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What we need to know about drug interactions in patients with pulmonary arterial hypertension
Progress in Pediatric Cardiology 34 (2012) 119–122
Contents lists available at SciVerse ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
What we need to know about drug interactions in patients with pulmonary arterial hypertension K. Wustmann, P. Schmidheiny, M. Schwerzmann ⁎ Congenital Cardiac Center, University Hospital Inselspital, Bern, Switzerland
a r t i c l e
i n f o
Keywords: Pulmonary arterial hypertension Drug–drug interactions Endothelin receptor antagonists Prostacyclin analogs Phosphodiesterase 5 inhibitors
a b s t r a c t In the past years, the number of selective vasodilatory drugs available for the management of patients with pulmonary arterial hypertension (PAH) has increased remarkably. Concomitant chronic or temporary treatment with warfarin, oral contraceptives, some antibiotics, statins or other drugs can exert potential significant drug–drug interactions to some of the specific vasodilatory drugs by competition, induction or inhibition of metabolic pathways. These drug interactions can adversely affect treatment efficacy by changes of their plasma levels and can cause potential harm. An example of a significant drug interaction is given in a case report. Combination therapy with specific pulmonary vasodilatory drugs is more and more the focus of clinical studies, as many patients fail to respond to monotherapy. Each of the substances could add positive treatment effects but they can also interact to each other by their metabolic pathways and increase side-effects or add synergistic effectiveness. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary arterial hypertension (PAH) is characterized by uncontrolled remodeling and proliferation of the pulmonary resistance vessels which lead to an increased pulmonary vascular resistance, right ventricular (RV) hypertrophy with the potential for progression to RV failure and premature death. PAH has an estimated prevalence in the entire population of 15–25 cases/million [1]. The most common causes of PAH in the pediatric and young adult population are idiopathic PAH and PAH related to congenital heart disease (CHD). An estimated 5– 10% of CHD patients will develop PAH mainly due to left–right shunting, with 35–50% of these developing Eisenmenger Syndrome [2]. The recent years were a milestone for patients with PAH after several specific vasodilatory drugs came on the market. Endothelin-1 receptor antagonists (ERA; bosentan, sitaxentan, ambrisentan), phosphodiesterase-5 inhibitors (PDE5I; sildenafil, tadalafil, vardenafil) and prostacyclin derivatives act specifically on pulmonary resistance vessels and have been shown to increase 6 min walking distance [3–6], quality of life [5] and survival [7–9]. 2. Drug–drug interaction—a case report A 48 year old man with tetralogy of Fallot, hypoplastic pulmonary arteries and multiple major aorto-pulmonary collaterals (MAPCAs) ⁎ Corresponding author at: Congenital Cardiac Center, Inselspital, University Hospital Bern, Freiburgstrasse, CH‐3010 Bern, Switzerland. Tel.: +41 31 632 78 59; fax: +41 31 632 42 99. E-mail address: [email protected] (M. Schwerzmann). 1058-9813/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ppedcard.2012.08.011
was referred to the hospital due to acute fever. First operated at age of 16 years with ligation of multiple MAPCAs, resection of subpulmonary stenosis, RVOT enlargement, pulmonary valve replacement and VSD closure, he underwent 22 years later a pulmonary valve replacement by a homograft and residual VSD closure. At age of 33 years, one large MAPCA and a coronary RV-fistula were percutaneously closed. Two years later, he was hospitalized for pneumonia and biventricular decompensation. After successful antibiotic treatment, he was treated with bosentan for confirmed PAH, in addition to torsemide, perindopril and digoxin. Current blood cultures were positive for Staphylococcus aureus and by transthoracic echocardiography, there was high suspicion for endocarditis of the pulmonary homograft. An antibiotic regime with rifampicin and ciprofloxacin was started. Although infection parameters and fever resolved, the patient suffered 2 weeks later from increasing shortness of breath, and NT-pro-BNP levels rose from 3800 pg/ml to 5900 pg/ml. Transthoracic echo confirmed an increase of the tricuspid regurgitation gradient (reflecting RV systolic pressure) despite a stable flow velocity across the homograft as well as increasing early and late diastolic regurgitation flow velocities across the homograft (reflecting mean and diastolic pulmonary artery pressures) compared to 2 weeks before. What caused the acute clinical deterioration and increased pulmonary arterial pressures? In fact, the antibiotic treatment with rifampicin, although effective for the bacterial infection, had a deleterious effect on pulmonary vasodilatory treatment with Bosentan. Rifampicin as an inducer of the cytochrome P450 3A4 (CYP3A4) caused an accelerated metabolism of the ERA and reduced its plasma levels. Drug pharmacokinetics can be influenced by the absorption rate, biotransformation, distribution in the body, clearance rate as well as
