hemostasis combining antiplatelet agents (iloprost) and apixaban | Bleeding | ||
| Sertraline | N06AB06 | 1 | Major | Additive effects combining antiplatelet agents (iloprost) with sertraline | Bleeding | ||
| Duloxetine | N06AX21 | 1 | Major | Additive effects on hemostasis combining antiplatelet agents (iloprost) and duloxetine | Bleeding | ||
| Tinzaparin | B01AB10 | 1 | Major | Additive effects combining antiplatelet agents (iloprost) and low molecular weight heparin (tinzaparin) | Bleeding | ||
| Diclofenac | M02AA15 | 1 | Major | Additive effects on hemostasis combining antiplatelet agents (iloprost) with NSAID (diclofenac) | Bleeding | ||
| Dipyridamole | B01AC07 | 1 | Moderate | Additive antiplatelet effects | Bleeding | ||
| Riociguat (n = 32) (C02KX05) | Hepatic metabolism by CYP1A1, ‐3A4, ‐3A5, ‐2J2 and ‐2C8 | Calcium carbonate | A12AX | 4 | Moderate | Decreased riociguat absorption due to calcium carbonate | ↓ Riociguat exposure |
| Sodium picosulfate | A06AB08 | 1 | Moderate | Decreased riociguat absorption due to sodium picosulfate (prepopik) | ↓ Riociguat exposure | ||
| Magnesium hydroxide | G04BX01 | 1 | Moderate | Decreased riociguat absorption due to magnesium hydroxide | ↓ Riociguat exposure | ||
| Selexipag (n = 29) (B01AC27) | Hepatic metabolite activation by carboxylesterase 1 | Apixaban | B01AF02 | 4 | Major | Additive effects combining antiplatelet agents (selexipag) with apixaban | Bleeding |
| Hepatic metabolism by CYP3A4 and ‐2C8 | |||||||
| Glucuronidation of metabolite by UGT1A3 and ‐2B7 | |||||||
| Sertraline | N06AB06 | 2 | Major | Combining antiplatelet agents (selexipag) with SSRIs (sertraline) may alter platelet function and induce bleeding | Bleeding | ||
| Citalopram | N06AB04 | 1 | Major | Combining antiplatelet agents (selexipag) with SSRIs (citalopram) may alter platelet function and induce bleeding | Bleeding | ||
| Paroxetine | N06AB05 | 1 | Major | Additive effects combining antiplatelet agents (iloprost) with paroxetine | Bleeding | ||
| Sildenafil (n = 199) (G04BE03) | Hepatic metabolism primarily by CYP3A4, to lesser extent ‐2C9 | Fluconazole | J02AC01 | 3 | Major | CYP3A4‐ and CYP2C9‐mediated sildenafil metabolism inhibition by fluconazole | ↑ Sildenafil exposure, toxicity risk |
| Esomeprazole + amoxicillin + clarithromycin | A02BD06 | 2 | Major | CYP3A4‐mediated sildenafil metabolism inhibition by clarithromycin | ↑ Sildenafil exposure | ||
| Clarithromycin | J01FA09 | 2 | Major | CYP3A4‐mediated sildenafil metabolism inhibition by clarithromycin | ↑ Sildenafil exposure | ||
| Itraconazole | J02AC02 | 1 | Major | Itraconazole is a CYP3A4 inhibitor which may increase sildenafil exposure | ↑ Sildenafil exposure | ||
| Furosemide | C03CA01 | 119 | Moderate | Additive ototoxicity, potentiation of antihypertensive activities of furosemide | Ototoxicity (hearing loss) | ||
| Bosentan | G04BE03 | 35 | Moderate | CYP3A4 metabolism alterations (increased bosentan and decreased sildenafil exposure) | ↓ Sildenafil, ↑ bosentan, plasma levels | ||
| Ciprofloxacin | J01MA02 | 9 | Moderate | CYP3A‐mediated sildenafil metabolism inhibition by ciprofloxacin | ↑ Sildenafil exposure and plasma levels | ||
| Alfuzosin | G04CA01 | 4 | Moderate | Sildenafil inhibits PDE5‐mediated degradation of cyclic guanosine monophosphate (cGMP) which could cause peripheral vasodilation that may be additive with alfuzosin effects | Potentiation hypotensive effects | ||
| Erythromycin | J01FA01 | 3 | Moderate | Erythromycin is a CYP3A4 inhibitor and may inhibit sildenafil metabolism | Sildenafil adverse effects ↑ ; hypotension, visual changes, priapism | ||
| Ciprofloxacin | S02AA15 | 1 | Moderate | Ciprofloxacin is a CYP3A4 inhibitor and may inhibit sildenafil metabolism | ↑ Sildenafil exposure and plasma levels | ||
