TREPROSTINIL Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Bosentan In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed.

7.2 Sildenafil In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed.

7.3 Effect of Cytochrome P450 Inhibitors and Inducers In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both C max and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

7.4 Effect of Other Drugs on Treprostinil Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively, in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the international normalized ratio (INR) in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

Severe hepatic impairment (Child Pugh Class C) [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Severe hepatic impairment (Child Pugh Class C). ( 4 )

AND PRECAUTIONS

• Chronic intravenous infusions delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. (5.1)
• Do not abruptly lower the dose or withdraw dosing. (5.2)
• Treprostinil injection may cause symptomatic hypotension. (5.4)
• Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding. (5.5)

5.1 Risk of Catheter-Related Bloodstream Infection Chronic intravenous infusions of Treprostinil injection delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous infusion is the preferred mode of administration. In an open-label study of IV treprostinil (n=47) using an external infusion pump, there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use. Administration of IV Treprostinil injection with a high pH glycine diluent has been associated with a lower incidence of BSIs when compared to neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care guidelines. In an open-label study of an implantable pump (n=60), there were two blood stream infections (BSIs) related to the implant procedure during approximately 265 patient years.

5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction Avoid abrupt withdrawal or sudden large reductions in dosage of Treprostinil injection, which may result in worsening of PAH symptoms.

5.3 Patients with Hepatic Insufficiency Titrate slowly in patients with hepatic insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic function <span class="opacity-50 text-xs">[see Dosage and Administration (2.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]</span> .

5.4 Risk of Symptomatic Hypotension Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Treprostinil injection may produce symptomatic hypotension.

5.5 Risk of Bleeding Treprostinil injection inhibits platelet aggregation and increases the risk of bleeding.