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genetics, age and—as in this case—interaction with other medications. Drug interactions can be difficult to notice but have a significant impact on morbidity and mortality, especially for drugs with a narrow therapeutic window. A survey showed that only 53% of drug interactions of moderate to severe intensity and only 54% of potentially fatal combinations were discovered by clinicians [10]. Drug interactions have also substantial effects on healthcare costs by prolongation of the duration and rate of hospitalization [11,12]. 3. Pulmonary vasodilatory drug classes, their metabolism and drug interactions 3.1. Endothelin-1 receptor antagonists Endothelin-1 is a very potent endogenous vasoconstrictor and binds either to ET type A receptors (mediating vasoconstriction), or to ET type B receptors (mediating vasodilation). Bosentan is an ERA binding non-specifically to both receptors whereas ambrisentan and sitaxentan are specific antagonists of the ET type A receptor. Clinical studies have proven the efficacy of ERAs in patients with PAH, especially in CHD-PAH [3–5]. The class side-effect of ERAs is hepatic toxicity. Increases in hepatic aminotransferases occurred in 10% of the subjects treated with bosentan but were found to be dose dependent and reversible after dose reduction or discontinuation [13]. They seem to be less frequent under treatment with Ambrisentan [14]. All three ERAs are active drugs. Bosentan and sitaxentan are mainly metabolized via the cytochromes CYP2C9 and CYP3A4, and additional via CYP3A5 for sitaxentan. The clearance of ambrisentan follows the CYP3A4, CYPC19 and CYP3A5 pathways [15]. Bosentan and sitaxentan are recognized to possess several important drug interactions through induction or inhibition of cytochrome P450 isoenzymes. Both reduce CYP3A4 dependent levels of statins (e.g. simvastatin, atorvastatin) and cyclosporine. Bosentan acts as an inducer of CYP3A4 and CYP2C9 which causes subtherapeutic plasma levels of hormonal contraceptives. To prevent failure of hormonal contraception in women with PAH in child-
bearing age with the given high maternal mortality risk, the use of additional mechanical contraception is required. Conversely, sitaxentan increases estrogen and progesterone levels and could theoretically increase the risk for thromboembolism [13]. Furthermore, bosentan and sitaxentan alter the clearance of warfarin, a drug with a very narrow therapeutic window, via the CYP2C9 pathway, which could cause sub-therapeutic anticoagulation (bosentan) or overanticoagulation and fatal bleedings (sitaxentan); demanding more frequent INR monitoring after treatment starts with an ERA. Bosentan and sitaxentan reduce plasma levels of PDE5I sildenafil, vardenafil and tadalafil significantly [13,16]. Due to fatal increase of bosentan and sitaxentan plasma concentrations with high risk for hepatic toxicity, the combination with cyclosporine is contraindicated. Interactions are also reported for combinations with ketoconazole, fluconazole, ritonavir, amiodarone, tacrolimus, sirolimus, carbamazepine, phenytoin, rifampicin, erythromycin, and St John's Wort [13], Fig. 1. There are no data suggesting an inductive or inhibitory effect for ambrisentan on CYP3A4 or CYP2C9 pathway and therefore no significant drug interactions are reported to date. 3.2. Phosphodiesterase type-5 inhibitors PDE5Is like sildenafil, vardenafil, tadalafil act by inhibition of the cGMP-degrading enzyme phosphodiesterase type-5 in vascular smooth muscle cells which results in vasodilatation through the nitric oxide/cGMP pathway. Nowadays used as first-line therapy in patients with idiopathic PAH [13], only few studies proved their efficacy in small CHD-PAH populations [17–19]. The vasodilatory action of the PDE5Is manifests not only in the pulmonary vascular bed but also in the systemic arterioles and the coronary arteries and could cause systemic hypotension and coronary steal when combined with vasodilators like nitrates, calcium channel blockers and alphablockers. Organic nitrates should be avoided for up to 4 h after sildenafil, 24 h after vardenafil, and up to 48 h after tadalafil intake [20]. PDE5Is are active drugs. Their clearance is metabolic mainly via the CYP3A4 (sildenafil and vardenafil up to 80%) and a lesser
Warfarin Hormonal contraceptives Amiodarone Statins Phenytoin
Bosentan
Cyclosporine Tacrolimus Rifampicin Erythromycin/ Clarithromycin Carbamazepine Sildenafil Protease inhibitors Antifungals Cimetidine Ciprofloxacin Platelet aggregation inhibitors
?