| Tadalafil (n = 146) (G04BE08) | Hepatic metabolism by CYP3A4 | Isosorbide dinitrate | C01DA14 | 2 | Contraindicated | increased levels of cGMP from tadalafil and nitrates | Potentiation hypotensive effects |
| Simvastatin | C10AA01 | 21 | Major | Unknown; may be due to CYP3A4 | Myopathy | ||
| Alfuzosin | G04CA01 | 1 | Major | Additive hypotensive effects (vasodilation and lowered blood pressure) | Potentiation hypotensive effects | ||
| Esomeprazole + amoxicillin + clarithromycin | A02BD06 | 1 | Major | CYP3A4‐mediated tadalafil metabolism inhibition by clarithromycin | ↑ Tadalafil bioavailability | ||
| Clarithromycin | J01FA09 | 1 | Major | CYP3A4‐mediated tadalafil metabolism inhibition by clarithromycin | ↑ Tadalafil bioavailability | ||
| Itraconazole | J02AC02 | 1 | Major | CYP3A4‐mediated tadalafil metabolism inhibition by itraconazole | ↑ Tadalafil bioavailability | ||
| Bosentan | G04BE08 | 19 | Moderate | CYP3A4‐mediated metabolism of tadalafil by bosentan | ↓ Tadalafil plasma levels | ||
| Treprostinil (n = 27) (B01AC21) | Hepatic metabolism, primarily by CYP2C8 | Warfarin | B01AA03 | 20 | Major | Additive effects on hemostasis combining antiplatelet agents (treprostinil) with warfarin | Bleeding |
| Dalteparin | B01AB04 | 6 | Major | Additive effects combining antiplatelet agents (treprostinil) and low molecular weight heparin (dalteparin) | Bleeding | ||
| Sertraline | N06AB06 | 2 | Major | Combining antiplatelet agents (treprostinil) with SSRIs (sertraline) may alter platelet function and induce bleeding | Bleeding | ||
| Citalopram | N06AB04 | 1 | Major | Combining antiplatelet agents (treprostinil) with SSRIs (citalopram) may alter platelet function and induce bleeding | Bleeding | ||
| Aspirin | B01AC06 | 1 | Major | Additive effects on hemostasis combining antiplatelet agents (treprostinil) with aspirin | Bleeding | ||
| Apixaban | B01AF02 | 1 | Major | Additive effects on hemostasis combining antiplatelet agents (treprostinil) with apixaban | Bleeding | ||
| Trimethoprim | J01EA01 | 1 | Moderate | Trimethoprim is a CYP2C8 inhibitor and may inhibit treprostinil metabolism | ↑ Trimethoprim exposure |
Note: No potential interactions for epoprostenol were found in this population. Abbreviations: ATC, anatomical therapeutic chemical classification system; PH, pulmonary hypertension; ↑, increased; ↓, decreased.
The study population was evenly distributed between patients <65 years (50%) and ≥65 years (50%). ERA and PRO were prescribed more often to patients <65 years (ERA 65% vs. 58% and PRO 16% vs. 9%) while PDE‐5i and SGCs were more often prescribed to patients ≥65 years (PDE‐5i 57% vs. 64% and SGCs 4% vs. 8%).
Drug–drug interactions
There were 1842 different drug combinations involving a PH‐specific treatment. Of those drug combinations, 67 (3.5%) had a potential drug–drug interaction affecting 232 patients (41%), whereof 25 combinations were classified as moderate (183 patients), 41 combinations as major (97 patients), and one combination as contraindicated (2 patients) (Table 2). The codispensed contraindicated drug combination was tadalafil/isosorbide dinitrate that may lead to hypotension. Details of all codispensed, potentially interacting drugs or contraindicated drugs found in the present study are displayed in Table 3. No potential interactions were found for epoprostenol.
The PH‐specific drugs with the highest number of potential drug–drug interactions were bosentan (n = 23 interactions, affecting 171 patients) and sildenafil (n = 10 interactions, affecting 144 patients). Combination treatment between bosentan and sildenafil or bosentan and tadalafil that can lead to increased plasma levels of the PDE5‐5i was seen in 35 and 19 patients, respectively (Table 3).
