Drugs for the treatment of pulmonary arterial hypertension

Drug interaction

Drug interactions involving drugs for the treatment of pulmonary arterial hypertension, including

  1. Endothelin receptor antagonists: Bosentan, Ambrisentan, Macitentan
  2. Prostacyclin pathway agonists:
    a) Prostacyclin analogues: Epoprostenol, Iloprost, Treprostinil
    b) non-prostanoid prostacyclin IP2 receptor agonists: Selexipag
  3. Soluble Guanylate cuclase inhibitors: Riociguat
  4. Phosphodiesterase-5 inhibitors: Sildenafil, Tadalafil
  5. Other drugs (see other sections)

 

See other sections for drug interactions involving other cardiovascular drugs. Use of this content is subject to our disclaimer.

 

1. Endothelin receptor antagonists

Ambrisentan, Bosentan, Macitentan

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Amiodarone Amiodarone inhibits both CYP2C9 and CYP3A4, and P-gp, and increases bosentan plasma levelsAvoid this combination
Azole antifungals:
- Fluconazole
- Ketoconazole
- Itraconazole
- Voriconazole
Fluconazole inhibits CYP2C9 and CYP3A4 and increases plasma concentrations of bosentan
Ketoconoazole and Itraconazole are potent CYP3A4 inhibitors and increase plasma concentrations of bosentan
Avoid this combination
Ketoconazole may increase ambrisentan and macitentan levels due to CYP3A4 inhibitionUse with caution
Ciclosporin The combination markedly increases the exposure to bosentan or ambrisentan
It does not affect exposure to macitentan and its active metabolite
Avoid the combination of ciclosporin and bosentan.
The dose of ambrisentan should be limited to 5 mg od
Ciclosporin markedly increases the plasma concentrations of bosentan probably due to inhibition of transport protein-mediated uptake of bosentan into hepatocytes. Bosentan decreases ciclosporin levels because it is a CYP3A4 inducerCoadministration of bosentan and ciclosporin is contraindicated
CIclosporin does not alter the exposure to macitentan and its active metabolite
Factor Xa inhibitors:
- Apixaban
- Rivaroxaban
Bosentan increases the plasma levels of apixaban and rivaroxaban.With caution
Glibenclamide Bosentan decreases the hypoglycemic effect of glibenclamide. The combination increases aminotransfrasesDecrease the plasma levels of glibenclamide and bosentan. Both glibenclamide and bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferasesAvoid this combination
HIV protease inhibitors:
- Lopinavir + Ritonavir
- Other ritonavir-boosted drugs
Marked increases in bosentan plasma levels because HIV protease inhibitors inhibits the OATP and CYP3A4 reducing the clearance of bosentan. Monitor patient's tolerability to bosentan and HIV therapy. Patients should be closely monitored for adverse events (hepatotoxicity)
HIV protease inhibitors may increase ambrisentan and macitentan levelsUse with caution
Immunosuppressant drugs:
- Sirolimus
- Tacrolimus
Tacrolimus and sirolimus inhibits CYP3A4 and increase the plasma concentrations of bosentanPatients should be closely monitored for adverse events; monitor the tacrolimus and sirolimus blood concentrationns
NevirapineNevirapine produces hepatotoxicity which could be added to that induced by endothelin receptor anatgonistNevirapine is an inducer of CYP3A4 and may reduce plasma levels of endothelin agonistsPatients should be closely monitored for hepatotoxicity. This combination is not recommended
Oral contraceptivesAmbrisentan does not affect the pharmacokinetics of the ethinyl estradiol and norethindrone.
Bosentan decreases the exposure to oral contraceptives containing norethindrone and ethinyl estradiol
Oral contraceptives containing norethindrone and ethinyl estradiol; are not a reliable method of contraception. Females should practice additional methods of contraception.
Macitentan does not interact with oral contraceptives (norethisterone and ethinyl estradiol)
Phosphodiesterase 5 inhibitors:
- Sildenafil
- Tadalafil
Bosentan reduces sildenafil plasma concentrations (60%) and sildenafil increases (50%) bosentan plasma levels.
Sildenafill and tadalafil do not affect the pharmacokinetics of ambrisentan and macitentan
Caution is recommended. Dose adjustments are not necessary.
Macitentan does not interact with sildenafil
Potent CYP3A4 or CYP2C9 inducers:
- Rifampicin
Reduce the effects of bosentan and macitentanReduces the exposure to bosentan and macitentan Patients should be closely monitored when starting treatment with potent CYP inducers. These combinations are not recommended
Potent CYP3A4 or CYP2C9 inhibitors:
- 3A4 and 2C9: Fluconazol
- 3A4: Itraconazole, Ketoconazole, Ritonavir
- CYP2C9: Amioradone, Gemfibrozil, Voriconazole
Increase bosentan plasma levels
These combinations are not recommended. Monitor BP
Statins:
- Atorvastatin
- Lovastatin
- Simvastatin
Bosentan decreases (40%) the plasma concentrations of statins metabolized by CYP3A
Monitor cholesterol plasma levels and subsequent dosage adjustment should be considered
WarfarinAmbrisentan had no effects on the pharmacokinetics and anti-coagulant activity of warfarin.
Bosentan decreases plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate)
Macitentan has no effect on exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate). The pharmacokinetics of macitentan and its active metabolite were not affected by warfarin
Monitor the INR but dose adjustment is usually unnecessary