Prostacyclin analogues
Fig. 1. Potential drug interactions between bosentan and sildenafil and concomitant medication. The arrow targets the affected drug; solid lines for increasing plasma levels, broken lines for decreasing plasma levels of the affected drug. Red line for contraindication. The figure does not represent all possible drug interactions.
K Wustmann et al. / Progress in Pediatric Cardiology 34 (2012) 119–122
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Table 1 Overview of important drug interactions between pulmonary vasodilatory drugs and some commonly prescribed medications. Please note that this list does not represent all possible drug interactions. Drug
Pulmonary hypertension drug
Interaction
Warfarin
Bosentan Sitaxentan Bosentan Sitaxentan Ambrisentan Bosentan Sitaxentan Bosentan, (sitaxentan?) Sildenafil Bosentan, sitaxentan, sildenafil, vardenafil, tadalafil Bosentan, sitaxentan, sildenafil, vardenafil, tadalafil Bosentan, sildenafil, vardenafil (sitaxentan?)
Warfarin ↓, INR ↓, need re-adjustment Warfarin ↑, INR ↑, need re-adjustment Cyclosporine ↓, bosentan ↑ 4-fold, contraindicated Cyclosporine ↓, sitaxentan ↑ 8-fold, contraindicated Caution, may reduce ambrisentan dosage Contraception unreliable, add mechanical contraception Estrogen levels ↑, possible thromboembolic risk ↑ ? Statin ↓, cholesterol levels ↓, adjust statin dosage accordingly Statin ↑, risk for rhabdomyolysis ↑, reduce if suspected All levels (up to 2–5 fold) ↑, reduce dosage if side effects
Cyclosporine
Hormonal contraception Simvastatin, Atorvastatin Amiodarone Rifampicin, phenytoin, carbamazepine Erythromycin, clarithromycin, tacrolimus, (sirolimus?) Ketoconazole, fluconazole, itraconazole Ciprofloxacin Cimetidine HIV protease inhibitors (e.g. ritonavir) Diltiazem, verapamil
Bosentan, sitaxentan Sildenafil, vardenafil, tadalafil Sildenafil, (bosentan?, sitaxentan?, vardenafil?) Sildenafil, (vardenafil?) Bosentan, sitaxentan, sildenafil, vardenafil, Bosentan Sitaxentan Sildenafil, vardenafil, tadalafil
extent via 2C9 (20%). Tadalafil is almost solely metabolized by CYP2C9 [20]. Potent competitors of the CYP3A4 like grapefruit, ketoconazole, erythromycin, clarithromycin, tacrolimus, ciprofloxacin, cimetidine, ritonavir cause an increase in effective drug plasma level and half time. Conversely, CYP3A4 inducers like rifampicin, carbamazepine, phenytoin, ERA bosentan (plasma level of sildenafil is reduced by 63% [16]) and sitaxentan stimulate the metabolic clearance and reduce plasma levels and half time of PDE5I sildenafil and vardenafil. Sildenafil is also reported to reduce the clearance of CYP3A4 dependent statins (simvastatin, atorvastatin) and could increase the risk for rhabdomyolysis [21]. Tadalafil does not inhibit or stimulate CYP3A4 but can be reduced in its plasma levels by ERA (up to 40% [13]) and rifampicin and increased by ketoconazole [20].