The most commonly codispensed, potentially interacting drug combination was sildenafil/furosemide (119 patients), which may lead to hearing loss (Table 3). Other common codispensed and potentially interacting drugs were anticoagulants (n = 11 interactions, affecting 100 patients) and antidepressant treatments (n = 7 interactions, affecting nine patients) that might increase the risk of bleeding, and to antibiotic treatment (n = 12 interactions, affecting 26 patients) that might increase the bioavailability of PH‐specific drugs (Table 4).
Table 4.
Potential drug–drug interactions and their related risks observed between PH‐specific drugs and treatments with anticoagulants, antibiotics, or antidepressants
| Drug class | Codispensed drug | ATC codispensed drug | PH‐drug | PH‐drug ATC | Patients on combination treatment (n) | Severity | Risk |
|---|---|---|---|---|---|---|---|
| Anticoagulants (B01) | Warfarin | (B01AA03) | Bosentan | (C02KX01) | 55 | Moderate | ↓ Warfarin efficacy |
| Warfarin | (B01AA03) | Treprostinil | (B01AC21) | 20 | Major | Bleeding | |
| Dalteparin | (B01AB04) | Treprostinil | (B01AC21) | 6 | Major | Bleeding | |
| Warfarin | (B01AA03) | Iloprost | (B01AC11) | 5 | Major | Bleeding | |
| Dalteparin | (B01AB04) | Iloprost | (B01AC11) | 4 | Major | Bleeding | |
| Apixaban | (B01AF02) | Selexipag | (B01AC27) | 4 | Major | Bleeding | |
| Apixaban | (B01AF02) | Iloprost | (B01AC11) | 2 | Major | Bleeding | |
| Tinzaparin | (B01AB10) | Iloprost | (B01AC11) | 1 | Major | Bleeding | |
| Aspirin | (B01AC06) | Treprostinil | (B01AC21) | 1 | Major | Bleeding | |
| Apixaban | (B01AF02) | Treprostinil | (B01AC21) | 1 | Major | Bleeding | |
| Dipyridamole | (B01AC07) | Iloprost | (B01AC11) | 1 | Moderate | Bleeding | |
| Antibiotics (J01, J02, J04) | Ciprofloxacin | (J01MA02) | Sildenafil | (G04BE03) | 9 | Moderate | ↑ Sildenafil plasma concentration |
| Erythromycin | (J01FA01) | Sildenafil | (G04BE03) | 3 | Moderate | Ssildenafil adverse effects; hypotension, visual changes, priapism | |
| Fluconazole | (J02AC01) | Sildenafil | (G04BE03) | 3 | Major | ↑ Sildenafil exposure, toxicity risk | |
| Fluconazole | (J02AC01) | Macitentan | (C02KX04) | 2 | Major | ↑ Macitentan exposure, toxicity risk | |
| Clarithromycin | (J01FA09) | Sildenafil | (G04BE03) | 2 | Major | ↑ Sildenafil exposure | |
| Clarithromycin | (J01FA09) | Macitentan | (C02KX04) | 1 | Major | ↑ Macitentan exposure | |
| Itraconazole | (J02AC02) | Sildenafil | (G04BE03) | 1 | Major | ↑ Sildenafil exposure | |
| Fluconazole | (J02AC01) | Bosentan | (C02KX01) | 1 | Moderate | ↑ Bosentan plasma concentrations | |
| Clarithromycin | (J01FA09) | Tadalafil | (B01AC21) | 1 | Major | ↑ Tadalafil bioavailability | |
| Itraconazole | (J02AC02) | Tadalafil | (B01AC21) | 1 | Major | ↑ Tadalafil bioavailability | |
| Trimethoprim | (J01EA01) | Treprostinil | (B01AC21) | 1 | Moderate | ↑ Treprostinil exposure | |
| Clarithromycin | (J01FA09) | Bosentan | (C02KX01) | 1 | Moderate | ↑ Bosentan plasma concentrations | |
| Antidepressants (N06A) | Sertraline | (N06AB06) | Treprostinil | (B01AC21) | 2 | Major | Bleeding |
| Sertraline | (N06AB06) | Selexipag | (B01AC27) | 2 | Major | Bleeding | |
| Citalopram | (N06AB04) | Treprostinil | (B01AC21) | 1 | Major | Bleeding | |
| Sertraline | (N06AB06) | Iloprost | (B01AC11) | 1 | Major | Bleeding | |
| Citalopram | (N06AB04) | Selexipag | (B01AC27) | 1 | Major | Bleeding | |
| Paroxetine | (N06AB05) | Selexipag | (B01AC27) | 1 | Major | Bleeding | |
| Duloxetine | (N06AX21) | Iloprost | (B01AC11) | 1 | Major | Bleeding |
Abbreviations: ATC, anatomical therapeutic chemical classification system; PH, pulmonary hypertension; ↑, increased; ↓, decreased.