Bosentan is an inducer of CYP3A and CYP2C9 that reduces the plasma levels of drugs metabolised by these isoenzymes. Bosentan is also metabolised by these enzymes, so that their inhibition may increase the plasma concentration of bosenta.

Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters, including the OATP1B1 and OATP1B3.

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2. Prostacyclin pathway agonists

A) Prostacyclin analogues: Epoprostenol, Iloprost, Treprostinil

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AnticoagulantsProstacyclin inhibits platelet aggregation and increases the risk of bleedingMonitor the risk of bleeding
AntihypertensivesAdditive effects. The risk of hypotension increasesDose adjustment might be required
Avoid teprostinil in patients with SBP <85 mmHg
DigoxinEpoprostenol increase digoxin plasma levels.
Intravenous infusion of iloprost has no effect on the pharmacokinetics of digoxin
Careful in in patients prone to digoxin toxicity
Drugs that increase the risk of bleeding:
- Anticoagulants
- Antiplatelet agents
- Cilostazol
- NSAIDs
- Pentoxifylline
- Thrombolytics
- Warfarin
PGI2 analogues inhibit platelet aggregation and may increase the risk of bleedingCareful monitoring is required in patients taking anticoagulants or other inhibitors of platelet aggregation
GemfibrozilThis CYP2C8 inhibitor increases exposure to treprostinilWith caution
RifampicinThis CYP2C8 enzyme inducer decreases exposure to treprostinilAvoid the combination
Sympathomimetics Reduce the vasodilator effect of PGI2 analogues
Tissue plasminogen activator (t-PA)PGI2 analogues may reduce the thrombolytic efficacy of t-PA.PGI2 analogues increae the hepatic clearance of t-PA.
Intravenous infusion of iloprost has no effect on the pharmacokinetics of t-PA
Avoid the combination
Vasodilators:
- Alcohol
- Nitrates
- Papaverine
- Riociguat
- Sildenafil
Additive vasodilator effectsMonitor BP. Dose adjustment might be required.
Avoid teprostinil in patients with SBP <85 mmHg

No interactions have been found between treprostinil and acetaminophen, fluconazole, sildenafil or warfarin

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B) Non-prostanoid prostacyclin IP2 receptor agonists: Selexipag

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
CYP2C8 inducers:
- Carbamazepine
- Phenytoin
- Rifampicin
Increase the biotransformation of selexipagDose adjustment of selexipag may be required
Moderate CYP2C8 inhibitors:
- Clopidogrel
- Deferasirox
- Gemfibrozil
- Teriflunomide
Increases exposure to selexipag and its active metaboliteAdjustment of the dose of selexipag should be considered. Use with caution
Potent CYP3A4 inhibitors:
- Lopinavir/ritonavir
Increases the exposure to selexipag but not the exposure to the active metabolitePossibly not clinically relevant

The pharmacokinetics of selexipag and its active metabolite are not affected by warfarin.

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3. Soluble guanylate cuclase inhibitors