All drug levels ↓, adjust dosage if needed All drug levels ↑, adjust dosage if side effects Bosentan ↑ 2-fold, caution, may reduce bosentan dosage Sildenafil, vardenafil, tadalafil ↑, adjust dosage if side effects Sildenafil (and others?) ↑, adjust dosage if side effects Sildenafil, (vardenafil?) ↑, adjust dosage if side effects All levels PAH drug levels ↑, adjust dosage if side effects Bosentan ↓, adjust dosage if needed Sitaxentan ↑, adjust dosage if side effects Blood pressure
evidence of increased bleeding. No other drug–drug interactions are reported. 3.4. Calcium channel blockers Until the 1990s, the only treatment available for PAH included calcium channel blockers (CCB) and anticoagulation. Today, CCB are only recommended for patients with idiopathic PAH who demonstrate a favorable response to acute vasodilator testing during right heart catheterization and undergo close follow-up [13,22]. A majority of CCBs are metabolized primarily through CYP3A4, making them sensitive to potent 3A4 inhibitors like clarithromycin and St. John's Wort, and 3A4 inducers, such as carbamazepine and rifampicin [23]. 4. Combination therapies in PAH
3.3. Prostacyclin analogs Prostacyclin is produced by the vascular endothelium and exerts its pulmonary and systemic vasodilatory action by increasing intracellular cAMP in vascular smooth muscle cells. It furthermore inhibits smooth muscle cell proliferation, inflammation and oxidative stress and platelet aggregation. Continuous intravenous infusion of epoprostenol is one of the most effective treatments for PAH [9]. Due to a short half-time, prostacyclin (epoprostenol, iloprost, treprostinil) therapy is only effective by either continuous intravenous, subcutaneous (both complicated by potential infections at the administration site) or frequent inhalative administration. Prostacyclin analogs are metabolized via beta-oxygenation and do not follow the cytochrome P450 pathway. As they don't work as competitors, inducer or inhibitor at this site, no potential interactions with concomitant drugs utilizing the cytochrome P450 isoenzymes are reported. Headache, flush, skin rush and diarrhea are the most common side effects. By platelet aggregation inhibition, prostacyclin analogs may theoretically potentiate the risk of bleeding in patients treated with other agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that potentially cause thrombocytopenia. In clinical trials for pulmonary hypertension, patients received concomitant anticoagulants and/or nonsteroidal anti-inflammatory agents without
Combination therapy can provide benefits for patients with PAH, addressing more than one of the disease mechanisms and is used to treat patients deteriorating under vasodilatory monotherapy. Furthermore, the question arises whether an initial start with a lowdose combination treatment could offer a synergistic and favorable treatment option especially for prevention of disease progression. Therefore, there is an increasing need for a better understanding in drug interactions not only to prevent harmful side-effects but also to bundle synergistic effects of combinations. Co-administration of sildenafil (80 mg three times daily) increases bosentan (125 mg twice daily) concentration by 50% whereas bosentan reduces plasma sildenafil concentration by 63% [16]. In clinical practice, the dose of bosentan does not have to be adjusted during combination therapy, if hepatic aminotransferases do not rise > 3 × above the normal upper limit. Close laboratory monitoring is recommended. Tadalafil plasma levels are reported to be reduced by 40% in combination with bosentan, whereas bosentan levels remained unchanged [13]. For the combination of ERA with prostacyclin derivatives epoprostenol, treprostinil or iloprost, no drug interactions are reported. Sildenafil prolonged the effect of inhaled nitric oxide on pulmonary vasodilatation and prevented rebound vasoconstriction after inhaled nitric oxide [24]. The addition of sildenafil on long-term epoprostenol therapy increased rates of headache
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and dyspepsia [25]. Epoprostenol reduces plasma concentration of sildenafil by 25% (Pfizer, REVATIO prescribing information, 2010). The question arises as to which extent combination targeted therapy will increase drug interactions. 5. In daily practice Table 1 gives a brief overview over drug interactions between ERA or PDF5Is and commonly prescribed concomitant medication. Please note that not all potential interactions are displayed in the table. 6. Conclusion Specific vasodilatory drugs to treat PAH can exert significant and harmful drug interactions with fatal side-effects in combination with chronic or temporarily prescribed medication. These interactions should be kept in mind in order prevent avoidable morbidity and mortality. References [1] Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30. [2] Galie N, Manes A, Palazzini M, et al. Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome. Drugs 2008;68:1049-66. [3] Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48-54. [4] Gatzoulis MA, Beghetti M, Galie N, et al. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 openlabel extension study. Int J Cardiol 2008;127:27-32. [5] Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117:3010-9. [6] Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S. Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome—a randomized, placebo-controlled, double-blind crossover study. Congenit Heart Dis 2011;6: 424-31. [7] Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A metaanalysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
[8] Dimopoulos K, Inuzuka R, Goletto S, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010;121:20-5. [9] McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82. [10] Glassman PA, Simon B, Belperio P, Lanto A. Improving recognition of drug interactions: benefits and barriers to using automated drug alerts. Med Care 2002;40:1161-71. [11] Sandson N. Drug–drug interactions: the silent epidemic. Psychiatr Serv 2005;56: 22-4. [12] Shad MU, Marsh C, Preskorn SH. The economic consequences of a drug–drug interaction. J Clin Psychopharmacol 2001;21:119-20. [13] Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the 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 the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537. [14] McGoon MD, Frost AE, Oudiz RJ, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009;135:122-9. [15] Ghofrani HA, Schermuly R, Weissmann N, et al. Drug interactions in pulmonary arterial hypertension and their implications. Eur Cardiol 2009;5:46-51. [16] Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008;64:43-50. [17] Huddleston AJ, Knoderer CA, Morris JL, Ebenroth ES. Sildenafil for the treatment of pulmonary hypertension in pediatric patients. Pediatr Cardiol 2009;30:871-82. [18] Zeng WJ, Lu XL, Xiong CM, et al. The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with the different types of congenital heart disease. Clin Cardiol 2011;34:513-8. [19] Zhang ZN, Jiang X, Zhang R, et al. Oral sildenafil treatment for Eisenmenger syndrome: a prospective, open-label, multicentre study. Heart 2011;97:1876-81. [20] Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation 2010;122:88-95. [21] Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation Jun 15 2004;109 (23 Suppl 1):III50–7. [22] McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250-94. [23] Williams S, Wynn G, Cozza K, Sandson NB. Cardiovascular medications. Psychosomatics 2007;48:537-47. [24] Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90:677-80. [25] Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30.