Patients <65 years had more different drug combinations involving a PH‐specific treatment than patients ≥65 years (1318 vs. 1281). Potential drug–drug interactions affected 125 patients (44%) <65 years and 157 patients (55%) ≥65 years. This difference between the age groups related to a higher proportion of drug combinations classified as moderate among patients ≥65 years.
DISCUSSION
Forty‐one percent of the patients treated with a PH‐specific treatment were simultaneously codispensed potentially interacting drugs or contraindicated drugs. The most common potential interaction was between sildenafil and furosemide, whereas bosentan had the highest total number of related potential interactions and affected the largest number of patients. Anticoagulants, antibiotics, and antidepressants were commonly dispensed in combination with a PH‐specific treatment and presented with major potential drug–drug interactions.
Potential drug–drug interactions between PH‐specific treatment and other concomitant drug treatments are common. It has been reported to affect 67% in a PAH and CTEPH population, whereof 16% of potential drug–drug interactions were considered contraindicated. 19 The prevalence of potentially interacting or contraindicated drugs among codispensed drugs in the present study was low, only one contraindicated potential drug–drug interaction was dispensed, and it affected only two patients. The declining use of bosentan in Sweden during the studied time period is likely a contributing factor to this. Another contributing factor might be the direct communication link that exists between the Swedish medical records systems and the Janus Interactions database. 17 This provides an easy access, one‐click‐tool that allow the prescriber to consider the presence of drug–drug interaction already at the time of writing the prescription. In addition, using the tool will likely increase the familiarity with common drug–drug interactions that can then be avoided in upcoming prescriptions.
A third of the study population in the present study was treated with sildenafil and two‐thirds with diuretics, rendering the single most common potential drug–drug interaction to be between sildenafil and furosemide. The hypotensive effect of this drug combination is well known and careful monitoring of patients will likely be sufficient. 9 , 12 A less known effect is ototoxicity that can cause hearing loss. 20 The mechanism behind this may be further enhanced as an additive effect, as hearing loss can be induced temporarily by diuretics 21 and as a sensorineural effect induced by sildenafil. 22 The synergistic ototoxic effect might also be further enhanced if combined with other drugs inhibiting cytochrome P450 enzymes. 12 Underreporting of this drug–drug interaction is plausible since hearing loss is commonly attributed to ageing 23 both by the patients themselves and by the health care staff.
Anticoagulant treatment with the vitamin K antagonist warfarin is recommended for patients with CTEPH, 1 and though no longer recommended for patients with PAH, 1 it is still commonly used in this population. 10 In the present study, a vast majority of patients with CTEPH and almost half of the patients with PAH were treated with warfarin. The combination with bosentan may induce hepatic metabolism (cytochrome P2C9) and reduce warfarin plasma concentration. 12 , 14 Combination of warfarin with prostacyclin analogs may cause additive effects of antiplatelets and result in bleeding, however, reports in the literature are conflicting. 24 , 25 Careful monitoring of the prothrombin time in patients with warfarin should thus be undertaken when initiating or discontinuing PH‐treatments.
Antibiotic treatment was common and more than half of the study population filled a prescription at least once during the study period. Some antibiotic and antifungal treatments may increase plasma concentrations of sildenafil, tadalafil, bosentan and macitentan due to decreased systemic clearance by cytochrome P3A4. 12 Interactions between antibiotic drugs and PH‐specific treatment are well‐known but its effect limited as antibiotics are generally administered occasionally and for short periods at a time. This allows for dose adjustment or, if warranted, even discontinuation of the PH‐specific treatment during antibiotic treatment when needed. For long‐term treatment with antibiotics, adjustments of PH‐specific drugs might be warranted.
While it is recommended that patients with PAH and CTEPH are cared for by PH‐specialist centers, 1 other health care facilities will often meet the need for care of comorbidities and common colds and flues. Awareness of potential drug–drug interactions between PH‐specific treatment and commonly prescribed treatments like diuretics, anticoagulants, and antibiotics are warranted, but awareness of less common drug–drug interactions also needs attention. In addition, nonprescriptions drugs and supplements such as vitamins or herbal products should also be closely monitored as they might contribute to unwanted drug–drug interactions. Close collaboration between the PH‐specialist centres and other care facilities as well as easy access to available and reliable drug–drug interaction databases are important to increase patient safety.