Riociguat

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AntiacidsAntacids containing aluminum hydroxide/magnesium hydroxide decrease riociguat absorptionThey should not be taken within 1-2 h before or 1 h after riociguat
Antihypertensives
Riociguat produces additive BP lowering effects Monitor BP
Azole antifungals:
- Clotrimazole
- Itraconazole
- Ketoconazole
- Miconazole
Markedly increase riociguat exposureConsider starting with lower doses. Monitor BP
Bosentan Bosentan reduces riociguat steady-state plasma concentrations by 27%Monitor the clinical response
CiclosporinMay result in hypotensionIncreases riociguat exposureWith caution. Monitor BP
HIV protease inhibitors:
- Ritonavir
- Saquinavir
May result in hypotensionIncreases riociguat exposureConsider starting with lower doses. Monitor BP
HCV protease inhibitors:
- Paritaprevir
May result in hypotensionIncreases riociguat exposureConsider starting with lower doses. Monitor BP
NO donors:
- Nicorandil
- Nitrates
- Nitric oxide
Risk of systemic hypotension Avoid the combination
Nonspecific PDE inhibitors:
- Dipyridamole
- Theophylline
Additive hypotensive responseAvoid the combination. Discontinue sildenafil at least 24 hs and tadalafil at least 48 hs before administering riociguat
Specific PDE-5 inhibitors:
- Sildenafil
- Tadalafil
- Vardenafil
Additive hypotensive responseAvoid the combination
Potent CYP1A1 inhibitors:
- Carvedilol
- Erlotinib
- Gefitinib
- Granisetron
May result in hypotensionIncrease riociguat exposure With caution. Monitor BP
Potent CYP3A4 inducers:
- Carbamazepine
- Phenobarbitone
- Phenytoin
- Rifampicin
- St. John's Wort
Reduce riociguat plasma levelsIncrease the dose of riociguat. Avoid the combination
Potent CYP3A4 inhibitors:
- Macrolides: Clarithromycin
- HIV-protease inhibitors
Increase riociguat plasma levelsReduce the dose of riociguat. Avoid the combination
TobaccoTobacco increases the metabolism of riociguat via CYP1A1 and reduces its plasma levels . Plasma concentrations of riociguat are reduced by 50-60% in smokers as compared to nonsmokersA dose reduction should be considered in patients who stop smoking

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4. Phosphodiesterase-5 inhibitors

Sildenafil

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
α1-adrenergic blockers:
- Doxazosin
- Prazosin
- Silodosine
- Terazosin
Risk of symptomatic hypotensionThe interaction is minimized if they are taken at least 4 h apart. Start sildenafil at low doses
AntihypertensivesIncreases the risk of hypotensionMonitor BP
BosentanReduces the efficacy of sildenafilDecreases sildenafil plasma levels. Sildenafil increases bosentan plasma levelsMonitor the response to sildenafil
Calcium channel blockers:
- Diltiazem
- Verapamil
Increases the risk of hypotensionMonitor BP
Cimetidine Increase sildenafil plasma levelsSometimes dose adjustements may not be required. No interaction with nizatidine
NO donors:
- Nicorandil
- Nitrates
- Nitric oxide
Risk of symptomatic hypotensionAvoid the combination
Potent CYP450 3A4, and 2C9 inhibitors:
- Amiodarone
- Azole antifungals: Fluconazole, Itraconazole, Ketoconazole, Niconazole, Voriconazole
- Ciclosporin
- Fluoxetine
- HIV-protease inhibitors: Darunavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir
- Macrolides: Chlarythromycin, Erythromycin, Telithromycin
- Sertraline
Increase sildenafil plasma levelsSometimes dose adjustements may not be required
Use a low starting dose of sildenafil
Avoid the combination with ritonavir and saquinavir
Potent CYP450 3A4 inducers:
- Carbamazepine
- Phenytoin
- Phenobarbital
- Rifampicin
- St John’s wort
Significantly lower sildenafil levelsDose adjustment may be required
RiociguatRisk of symptomatic hypotensionAvoid the combination
Statins:
- Simvastatin
Possible increased risk of rabdomyolysis.Sildenafil can increase atorvastatin and simvastatin plasma levels and these drugs can increase the levels of sildenafilReplace by another statin
VasodilatorsIncreases the risk of hypotensionMonitor BP
Vitamin K antagonists Increased risk of bleeding, particularly in patients with PAH secondary to connective tissue disease.Monitor BP

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Abbreviations

BP: blood pressure.
CYP: cytochrome P450 superfamily.
ECG: electrocardiogram.
HCV: hepatitis C viral infection.
HIV: human immunodeficiency virus.
INR: international normalized ratio.
NSAIDs: nonsteroidal anti-inflammatory drugs.
OATP: organic anion transport protein.
PDE: phosphodiesterase.
P-gp: P-glycoprotein.
PAH: pulmonary arterial hypertension.
SBP: sysolic blood pressure. t-PA: tissue plasminogen activator.

 

Disclaimer: The information contained in these tables is intended for use by medical professionals and is for informational purposes only. The tables do not cover all possible drug interactions. As a medical professional you retain full responsibility and should use your own clinical judgement and expertise. Although we attempt to provide accurate and up-to-date information, no guarantee is made to that effect.

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