Contents lists available at SciVerse ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
What we need to know about drug interactions in patients with pulmonary arterial hypertension K. Wustmann, P. Schmidheiny, M. Schwerzmann ⁎ Congenital Cardiac Center, University Hospital Inselspital, Bern, Switzerland
a r t i c l e
i n f o
Keywords: Pulmonary arterial hypertension Drug–drug interactions Endothelin receptor antagonists Prostacyclin analogs Phosphodiesterase 5 inhibitors
a b s t r a c t In the past years, the number of selective vasodilatory drugs available for the management of patients with pulmonary arterial hypertension (PAH) has increased remarkably. Concomitant chronic or temporary treatment with warfarin, oral contraceptives, some antibiotics, statins or other drugs can exert potential significant drug–drug interactions to some of the specific vasodilatory drugs by competition, induction or inhibition of metabolic pathways. These drug interactions can adversely affect treatment efficacy by changes of their plasma levels and can cause potential harm. An example of a significant drug interaction is given in a case report. Combination therapy with specific pulmonary vasodilatory drugs is more and more the focus of clinical studies, as many patients fail to respond to monotherapy. Each of the substances could add positive treatment effects but they can also interact to each other by their metabolic pathways and increase side-effects or add synergistic effectiveness. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary arterial hypertension (PAH) is characterized by uncontrolled remodeling and proliferation of the pulmonary resistance vessels which lead to an increased pulmonary vascular resistance, right ventricular (RV) hypertrophy with the potential for progression to RV failure and premature death. PAH has an estimated prevalence in the entire population of 15–25 cases/million [1]. The most common causes of PAH in the pediatric and young adult population are idiopathic PAH and PAH related to congenital heart disease (CHD). An estimated 5– 10% of CHD patients will develop PAH mainly due to left–right shunting, with 35–50% of these developing Eisenmenger Syndrome [2]. The recent years were a milestone for patients with PAH after several specific vasodilatory drugs came on the market. Endothelin-1 receptor antagonists (ERA; bosentan, sitaxentan, ambrisentan), phosphodiesterase-5 inhibitors (PDE5I; sildenafil, tadalafil, vardenafil) and prostacyclin derivatives act specifically on pulmonary resistance vessels and have been shown to increase 6 min walking distance [3–6], quality of life [5] and survival [7–9]. 2. Drug–drug interaction—a case report A 48 year old man with tetralogy of Fallot, hypoplastic pulmonary arteries and multiple major aorto-pulmonary collaterals (MAPCAs) ⁎ Corresponding author at: Congenital Cardiac Center, Inselspital, University Hospital Bern, Freiburgstrasse, CH‐3010 Bern, Switzerland. Tel.: +41 31 632 78 59; fax: +41 31 632 42 99. E-mail address: [email protected] (M. Schwerzmann). 1058-9813/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ppedcard.2012.08.011
was referred to the hospital due to acute fever. First operated at age of 16 years with ligation of multiple MAPCAs, resection of subpulmonary stenosis, RVOT enlargement, pulmonary valve replacement and VSD closure, he underwent 22 years later a pulmonary valve replacement by a homograft and residual VSD closure. At age of 33 years, one large MAPCA and a coronary RV-fistula were percutaneously closed. Two years later, he was hospitalized for pneumonia and biventricular decompensation. After successful antibiotic treatment, he was treated with bosentan for confirmed PAH, in addition to torsemide, perindopril and digoxin. Current blood cultures were positive for Staphylococcus aureus and by transthoracic echocardiography, there was high suspicion for endocarditis of the pulmonary homograft. An antibiotic regime with rifampicin and ciprofloxacin was started. Although infection parameters and fever resolved, the patient suffered 2 weeks later from increasing shortness of breath, and NT-pro-BNP levels rose from 3800 pg/ml to 5900 pg/ml. Transthoracic echo confirmed an increase of the tricuspid regurgitation gradient (reflecting RV systolic pressure) despite a stable flow velocity across the homograft as well as increasing early and late diastolic regurgitation flow velocities across the homograft (reflecting mean and diastolic pulmonary artery pressures) compared to 2 weeks before. What caused the acute clinical deterioration and increased pulmonary arterial pressures? In fact, the antibiotic treatment with rifampicin, although effective for the bacterial infection, had a deleterious effect on pulmonary vasodilatory treatment with Bosentan. Rifampicin as an inducer of the cytochrome P450 3A4 (CYP3A4) caused an accelerated metabolism of the ERA and reduced its plasma levels. Drug pharmacokinetics can be influenced by the absorption rate, biotransformation, distribution in the body, clearance rate as well as