Strengths and limitations
Drug interaction databases have different capacities to detect and classify severities of drug–drug interaction that might affect the results of a study investigating interactions between drugs. 26 The decision to use Micromedex® as the primary database might have affected the results.
The study population consisted of all patients with PAH or CTEPH registered in SPAHR 13 and alive during the study period of 2016–2017. Due to the high national coverage of SPAHR (>90%), the study population ably represents patients with PAH and CTEPH in Sweden. The study included all prescriptions filled by patients with PAH or CTEPH in Sweden, available from the National Board of Health and Welfare's pharmaceutical registry (Swedish Prescribed Drug Registry). Limitations are that dose adjustments or drug discontinuation of prescribed drugs are not available and drug adherence was not considered. The registry‐based design of the study did not allow for investigation if actual drug–drug interaction occurred.
CONCLUSION
Codispensing of PH‐specific therapy and potentially interacting drugs was common in the Swedish PAH and CTEPH population, but codispensing of potentially contraindicated drugs was rare. The most prevalent codispensed and potentially interacting drug combination were between sildenafil and furosemide while bosentan was associated with a higher proportion of potential drug–drug interactions and affected the highest number of patients. Potential drug–drug interactions of major severity were observed between PH‐specific treatment and anticoagulants, antibiotics and antidepressants, and should warrant attention.
AUTHOR CONTRIBUTIONS
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Puck N. Norell, Bodil Ivarsson, Maria Selin, and Barbro Kjellström. The first draft of the manuscript was written by Puck N. Norell and Barbro Kjellström and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ETHICS STATEMENT
The study was approved by the Regional Ethics Committee in Lund, Sweden (LU 2016/766), and performed in accordance with the Declaration of Helsinki. The study used retrospective, anonymized data from Swedish National Registries and in accordance to Swedish law, no informed consent from patients was needed.
ACKNOWLEDGMENTS
We acknowledge the work of the SPAHR registrars at the PAH/CTEPH‐specialist clinics, the members of the SPAHR steering committee and Uppsala Clinical Research Centre for administrating SPAHR; pharmacist and PhD Anna Sandqvist at Umeå University for support in designing the study, interpretation of the results and drafting the manuscript; and associate professor Per Näsman at the Royal Institute of Technology in Stockholm (KTH) for doing the statistic calculations.
Norell PN, Ivarsson B, Selin M, Kjellström B. Prevalence of potential drug–drug interactions with disease‐specific treatments in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension: a registry study. Pulm Circ. 2022;12:e12114. 10.1002/pul2.12114
REFERENCES
- 1. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119. [DOI] [PubMed] [Google Scholar]
- 2. Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig E, Oudiz RJ, Vonk‐Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ, Ambition I. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–44. [DOI] [PubMed] [Google Scholar]
- 3. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV, Griphon I. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–33. [DOI] [PubMed] [Google Scholar]
- 4. Coghlan JG, Channick R, Chin K, Di Scala L, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Gaine S. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: insights from the randomized controlled GRIPHON study. Am J Cardiovasc Drugs. 2018;18:37–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Galiè N, Channick RN, Frantz RP, Grünig E, Jing ZC, Moiseeva O, Preston IR, Pulido T, Safdar Z, Tamura Y, McLaughlin VV. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53:1801889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Rådegran G, Kjellström B, Ekmehag B, Larsen F, Rundqvist B, Blomquist SB, Gustafsson C, Hesselstrand R, Karlsson M, Kornhall B, Nisell M, Persson L, Ryftenius H, Selin M, Ullman B, Wall K, Wikström G, Willehadson M, Jansson K, Stefan Söderberg j, on behalf of SveFPH and SPAHR . Characteristics and survival of adult Swedish PAH and CTEPH patients 2000‐2014. Scand Cardiovasc J. 2016;50:243–50. [DOI] [PubMed] [Google Scholar]