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K Wustmann et al. / Progress in Pediatric Cardiology 34 (2012) 119–122
genetics, age and—as in this case—interaction with other medications. Drug interactions can be difficult to notice but have a significant impact on morbidity and mortality, especially for drugs with a narrow therapeutic window. A survey showed that only 53% of drug interactions of moderate to severe intensity and only 54% of potentially fatal combinations were discovered by clinicians [10]. Drug interactions have also substantial effects on healthcare costs by prolongation of the duration and rate of hospitalization [11,12]. 3. Pulmonary vasodilatory drug classes, their metabolism and drug interactions 3.1. Endothelin-1 receptor antagonists Endothelin-1 is a very potent endogenous vasoconstrictor and binds either to ET type A receptors (mediating vasoconstriction), or to ET type B receptors (mediating vasodilation). Bosentan is an ERA binding non-specifically to both receptors whereas ambrisentan and sitaxentan are specific antagonists of the ET type A receptor. Clinical studies have proven the efficacy of ERAs in patients with PAH, especially in CHD-PAH [3–5]. The class side-effect of ERAs is hepatic toxicity. Increases in hepatic aminotransferases occurred in 10% of the subjects treated with bosentan but were found to be dose dependent and reversible after dose reduction or discontinuation [13]. They seem to be less frequent under treatment with Ambrisentan [14]. All three ERAs are active drugs. Bosentan and sitaxentan are mainly metabolized via the cytochromes CYP2C9 and CYP3A4, and additional via CYP3A5 for sitaxentan. The clearance of ambrisentan follows the CYP3A4, CYPC19 and CYP3A5 pathways [15]. Bosentan and sitaxentan are recognized to possess several important drug interactions through induction or inhibition of cytochrome P450 isoenzymes. Both reduce CYP3A4 dependent levels of statins (e.g. simvastatin, atorvastatin) and cyclosporine. Bosentan acts as an inducer of CYP3A4 and CYP2C9 which causes subtherapeutic plasma levels of hormonal contraceptives. To prevent failure of hormonal contraception in women with PAH in child-
bearing age with the given high maternal mortality risk, the use of additional mechanical contraception is required. Conversely, sitaxentan increases estrogen and progesterone levels and could theoretically increase the risk for thromboembolism [13]. Furthermore, bosentan and sitaxentan alter the clearance of warfarin, a drug with a very narrow therapeutic window, via the CYP2C9 pathway, which could cause sub-therapeutic anticoagulation (bosentan) or overanticoagulation and fatal bleedings (sitaxentan); demanding more frequent INR monitoring after treatment starts with an ERA. Bosentan and sitaxentan reduce plasma levels of PDE5I sildenafil, vardenafil and tadalafil significantly [13,16]. Due to fatal increase of bosentan and sitaxentan plasma concentrations with high risk for hepatic toxicity, the combination with cyclosporine is contraindicated. Interactions are also reported for combinations with ketoconazole, fluconazole, ritonavir, amiodarone, tacrolimus, sirolimus, carbamazepine, phenytoin, rifampicin, erythromycin, and St John's Wort [13], Fig. 1. There are no data suggesting an inductive or inhibitory effect for ambrisentan on CYP3A4 or CYP2C9 pathway and therefore no significant drug interactions are reported to date. 3.2. Phosphodiesterase type-5 inhibitors PDE5Is like sildenafil, vardenafil, tadalafil act by inhibition of the cGMP-degrading enzyme phosphodiesterase type-5 in vascular smooth muscle cells which results in vasodilatation through the nitric oxide/cGMP pathway. Nowadays used as first-line therapy in patients with idiopathic PAH [13], only few studies proved their efficacy in small CHD-PAH populations [17–19]. The vasodilatory action of the PDE5Is manifests not only in the pulmonary vascular bed but also in the systemic arterioles and the coronary arteries and could cause systemic hypotension and coronary steal when combined with vasodilators like nitrates, calcium channel blockers and alphablockers. Organic nitrates should be avoided for up to 4 h after sildenafil, 24 h after vardenafil, and up to 48 h after tadalafil intake [20]. PDE5Is are active drugs. Their clearance is metabolic mainly via the CYP3A4 (sildenafil and vardenafil up to 80%) and a lesser
Warfarin Hormonal contraceptives Amiodarone Statins Phenytoin
Bosentan
Cyclosporine Tacrolimus Rifampicin Erythromycin/ Clarithromycin Carbamazepine Sildenafil Protease inhibitors Antifungals Cimetidine Ciprofloxacin Platelet aggregation inhibitors
?
Prostacyclin analogues
Fig. 1. Potential drug interactions between bosentan and sildenafil and concomitant medication. The arrow targets the affected drug; solid lines for increasing plasma levels, broken lines for decreasing plasma levels of the affected drug. Red line for contraindication. The figure does not represent all possible drug interactions.
K Wustmann et al. / Progress in Pediatric Cardiology 34 (2012) 119–122
121
Table 1 Overview of important drug interactions between pulmonary vasodilatory drugs and some commonly prescribed medications. Please note that this list does not represent all possible drug interactions. Drug
Pulmonary hypertension drug
Interaction
Warfarin
Bosentan Sitaxentan Bosentan Sitaxentan Ambrisentan Bosentan Sitaxentan Bosentan, (sitaxentan?) Sildenafil Bosentan, sitaxentan, sildenafil, vardenafil, tadalafil Bosentan, sitaxentan, sildenafil, vardenafil, tadalafil Bosentan, sildenafil, vardenafil (sitaxentan?)
Warfarin ↓, INR ↓, need re-adjustment Warfarin ↑, INR ↑, need re-adjustment Cyclosporine ↓, bosentan ↑ 4-fold, contraindicated Cyclosporine ↓, sitaxentan ↑ 8-fold, contraindicated Caution, may reduce ambrisentan dosage Contraception unreliable, add mechanical contraception Estrogen levels ↑, possible thromboembolic risk ↑ ? Statin ↓, cholesterol levels ↓, adjust statin dosage accordingly Statin ↑, risk for rhabdomyolysis ↑, reduce if suspected All levels (up to 2–5 fold) ↑, reduce dosage if side effects
Cyclosporine
Hormonal contraception Simvastatin, Atorvastatin Amiodarone Rifampicin, phenytoin, carbamazepine Erythromycin, clarithromycin, tacrolimus, (sirolimus?) Ketoconazole, fluconazole, itraconazole Ciprofloxacin Cimetidine HIV protease inhibitors (e.g. ritonavir) Diltiazem, verapamil
Bosentan, sitaxentan Sildenafil, vardenafil, tadalafil Sildenafil, (bosentan?, sitaxentan?, vardenafil?) Sildenafil, (vardenafil?) Bosentan, sitaxentan, sildenafil, vardenafil, Bosentan Sitaxentan Sildenafil, vardenafil, tadalafil
extent via 2C9 (20%). Tadalafil is almost solely metabolized by CYP2C9 [20]. Potent competitors of the CYP3A4 like grapefruit, ketoconazole, erythromycin, clarithromycin, tacrolimus, ciprofloxacin, cimetidine, ritonavir cause an increase in effective drug plasma level and half time. Conversely, CYP3A4 inducers like rifampicin, carbamazepine, phenytoin, ERA bosentan (plasma level of sildenafil is reduced by 63% [16]) and sitaxentan stimulate the metabolic clearance and reduce plasma levels and half time of PDE5I sildenafil and vardenafil. Sildenafil is also reported to reduce the clearance of CYP3A4 dependent statins (simvastatin, atorvastatin) and could increase the risk for rhabdomyolysis [21]. Tadalafil does not inhibit or stimulate CYP3A4 but can be reduced in its plasma levels by ERA (up to 40% [13]) and rifampicin and increased by ketoconazole [20].