- 7. Rosenkranz S, Channick R, Chin KM, Jenner B, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, McLaughlin VV, Du Roure C, Rubin LJ, Sitbon O, Tapson V, Lang IM. The impact of comorbidities on selexipag treatment effect in patients with pulmonary arterial hypertension: insights from the GRIPHON study. Eur J Heart Fail. 2021;24:205–14. 10.1002/ejhf.2369 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Bouzina H, Rådegran G, Butler O, Hesselstrand R, Hjalmarsson C, Holl K, Jansson K, Klok R, Söderberg S, Kjellström B. Longitudinal changes in risk status in pulmonary arterial hypertension. ESC Heart Fail. 2021;8:680–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Lang IM, Palazzini M. The burden of comorbidities in pulmonary arterial hypertension. Eur Heart J Suppl. 2019;21:K21–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Kjellström B, Sandqvist A, Hjalmarsson C, Nisell M, Näsman P, Ivarsson B. Adherence to disease‐specific drug treatment among patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. ERJ Open Res. 2020;6:00299. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Cascorbi I. Drug Interactions—principles, examples and clinical consequences. Dtsch Ärztebl Int. 2012;109:546–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Ciracì R, Tirone G, Scaglione F. The impact of drug‐drug interactions on pulmonary arterial hypertension therapy. Pulm Pharmacol Ther. 2014;28:1–8. [DOI] [PubMed] [Google Scholar]
- 13.Swedish Pulmonary Arterial Hypertension Registry Annual Report 2019. (SPAHR Årsrapport 2019) [Internet]. [cited 2021 Feb 27]. Available from: https://www.ucr.uu.se/spahr/arsrapporter
- 14.Socialstyrelsen (Swedish National Board of Health and Welfare. The Prescribed Drug Registry at the Swedish National Board of Health and Welfare, in Swedish) [Internet]. Socialstyrelsen. [cited 2021 Feb 27]. Available from: https://www.socialstyrelsen.se/statistik-och-data/register/alla-register/lakemedelsregistret/
- 15.Truven Health Analytics. Micromedex Solutions Drug Interactions [Internet]. 2021. [cited 2021 Feb 28]. Available from: http://www.micromedexsolutions.com
- 16.Kluwer Wolters. Lexicomp® Interactions [Internet]. 2021. Available from: http://online.lexi.com/lco/action/interact
- 17.Region Stockholm. Janusmed Interaktioner [Internet]. Available from: https://janusmed.sll.se/interaktioner
- 18.Socialstyrelsen (Swedish National Board of Health and Welfare). Pulmonell arteriell hypertension och kronisk tromboembolisk pulmonell hypertension [Internet]. Socialstyrelsen. [cited 2021 Apr 16]. Available from: https://www.socialstyrelsen.se/stod-i-arbetet/sallsynta-halsotillstand/pulmonell-arteriell-hypertension-och-kronisk-tromboembolisk-pulmonell-hypertension
- 19. Suárez JA, Manzaneque A, Garcia NC, Creus MT, Mir JB. DI‐058 risk of drug–drug interactions in a pulmonary arterial hypertension population. Eur J Hosp Pharm. 2017;24:A138–39. [Google Scholar]
- 20. Skeith L, Yamashita C, Mehta S, Farquhar D, Kim RB. Sildenafil and furosemide associated ototoxicity: consideration of drug‐drug interactions, synergy, and broader clinical relevance. J Ther Popul Pharmacol Clin. 2013;20:e128–31. [PubMed] [Google Scholar]
- 21. Ding D, Liu H, Qi W, Jiang H, Li Y, Wu X, Sun H, Gross K, Salvi R. Ototoxic effects and mechanisms of loop diuretics. J Otol. 2016;11:145–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Barreto M, Bahmad F. Phosphodiesterase type 5 inhibitors and sudden sensorineural hearing loss. Braz J Otorhinolaryngol. 2013;79:727–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Cunningham LL, Tucci DL. Hearing loss in adults. N Engl J Med. 2017;377:2465–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Ascha M, Zhou X, Rao Y, Minai OA, Tonelli AR. Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil. Cardiovasc Ther. 2017;35:e12281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Ogawa A, Matsubara H, Fujio H, Miyaji K, Nakamura K, Morita H, Saito H, Kusano KF, Emori T, Date H, Ohe T. Risk of alveolar hemorrhage in patients with primary pulmonary hypertension—anticoagulation and epoprostenol therapy. Circ J Off J Jpn Circ Soc. 2005;69:216–20. [DOI] [PubMed] [Google Scholar]
- 26. Suriyapakorn B, Chairat P, Boonyoprakarn S, Rojanarattanangkul P, Pisetcheep W, Hunsakunachai N, Vivithanaporn P, Wongwiwatthananukit S, Khemawoot P. Comparison of potential drug‐drug interactions with metabolic syndrome medications detected by two databases. PLoS One. 2019;14:e0225239. [DOI] [PMC free article] [PubMed]