All drug levels ↓, adjust dosage if needed All drug levels ↑, adjust dosage if side effects Bosentan ↑ 2-fold, caution, may reduce bosentan dosage Sildenafil, vardenafil, tadalafil ↑, adjust dosage if side effects Sildenafil (and others?) ↑, adjust dosage if side effects Sildenafil, (vardenafil?) ↑, adjust dosage if side effects All levels PAH drug levels ↑, adjust dosage if side effects Bosentan ↓, adjust dosage if needed Sitaxentan ↑, adjust dosage if side effects Blood pressure
evidence of increased bleeding. No other drug–drug interactions are reported. 3.4. Calcium channel blockers Until the 1990s, the only treatment available for PAH included calcium channel blockers (CCB) and anticoagulation. Today, CCB are only recommended for patients with idiopathic PAH who demonstrate a favorable response to acute vasodilator testing during right heart catheterization and undergo close follow-up [13,22]. A majority of CCBs are metabolized primarily through CYP3A4, making them sensitive to potent 3A4 inhibitors like clarithromycin and St. John's Wort, and 3A4 inducers, such as carbamazepine and rifampicin [23]. 4. Combination therapies in PAH
3.3. Prostacyclin analogs Prostacyclin is produced by the vascular endothelium and exerts its pulmonary and systemic vasodilatory action by increasing intracellular cAMP in vascular smooth muscle cells. It furthermore inhibits smooth muscle cell proliferation, inflammation and oxidative stress and platelet aggregation. Continuous intravenous infusion of epoprostenol is one of the most effective treatments for PAH [9]. Due to a short half-time, prostacyclin (epoprostenol, iloprost, treprostinil) therapy is only effective by either continuous intravenous, subcutaneous (both complicated by potential infections at the administration site) or frequent inhalative administration. Prostacyclin analogs are metabolized via beta-oxygenation and do not follow the cytochrome P450 pathway. As they don't work as competitors, inducer or inhibitor at this site, no potential interactions with concomitant drugs utilizing the cytochrome P450 isoenzymes are reported. Headache, flush, skin rush and diarrhea are the most common side effects. By platelet aggregation inhibition, prostacyclin analogs may theoretically potentiate the risk of bleeding in patients treated with other agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin inhibitors, thrombolytic agents, or agents that potentially cause thrombocytopenia. In clinical trials for pulmonary hypertension, patients received concomitant anticoagulants and/or nonsteroidal anti-inflammatory agents without
Combination therapy can provide benefits for patients with PAH, addressing more than one of the disease mechanisms and is used to treat patients deteriorating under vasodilatory monotherapy. Furthermore, the question arises whether an initial start with a lowdose combination treatment could offer a synergistic and favorable treatment option especially for prevention of disease progression. Therefore, there is an increasing need for a better understanding in drug interactions not only to prevent harmful side-effects but also to bundle synergistic effects of combinations. Co-administration of sildenafil (80 mg three times daily) increases bosentan (125 mg twice daily) concentration by 50% whereas bosentan reduces plasma sildenafil concentration by 63% [16]. In clinical practice, the dose of bosentan does not have to be adjusted during combination therapy, if hepatic aminotransferases do not rise > 3 × above the normal upper limit. Close laboratory monitoring is recommended. Tadalafil plasma levels are reported to be reduced by 40% in combination with bosentan, whereas bosentan levels remained unchanged [13]. For the combination of ERA with prostacyclin derivatives epoprostenol, treprostinil or iloprost, no drug interactions are reported. Sildenafil prolonged the effect of inhaled nitric oxide on pulmonary vasodilatation and prevented rebound vasoconstriction after inhaled nitric oxide [24]. The addition of sildenafil on long-term epoprostenol therapy increased rates of headache
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and dyspepsia [25]. Epoprostenol reduces plasma concentration of sildenafil by 25% (Pfizer, REVATIO prescribing information, 2010). The question arises as to which extent combination targeted therapy will increase drug interactions. 5. In daily practice Table 1 gives a brief overview over drug interactions between ERA or PDF5Is and commonly prescribed concomitant medication. Please note that not all potential interactions are displayed in the table. 6. Conclusion Specific vasodilatory drugs to treat PAH can exert significant and harmful drug interactions with fatal side-effects in combination with chronic or temporarily prescribed medication. These interactions should be kept in mind in order prevent avoidable morbidity and mortality. References [1] Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30. [2] Galie N, Manes A, Palazzini M, et al. Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome. Drugs 2008;68:1049-66. [3] Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48-54. [4] Gatzoulis MA, Beghetti M, Galie N, et al. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 openlabel extension study. Int J Cardiol 2008;127:27-32. [5] Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008;117:3010-9. [6] Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S. Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome—a randomized, placebo-controlled, double-blind crossover study. Congenit Heart Dis 2011;6: 424-31. [7] Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A metaanalysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.
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